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1. MolecularBiologyof FifthEdition
2. FifthEdition MolecularBiologyof BruceAlberts
AlexanderJohnson JulianLewis MartinRaff KeithRoberts PeterWalter
Withproblemsby JohnWilson TimHunt GarlandScience Taylor&
FrancisGroup
3. Garland Science Vice President:Denise Schanck
AssistantEditor: Sigrid Masson Production Editor and Layout: Emma
leffcock Senior Publisher: JackieHarbor Illustrator: Nigel Orme
Designer:Matthew McClements,Blink Studio,Ltc. Editors:Marjorie
Anderson and SherryGranum Copy Editor: Bruce Goatly Indexer:
Merrall-RossInternational, Ltd. PermissionsCoordinator: Marv
Disoenza Cell Biology Interactiue Artistic and Scientific
Direction: PeterWalter Narrated by: Julie Theriot Production Design
and Development: Michael Morales @2008, 2002 by Bruce Alberts,
Alexander Johnson, Julian Lewis, Martin Rafi Keith Roberts,and
PeterWalter. @ f 983, f 989, 1994by Bruce Alberts, Dennis
Bray,Iulian Lewis, Martin Raff, Keith Roberts,and lames D.Watson.
Bruce Alberts received his Ph.D. from Harvard university and is
professor of Biochemistry and Biophysicsat the university of
california, san Francisco.For 12years,he servedas Presidentofthe
u.s. NationalAcademy ofSciences (1993-2005). Alexander Johnson
received his Ph.D. from Harvard University and is professor of
Microbiology and Immunology and Director of the Biochemistry cell
Biology,Genetics, and Developmental Biology Graduate Program at the
University of california, San Francisco. Iulian Lewis received his
D.Phil. from the University of Oxford and is a Principal
Scientistat the London ResearchInstitute of CancerResearchUK.
Martin Raffreceived his M.D. from McGill University and is at the
Medical Research Council Laboratory for Molecular Cell Biology and
the Biology Department at University College London. Keith Roberts
received his Ph.D. from the University of Cambridge and is Emeritus
Fellow at the John Innes Centre, Norwich. peterWalter received his
ph.D. from The Rockefeller University in Newyork and is professor
and chairman of the Department of Biochemistry and Biophysics at
the University of california, san Francisco, and an Investigator of
the Howard Hughes Medical Institute. All rights reserved. No part
of this book covered by the copyright heron may be reproduced or
used in any format in any form or by any means-graphic, electronic,
or mechanical, including photocopying, recording, taping, or
information storage and retrieval systems-without permission of the
publisher. Library of CongressCataloging-in-Publication Data
Molecularbiologyof the cell / BruceAlberts... [etal.].--5th ed.
p.cm
ISBN978-0-8153-4r05-5(hardcover)---ISBN978-0-8f5g-4t06_Z(paperback)
L Cytology.2. Molecular biology.I. Alberts, Bruce. QHsB1.2.M642008
571.6--dc22 2007005475CIP Published by Garland science, Taylor
& Francis Group, LLC, an informa business, 270 Madison
Avenue,NewYork NY f 0016,USA,and 2 park Square,Milton park,
Abingdon,OXl4 4RN,UK. Printed in the United Statesof America 15 14
13 12 lt 1 0 I B 7 6 5 4 3 2 |
4. Preface In many respects,we understandthe structureof the
universebetter than the workingsof living cells.Scientistscan
calculatethe ageof the Sunand predict when it will ceaseto
shine,but we cannotexplainhow it is that a human being may live for
eighty yearsbut a mouse for only two. We know the complete
genomesequencesof theseandmany other species,but we still
cannotpredict how a cell will behaveif we mutate a
previouslyunstudiedgene.Starsmay be l0a3times bigger,but
cellsaremore complex,more intricately structured,and
moreastonishingproductsof
thelawsofphysicsandchemistry.Throughhered- ity and natural
selection,operatingfrom the beginningsof life on Earthto the
presentday-that is,for about20Voof theageof the universe-living
cellshave been progressivelyrefining and extending their molecular
machinery and recordingthe resultsof their experimentsin the
geneticinstructionsthey pass on to their progeny. With eachedition
of this book,we marvelat the new information that cell
biologistshavegatheredin just a fewyears.But we areevenmore
amazedand dauntedatthe sophisticationofthe mechanismsthat
weencounter.Thedeeper weprobeinto the cell,themorewe reafizehowmuch
remainsto beunderstood. In the daysof our innocence,working on the
first edition,we hailedthe identi- fication of asingleprotein-a
signalreceptol say-as agreatstepforward'Now we appreciatethat
eachprotein isgenerallypart of acomplexwith manyothers, working
togetherasa system,regulatingone another'sactivitiesin subtleways,
andheldin specificpositionsbybinding to scaffoldproteinsthat
givethechem- ical factorya definite
spatialstructure.Genomesequencinghasgivenusvirtu- ally
completemolecularparts-listsfor many different
organisms;geneticsand biochemistryhavetold us a greatdeal about
what thoseparts are capableof individually and which onesinteract
with which others;but we haveonly the most primitive graspof the
dynamicsof thesebiochemicalsystems,with all their interlocking
control loops.Therefore,although there are great achieve- mentsto
report,cellbiologistsfaceevengreaterchallengesfor the future. In
this edition,wehaveincludednewmaterialon manytopics,rangingfrom
epigenetics,histonemodifications,smallRNAs,and
comparativegenomics,to
geneticnoise,cytoskeletaldlmamics,cell-cyclecontrol,apoptosis,stemcells,
and novelcancertherapies.As in previouseditions,we havetried
aboveall to givereadersa conceptualframeworkfor the massof
information that we now haveabout cells.This meansgoingbeyondthe
recitationof facts.Thegoalis to learn how to put the facts to
use-to reason,to predict, and to control the behaviorof living
systems. Tohelp readerson the wayto an activeunderstanding,we
havefor the first time incorporatedend-of-chapterproblems,written
by Iohn Wilsonand Tim Hunt. Theseemphasizea quantitativeapproachand
the art of reasoningfrom experiments.A
companionvolume,MolecularBiologyof theCelI,Fifth Edition:
TheProblemsBook0SBN978-0-8153-4110-9),by the sameauthors,givescom-
pleteanswersto theseproblemsand alsocontainsmorethan 1700additional
problemsandsolutions. A further major adjunctto the main book is
the attachedMediaDVD-ROM
disc.Thisprovideshundredsofmoviesandanimations,includingmanythat
are new in this edition, showingcellsand cellularprocessesin action
and bringing thetextto life;thediscalsonowincludesall
thefiguresandtablesfrom themain
5.
book,pre-loadedintoPowerPoint@presentations.Otherancillariesavailablefor
thebookincludeabankof testquestionsandlectureoutlines,availableto
qual- ifiedinstructors,anda setof
200full-coloroverheadtransparencies. Perhapsthe biggestchangeis in
the physicalstructureof the book. In an effort to make the
standardStudentEdition somewhatmore portable,we are providing
chapters 2r-25, coveringmulticellular systems,in electronic (pDF)
form on the accompanyingdisc,while retainingin theprinted
volumechapters l-20, coveringthe core of the usual cell biology
curriculum. But we should emphasizethat the final
chaptershavebeenrevisedand updatedasthoroughly asthe restof the
book andwe sincerelyhopethat theywill beread!A Reference
Edition(ISBN97s-0-8153-4r11-6),containingthefull setof
chaptersasprinred pages,is alsoavailablefor thosewho preferit. Full
detailsof the conventionsadoptedin the book aregivenin the Noteto
the Readerthat followsthis Preface.Asexplainedthere,we havetakena
drastic approachin confrontingthe differentrulesfor thewriting of
genenamesin dif- ferent species:throughout this book, we use the
same style, regardlessof species,andoftenin defianceofthe
usualspecies-specificconventions. As always,we areindebtedto many
people.Full acknowledgmentsfor sci-
entifichelparegivenseparately,but wemustheresingleout
someexceptionally important contributions:Iulie Theriot is almost
entirely responsiblefor chap- ters 16(cytoskeleton)and 24
(Pathogens,Infection,and InnateImmunity), and David
Morganlikewisefor chapter 17(cell cycle).wallaceMarshalland Laura
Attardi provided substantialhelp with chapters 8 and
20,respectively,as did Maynardolsonfor
thegenomicssectionofchapter4,Xiaodongwangfor chap- ter
18,andNicholasHarberdfor theplantsectionof Chapter15. we also owe a
huge debt to the staff of Garlandscienceand otherswho helped
convert writers' efforts into a polished final product.
Deniseschanck directedthe whole enterpriseand shepherdedthe
waywardauthorsalongthe roadwith wisdom,skill,and kindness.Nigelorme
put the artworkinto its final form andsupervisedthevisualaspectsof
thebook,includingthebackcover,with his usual flair. Matthew
Mcclements designedthe book and its front cover. EmmaJeffcocklaid
out its pageswith extraordinaryspeedand unflappableeffi-
ciency,dealingimpeccablywithinnumerablecorrections.MichaelMoralesman-
agedthe transformationof a massof animations,video clips,and
othermateri- als into a user-friendly DVD-ROM. Eleanor Lawrence and
sherry Granum
updatedandenlargedtheglossary.JackieHarborandSigridMassonkeptusorga-
nized.AdamSendroffkeptusawareofour readersandtheir
needsandreactions.
MarjorieAnderson,BruceGoatly,andsherryGranumcombedthetextfor obscu-
rities,infelicities,and errors.we thank them all, not only for
their professional skill and dedicationand for efficiencyfar
surpassingour own,but alsofor their
unfailinghelpftrlnessandfriendship:theyhavemadeit apleasureto work
on the book. Lastly,and with no lessgratitude,we thank our
spouses,families,friends andcolleagues.without
theirpatient,enduringsupport,wecouldnot havepro- ducedanyof the
editionsof thisbook.
6. Contents Speci.alFeatures DetailedContents Acknowledgments A
Noteto theReader PARTI I. 2. 3. PARTII 4. 5. 6. 7. PARTIII B. 9.
PARTIV 10. 11. 12. 13. 14. 15. 16. t7. tB. PARTV 19. 20. 2I, 22.
23, 24. 25. Glossary Index TabIes uiii ix xxui xxxi
INTRODUCTIONTOTHECELL CellsandGenomes CellChemistryandBiosynthesis
Proteins BASICGENETICMECHANISMS DNA,Chromosomes,andGenomes DNA
Replication,Repair,and Recombination HowCellsReadthe
Genome:FromDNAto Protein Controlof GeneExpression METHODS
Manipulating Proteins,DNA,and RNA VisualizingCells
INTERNALORGANIZATIONOFTHECELL MembraneStructure MembraneTransportof
SmallMoleculesandthe Electrical Propertiesof Membranes
IntracellularCompartmentsand ProteinSorting
IntracellularVesicularTraffic
EnergyConversion:MitochondriaandChloroplasts Mechanismsof
CellCommunication TheCytoskeleton The CellCycle Apoptosis
CELLSINTHEIRSOCIALCONTEXT Celllunctions, CellAdhesion,and the
ExtracellularMatrix Cancer Chapters2I-25 availableon MediaDVD-ROM
SexualReproduction:Meiosis,GermCells,andFertilization Developmentof
MulticellularOrganisms
SpecializedTissues,StemCells,andTissueRenewal Pathogens,Infection,
and InnateImmunity TheAdaptiveImmune System The Genetic Code,Amino
Acids 195 263 329 41I I 45 t25 50r 579 6t7 651 695 749 Br3 879 965
1053 1115 1131 I205 1269 r305 L4l7 1485 1539 G-1 L1 T-1
7. SpecialFeatures Table l-l Table l-2 Table2-1 Table2-2 Table
2-3 Table2-4 Panel2-l Panel2-2 Panel 2-3 Panel2-4 Panel 2-5 Panel
2-6 Panel2-7 Panel 2-B Panel2-9 Panel3-l Panel 3-2 Table3-1 Panel
3-3 Table4-l Table 5-3 Table6-l PanelB-l Table 10-l Thble11-l
Panel1l-2 Panelll-3 Table l2-l Table l2-2 Table l4-l Panel l4-l
Thble r5-5 Panel 16-2 Panel 16-3 Table I7-2 Panel l7-l
SomeGenomesThatHaveBeenCompletelySequenced TheNumbersof
GeneFamilies,classifiedby Function,ThatArecommon to All
ThreeDomainsof the LivingWorld CovalentandNoncovalentChemicalBonds
TheTypesof MoleculesThatForma BacterialCell
ApproximateChemicalCompositionsof aTypicalBacteriumandaTypical
MammalianCell RelationshipBetweenthe StandardFree-EnergyChange,AG,
andthe EquilibriumConstant
ChemicalBondsandGroupsCommonlyEncounteredin BiologicalMolecules
WaterandItsInfluenceon theBehaviorof BiologicalMolecules
ThePrincipalTypesofweakNoncovalentBondsthat HoldMacromolecules
Together An Outlineof Someof theTypesof SugarsCommonlyFoundin Cells
FattyAcidsandOtherLipids A Surveyof the Nucleotides
FreeEnergyandBiologicalReactions Detailsof the t0 Stepsof
Glycolysis TheCompleteCitricAcidCycle The20AminoAcidsFoundin
Proteins FourDifferentWaysof Depictinga SmallProtein,the SH2Domain
SomeCommonTypesof Enzymes Someof the MethodsUsedto StudyEnzymes
SomeVitalStatisticsfor theHumanGenome
ThreeMajorClassesofTransposableElements PrincipalTlpesof
RNAsProducedin Cells Reviewof ClassicalGenetics pp.
ApproximateLipid Compositionsof DifferentCellMembranes A
Comparisonof Ion
ConcentrationsInsideandOutsideaTypicalMammalianCell TheDerivationof
the NernstEquation SomeClassicalExperimentson the SquidGiantAxon
RelativeVolumesOccupiedby theMajorIntracellularCompartmentsin a
Liver Cell(Hepatocyre) RelativeAmounts of MembraneTypesin
TwoKindsof Eucaryoticcells ProductYieldsfrom the Oxidationof
SugarsandFats RedoxPotentials TheRasSuperfamilyof MonomericGTpases
The Polymerizationof Actin andTubulin pp. 978-979
AccessoryProteinsthat ControltheAssemblyandpositionof Cvtoskeletal
Filaments pp.994-995 Summaryof theMajorCell-CycleRegulatoryproteins
p. 1066 The Princinle Stases of M Phasp (Mitnsis nnrl Crrfnlrinpcic
in qn Animal /-oll nn rATo rA?a p. 18 p.24 p.53 p.55 p.63 p.77 pp.
106-107 pp. 108-109 pp. pp. pp. pp. pp. pp. pp. pp. pp. r10-111
112-113 I l4-1I5 I 16-1r7 I IB-t 19 r20-I2l I22-t23 tzg-729 132-133
p.159 162-163 p.206 p.318 p.336 554-555 p.624 p.652 p.670 p.679
p.697 p.697 p.824 p.830 p.926 pp.
8. DetailedContents Chapter 1 Cells and Genomes
THEUNIVERSALFEATURESOFCELLSON EARTH
AllCellsStoreTheirHereditaryInformationintheSameLinear
ChemicalCode(DNA)
AllCellsReplicateTheirHereditaryInformationbyTemplated
Polymerization
AllCellsTranscribePortionsofTheirHereditaryInformationinto
theSameIntermediaryForm(RNA) AllCellsUseProteinsasCatalysts
AllCellsTranslateRNAintoProteinin theSameWay TheFragmentof
GeneticInformationCorrespondingto One ProteinlsOneGene
LifeRequiresFreeEnergy
AllCellsFunctionasBiochemicalFactoriesDealingwiththe
SameBasicMolecularBuildingBlocks AllCellsAreEnclosedina
PlasmaMembraneAcrossWhich NutrientsandWasteMaterialsMustPass A
LivingCellCanExistwith FewerThan500Genes Summary
THEDIVERSITYOFGENOMESANDTHETREEOFLIFE CellsCanBePoweredbyaVarietyof
FreeEnergySources SomeCellsFixNitrogenandCarbonDioxideforOthers
TheGreatestBiochemicalDiversityExistsAmongProcaryoticCells
TheTreeof LifeHasThreePrimaryBranches:Bacteria,Archaea,
andEucaryotes SomeGenesEvolveRapidly;OthersAreHighlyConserved
MostBacteriaandArchaeaHave1000-6000Genes
NewGenesAreGeneratedfromPreexistingGenes GeneDuplicationsGiveRiseto
Familiesof RelatedGenesWithin a SingleCell
GenesCanBeTransferredBetweenOrganisms,Bothinthe Laboratoryandin
Nature SexResultsin HorizontalExchangesof GeneticInformation
Withina Species TheFunctionof aGeneCanOftenBeDeducedfromltsSequence
MoreThan200GeneFamiliesAreCommonto AllThreePrimary Branchesof
theTreeof Life MutationsRevealtheFunctionsof Genes
MolecularBiologistsHaveFocuseda SpotlightonE coli Summary
GENETICINFORMATIONIN EUCARYOTES
EucaryoticCellsMayHaveOriginatedasPredators
ModernEucaryoticCellsEvolvedfroma Symbiosis
EucaryotesHaveHybridGenomes EucaryoticGenomesAreBig
EucaryoticGenomesAreRichin RegulatoryDNA
TheGenomeDefinestheProgramof MulticellularDevelopment
ManyEucaryotesLiveasSolitaryCells:theProtists AYeastServesasa
MinimalModelEucaryote TheExpressionLevelsof AllTheGenesof
AnOrganismCanBe MonitoredSimultaneously ToMakeSenseof
Cells,WeNeedMathematics,Computers,and QuantitativeInformation
ArabidopsisHasBeenChosenOutof 300,000SpeciesAsa Model Plant 1 1
TheWorldof AnimalCellslsRepresentedByaWorm,a Fly, a Mouse,anda
Human 36 Studiesin DrosophilaProvidea Keyto VertebrateDevelopment
37 TheVertebrateGenomelsa Productof RepeatedDuplication 38
GeneticRedundancylsa ProblemforGeneticists,Butlt Creates
Opportunitiesfor EvolvingOrganisms TheMouseServesasa
ModelforMammals HumansReportonTheirOwnPeculiarities
WeAreAllDifferentin Detail Summory Problems References Chapter2
CellChemistryand Biosynthesis THECHEMICALCOMPONENTSOFACELL
CellsAreMadeFroma FewTypesof Atoms
TheOutermostElectronsDetermineHowAtomslnteract
CovalentBondsFormbytheSharingof Electrons ThereAreDifferentTypesof
CovalentBonds AnAtomOftenBehavesasif lt Hasa FixedRadius
WaterlstheMostAbundantSubstanceinCells
SomePolarMoleculesAreAcidsandBases FourTypesof
NoncovalentAttractionsHelpBringMolecules 5 4 5 o 8 9 1 0 1 1 1 1 1
2 1 3 1 4 t 5 t o 1 7 1 8 1 9 2 1 39 5> 40 41 42 42 44 45 45 45
46 48 50 51 51 52 7 8 58 59 61 oz 63 65 65 66 22 2 2 23 z ) 24 26
Togetherin Cells 53 A CelllsFormedfromCarbonCompounds 54
CellsContainFourMajorFamiliesof SmallOrganicMolecules 55
SugarsProvideanEnergySourceforCellsandAretheSubunits of
Polysaccharides 55 FattyAcidsAreComponentsof
CellMembranes,asWellasa Sourceof EnergY AminoAcidsAretheSubunitsof
Proteins NucleotidesAretheSubunitsof DNAandRNA TheChemistryof
CellslsDominatedbyMacromoleculeswith RemarkableProperties
NoncovalentBondsSpecifyBoththePreciseShapeof a
MacromoleculeanditsBindingto OtherMolecules Summary
CATALYSISANDTHEUSEOFENERGYBYCELLS
CellMetabolismlsOrganizedbyEnzymes
BiologicalOrderlsMadePossiblebytheReleaseof HeatEnergy fromCells
PhotosyntheticOrganismsUseSunlightto SynthesizeOrganic Molecules
CellsObtainEnergybytheOxidationof OrganicMolecules
OxidationandReductionInvolveElectronTransfers
EnzymesLowertheBarriersThatBlockChemicalReactions
HowEnzymesFindTheirSubstrates:TheEnormousRapidityof
MolecularMotions TheFree-EnergyChangefora
ReactionDeterminesWhetherlt CanOccur TheConcentrationof
ReactantsInfluencestheFree-Energy Changeanda Reaction'sDirection
ForSequentialReactions,AG"ValuesAreAdditive
ActivatedCarrierMoleculesAreEssentialfor Biosynthesis
TheFormationof anActivatedCarrierlsCoupledto an
EneroeticallvFavorableReaction 26 26 30 30 3 1 3 1 5Z 33 34 35 JO
66 68 70 71 72 74 75 76 77 78
9. ATPlstheMostWidelyUsedActivatedCarrierMolecule
EnergyStoredin ATPlsOftenHarnessedto JoinTwoMolecules Together
NADHandNADPHArelmportantElectronCarriers
ThereAreManyOtherActivatedCarrierMoleculesinCells TheSynthesisof
BiologicalPolymerslsDrivenbyATpHydrolysis Summary
HOWCELLSOBTAINENERGYFROMFOOD Glycolysislsa
CentralATP-producingpathway FermentationsProduceATPintheAbsenceof
Oxygen GlycolysislllustratesHowEnzymesCoupleOxidationto Energy
Storage OrganismsStoreFoodMoleculesin SpecialReservoirs
MostAnimalCellsDeriveTheirEnergyfromFattyAcidsBetween Meals
SugarsandFatsAreBothDegradedto AcetylCoAin Mitochondria
TheCitricAcidCycleGeneratesNADHbyOxidizingAcetylGroups to CO2
ElectronTransportDrivestheSynthesisof theMajorityof theATp
inMostCells AminoAcidsandNucleotidesArepartof theNitrogenCycle
MetabolismlsOrganizedandRegulated Summary Problems References
Chapter3 Proteins THESHAPEANDSTRUCTUREOFPROTEINS TheShapeof a
ProteinlsSpecifiedbyltsAminoAcidSequence
ProteinsFoldintoaConformationof LowestEnergy
ThecrHelixandtheBSheetAreCommonFoldingpatterns
ProteinDomainsAreModularUnitsfromwhichLargerproteins AreBuilt Fewof
theManyPossiblePolypeptideChainsWillBeUsefur to Cells
ProteinsCanBeClassifiedintoManyFamilies
SequenceSearchesCanldentifyCloseRelatives
SomeProteinDomainsFormpartsof ManyDifferentproteins CertainPairsof
DomainsAreFoundTogetherin Manyproteins
TheHumanGenomeEncodesaComplexSetof proteins,
RevealingMuchThatRemainsUnknown
LargerProteinMoleculesOftenContainMoreThanOne PolypeptideChain
SomeProteinsFormLongHelicalFilaments
ManyProteinMoleculesHaveElongated,FibrousShapes
ManyProteinsContaina SurprisinglyLargeAmountof
UnstructuredPolypeptideChain
CovalentCross-LinkagesOftenStabilizeExtracellularproteins
ProteinMoleculesOftenServeasSubunitsfortheAssembry of
LargeStructures ManyStructuresinCellsAreCapableof Self-Assembly
AssemblyFactorsOftenAidthe Formationof Comolex BiologicalStructures
Summary PROTEINFUNCTION AllProteinsBindto OtherMolecules
TheSurfaceConformationof a ProteinDeterminesltsChemistrv
SequenceComparisonsBetweenproteinFamilyMembers
HighlightCrucialLigand-BindingSites ProteinsBindto
OtherProteinsThroughSeveralTypesof Interfaces
AntibodyBindingSitesAreEspeciallyVersatile
TheEquilibriumConstantMeasuresBindingStrength
EnzymesArePowerfulandHighlySpecificCatalysts
SubstrateBindinglstheFirstStepin EnzymeCatalysis
EnzymesSpeedReactionsbySelectivelyStabilizingTransitron States
EnzymesCanUseSimultaneousAcidandBaseCatalysis
LysozymelllustratesHowanEnzymeWorks
TightlyBoundSmallMoleculesAddExtraFunctionsto prorerns
MolecularTunnelsChannelSubstratesin Enzymeswith
MultipleCatalyticSites MultienzymeComplexesHelpto IncreasetheRateof
Cell Metabolism TheCellRegulatestheCatalyticActivitiesof itsEnzymes
AllostericEnzymesHaveTwoor MoreBindingSitesThatInteract
TwoLigandsWhoseBindingSitesAreCoupledMust
ReciprocallyAffectEachOther'sBinding
SymmetricProteinAssembliesProduceCooperativeAllosteflc Transitions
TheAllostericTransitionin AspartateTranscarbamoylasels Understoodin
AtomicDetail 173 ManyChangesin ProteinsAreDrivenbyProtein
Phosphorylation A EucaryoticCellContainsa LargeCollectionof
ProteinKinases andProteinPhosphatases TheRegulationof
CdkandSrcProteinKinasesShowsHowa ProteinCanFunctionasa Microchip
ProteinsThatBindandHydrolyzeGTPAreUbiquitousCellular Regulators
RegulatoryProteinsControltheActivityof GTP-Bindingproteins
byDeterminingWhetherGTPor GDPlsBound
LargeProteinMovementsCanBeGeneratedFromSmallOnes
MotorProteinsProduceLargeMovementsin Cells
Membrane-BoundTransportersHarnessEnergyto Pump
MoleculesThroughMembranes
ProteinsOftenFormLargeComplexesThatFunctionasProtein Machines
ProteinMachineswithInterchangeablePartsMakeEfficientUse of
Geneticlnformation TheActivationof
ProteinMachinesOftenInvolvesPositioning Themat SpecificSites
ManyProteinsAreControlledbyMultisiteCovalentModification A
ComplexNetworkof ProteinInteractionsUnderliesCellFunction Summary
Problems References Chapter4 DNA,Chromosomes,and Genomes
THESTRUCTUREANDFUNCTIONOFDNA A
DNAMoleculeConsistsofTwoComplementaryChains of Nucleotides
TheStructureof DNAProvidesa Mechanismfor Heredity
InEucaryotes,DNAlsEnclosedina CellNucleus Summory CHROMOSOMALDNA
AND ITSPACKAGINGINTHE CHROMATINFIBER EucaryoticDNAlsPackagedintoa
Setof Chromosomes ChromosomesContainLongStringsof Genes
TheNucleotideSequenceoftheHumanGenomeShowsHow OurGenesAreArranged
GenomeComparisonsRevealEvolutionarilyConservedDNA )equences 207
ChromosomesExistin DifferentStatesThroughouttheLife ofa Cell 2OB
EachDNAMoleculeThatFormsa LinearChromosomeMust Containa
Centromere,TwoTelomeres,andReplicationOrigins 2Og
DNAMoleculesAreHighlyCondensedin Chromosomes 210 NucleosomesArea
BasicUnitof EucaryoticChromosome Structure 211 TheStructureofthe
NucleosomeCoreParticleRevealsHow DNAlsPackaged Z'tZ
NucleosomesHavea DynamicStructure,andAreFrequentry Subjectedto
ChangesCatalyzedbyATp-DependentChromatin- RemodelingComplexes 215
NucleosomesAreUsuallyPackedTogetherintoaCompact 80 8 1 82 83 84 87
88 88 Rq '167 168 169 171 171 172 175 176 177 178 179 179 1 8 1 182
184 184 185 t 6 0 187 190 1 9 1 193 9 1 9 1 95 vo o7 100 1 0 0 1 0
1 103 103 124 125 125 t z J 1 3 0 1 3 1 t J ) I Jt) 137 1 3 9 140
141 142 "t42 143 t 4 ) "146 147 148 149 1 5 1 't52 152 1 5 3 154 1
5 5 tf,o 1 5 6 157 1 5 8 i5 9 195 197 197 199 200 201 202 202 204
205 ChromatinFiber Summary l t o 218
THEREGULATIONOFCHROMATINSTRUCTURE 219
SomeEarlyMysteriesConcerningChromatinStructure 220 160 160 16"1
166
10. HeterochromatinlsHighlyOrganizedandUnusuallyResistant to
GeneExoression TheCoreHistonesAreCovalentlyModifiedat
ManyDifferentSites
ChromatinAcquiresAdditionalVarietythroughtheSite-Specific
lnsertionof a SmallSetof HistoneVariants
TheCovalentModificationsandtheHistoneVariantsActin Concertto
Producea"HistoneCode"ThatHelpsto DetermineBiologicalFunction
AComolexof Code-ReaderandCode-WriterProteinsCanSpread
SpecificChromatinModificationsfor LongDistancesAlonga Chromosome
BarrierDNASequencesBlocktheSpreadof Reader-WriterComplexes
andTherebySeparateNeighboringChromatinDomains TheChromatinin
CentromeresRevealsHowHistoneVariants CanCreateSpecialStructures
ChromatinStructuresCanBeDirectlyInherited
ChromatinStructuresAddUniqueFeaturesto Eucaryotic
ChromosomeFunction Summary THEGLOBALSTRUCTUREOFCHROMOSOMES
ChromosomesAreFoldedintoLargeLoopsof Chromatin
PolyteneChromosomesAreUniquelyUsefulforVisualizing
ChromatinStructures ThereAreMultipleFormsof Heterochromatin
ChromatinLoopsDecondenseWhentheGenesWithinThemAre Exoressed
ChromatinCanMoveto SpecificSitesWithintheNucleusto
AlterTheirGeneExoression Networksof MacromoleculesForma Setof
DistinctBiochemical EnvironmentsinsidetheNucleus
MitoticChromosomesAreFormedfromChromatinin ltsMost CondensedState
Summary HOWGENOMESEVOLVE GenomeAlterationsAreCausedbyFailuresof
theNorma MechanismsforCopyingandMaintainingDNA
TheGenomeSequencesofTwoSpeciesDifferin Proportionto
theLengthofTimeThatTheyHaveSeparatelyEvolved
PhylogeneticTreesConstructedfroma Comparisonof DNA
SequencesTracethe Relationshipsof AllOrganisms A Comoarisonof
HumanandMouseChromosomesShows HowtheStructuresof GenomesDiverge
TheSizeof aVertebrateGenomeReflectsthe RelativeRatesof
DNAAdditionandDNALossina Lineage WeCanReconstructtheSequenceof
SomeAncientGenomes
MultispeciesSequenceComparisonsldentifylmportantDNA Sequencesof
UnknownFunction AcceleratedChangesin
PreviouslyConservedSequencesCan HelpDecipherCriticalStepsin
HumanEvolution GeneDuplicationProvidesanlmportantSourceof Genetic
NoveltyDuringEvolution DuplicatedGenesDiverge TheEvolutionof
theGlobinGeneFamilyShowsHowDNA DuplicationsContributeto
theEvolutionof Organisms GenesEncodingNewProteinsCanBeCreatedbythe
Recombinationof Exons NeutralMutationsOftenSpreadto BecomeFixedin a
Population, witha ProbabilitythatDependson PopulationSize A
GreatDealCanBeLearnedfromAnalysesoftheVariation AmongHumans Summary
Problems References Chapter5 DNAReplication,Repair,and
Recombination THEMAINTENANCEOFDNASEQUENCES
MutationRatesAreExtremelyLow LowMutationRatesAreNecessaryfor
LifeasWeKnowlt Summory DNAREPLICATIONMECHANISMS
Base-PairingUnderliesDNAReplicationandDNARepair
TheDNAReplicationForklsAsymmetrical TheHighFidelityof
DNAReplicationRequiresSeveralProofreading Mechanisms
OnlyDNAReplicationin the5'-to-3'DirectionAllowsEfficientError
Correction A
5pecialNucleotide-PolymerizingEnzymeSynthesizesShortRNA
PrimerMoleculesontheLaggingStrand SpecialProteinsHelpto
OpenUptheDNADoubleHelixin Front oftheReplicationFork A
SlidingRingHoldsa MovingDNAPolymeraseontotheDNA TheProteinsata
ReplicationForkCooperateto Forma Replication Machine A
Strand-DirectedMismatchRepairSystemRemovesReplication
ErrorsThatEscapefromtheReplicationMachine
DNATopoisomerasesPreventDNATanglingDuringReplication
DNAReplicationlsFundamentallySimilarin Eucaryotesand Bacteria
Summary THEINITIATIONANDCOMPLETIONOFDNAREPLICATION INCHROMOSOMES
DNASynthesisBeginsat ReplicationOrigins
BacterialChromosomesTypicallyHavea SingleOriginof DNA Reolication
EucaryoticChromosomesContainMultipleOriginsof Replication
InEucaryotesDNAReplicationTakesPlaceDuringOnlyOnePart of
thecellcycle DifferentRegionsontheSameChromosomeReplicateat
Distinct Timesin SPhase
HighlyCondensedChromatinReplicatesLate,WhileGenesin
LessCondensedChromatinTendto ReplicateEarly
Well-DefinedDNASequencesServeasReplicationOriginsin a
SimpleEucaryote,theBuddingYeast A LargeMultisubunitComplexBindsto
EucaryoticOriginsof Reolication
TheMammalianDNASequencesThatSpecifythe Initiationof
ReplicationHaveBeenDifficultto ldentify
NewNucleosomesAreAssembledBehindtheReplicationFork TheMechanismsof
EucaryoticChromosomeDuplicationEnsure ThatPatternsof
HistoneModificationCanBeInheriteo TelomeraseReplicatesthe Endsof
Chromosomes TelomereLengthlsRegulatedbyCellsandOrganisms Summary
DNAREPAIR WithoutDNARepair,SpontaneousDNADamageWouldRapidly
ChangeDNASequences TheDNADoubleHelixlsReadilyRepaired
DNADamageCanBeRemovedbyMoreThanOnePathway CouplingDNARepairto
TranscriptionEnsuresThattheCell'sMost
lmportantDNAlsEfficientlyRepaired TheChemistryof
theDNABasesFacilitatesDamageDetection
SpecialDNAPolymerasesAreUsedin Emergenciesto RepairDNA
Double-StrandBreaksAreEfficientlyRepaired
DNADamageDelaysProgressionof theCellCycle Summary
HOMOLOGOUSRECOMBINATION HomologousRecombinationHasManyUsesintheCell
HomologousRecombinationHasCommonFeaturesin AllCells
DNABase-PairingGuidesHomologousRecombination
TheRecAProteinanditsHomologsEnablea DNA5ingleStrand to Pairwitha
HomologousRegionof DNADoubleHelix
BranchMigrationCanEitherEnlargeHetroduplexRegionsor
ReleaseNewlySynthesizedDNAasa SingleStrand
HomologousRecombinationCanFlawlesslyRepairDouble- StrandedBreaksin
DNA CellsCarefullyRegulatethe Useof HomologousRecombination in
DNARepair HollidayJunctionsAreOftenFormedDuringHomologous
RecombinationEvents 220 266 too 266 27"1 272 273 273 275 276 z I d
280 281 281 281 26l 282 zt6 230 231 233 233 234 236 256 239 239 241
243 245 245 246 247 248 249 251 251 2s2 284 285 285 260 287 288 289
290 292 zY5 294 253 z > 5 254 295 296 296 297 299 300 302 302
303 304 304 257 304 305 305 307 308 308 3 1 0 3 1 1 257 258 260 lou
262 263 263 205 265 265
11. MeioticRecombinationBeginswitha programmedDouble-
StrandBreak HomologousRecombinationOftenResultsin GeneConversron
MismatchProofreadingPreventspromiscuousRecombinatron
BetweenTwoPoorlyMatchedDNASequences Summary TRANSPOSITIONAND
CONSERVATIVESITE-SPECIFIC RECOMBINATION FROMRNATOPROTEIN 366 An
mRNASequencelsDecodedin SetsofThreeNucleotide 367
IRNAMoleculesMatchAminoAcidsto Codonsin mRNA 368
tRNAsAreCovalentlyModifiedBeforeTheyExitfromthe Nucleus 369
SpecificEnzymesCoupleEachAminoAcidto ltsAppropriateIRNA Molecule
EditingbyRNASynthetasesEnsuresAccuracy AminoAcidsAreAddedto
theC-terminalEndof a Growing PolypeptideChain
TheRNAMessagelsDecodedin Ribosomes
ElongationFactorsDriveTranslationForwardandlmprovelts Accuracy 377
TheRibosomelsa Ribozyme 379 NucleotideSequencesin mRNASignalWhereto
StartProtein Synthesis 379 StopCodonsMarktheEndofTranslation 381
ProteinsAreMadeon Polyribosomes 391 ThereAreMinorVariationsin
theStandardGeneticCode 392 Inhibitorsof
ProcaryoticProteinSynthesisAreUsefulas Antibiotics
AccuracyinTranslationRequiresthe Expenditureof FreeEnergy
QualityControlMechanismsActto PreventTranslationof Damaqed mRNAs
SomeProteinsBeginto FoldWhileStillBeingSynthesized
MolecularChaperonesHelpGuidethe Foldingof Mostproteins
ExposedHydrophobicRegionsProvideCritical5ignalsfor protein
QualityControl TheProteasomelsa CompartmentalizedProteasewith
SequesteredActiveSites An
ElaborateUbiquitin-ConjugatingSystemMarksProteinsfor Destruction
ManyProteinsAreControlledbyRegulatedDestruction
AbnormallyFoldedProteinsCanAggregateto CauseDestructive
HumanDiseases 396 ThereAreManyStepsFromDNAto Protein 3gg Summory
3gg THERNAWORLDANDTHEORIGINSOFLIFE 4OO
LifeRequiresStoredInformation 401
PolynucleotidesCanBothStoreInformationandCatalyze 312 314 3 1 5 5 t
o 3 1 6 329 331 345 346 347 349 349 351 352 370 371 5 t 5 373
ThroughTransposition,MobileGeneticElementsCanInsertlnto
AnyDNASequence y7
DNA-OnlyTransposonsMovebyBothCut-and-pasteandReplicative Mechanisms
317 SomeVirusesUseaTranspositionMechanismto MoveThemselves
intoHostCellChromosomes 319
Retroviral-likeRetrotransposonsResembleRetroviruses,but Lacka
ProteinCoat 320 A LargeFractionof the HumanGenomelsComoosedof
NonretroviralRetrotransposons 32,l
DifferentTransposableElementspredominatein Different Organisms 322
GenomeSequencesRevealtheApproximateTimesthat
TransposableElementsHaveMoved 323
ConservativeSite-SpecificRecombinationCanReversibly RearrangeDNA
323 ConservativeSite-SpecificRecombinationWasDiscoveredin
Bacteriophage), n+
ConservativeSite-SpecificRecombinationCanBeUsedto Turn GenesOnorOff
Summary Problems References Chapter6 HowCellsReadthe Genome:From
DNAto Protein FROMDNATORNA Portionsof
DNASequenceAreTranscribedintoRNA
TranscriptionProducesRNAComplementaryto OneStrandof DNA
CellsProduceSeveralTypesof RNA SignalsEncodedin
DNATellRNApolymeraseWhereto Startand Stop
TranscriptionStartandStopSignalsAreHeterogeneousin
NucleotideSequence TranscriptionInitiationin
EucaryotesRequiresManyproteins RNAPolymerasell
RequiresGeneralTranscriptionFactors Polymerasell
AlsoRequiresActivator,Mediator,andChromatin- ModifyingProteins
TranscriptionElongationProducesSuperhelicalTensionin DNA
TranscriptionElongationin EucaryoteslsTightlyCoupledto RNA
Processing RNACappinglstheFirstModificationof Eucaryoticpre-mRNAs
RNASplicingRemovesIntronSequencesfromNewlyTranscribed Pre-mRNAs
NucleotideSequencesSignalWhereSplicingOccurs
RNASplicinglsPerformedbytheSpliceosome
TheSpliceosomeUsesATPHydrolysisto producea ComplexSeries of
RNA-RNARearrangements OtherPropertiesof
Pre-mRNAandltsSynthesisHelpto Explain theChoiceof ProperSpliceSites
A Second5etof snRNPsSplicea SmallFractionof IntronSequences
inAnimalsandPlants RNASplicingShowsRemarkableplasticity
Spliceosome-CatalyzedRNASplicingprobablyEvolvedfrom
Self-SplicingMechanisms RNA-ProcessingEnzymesGeneratethe3,Endof
EucaryoticmRNAs MatureEucaryoticmRNAsAreSelectivelyExportedfromtne
Nucleus ManyNoncodingRNAsAreAlsoSynthesizedandprocessedinthe
Nucleus TheNucleoluslsa Ribosome-producingFactory
TheNucleusContainsaVarietyof SubnuclearStructures Summarv
ChemicalReactions A Pre-RNAWorldMayPredatetheRNAWorld
Single-StrandedRNAMoleculesCanFoldintoHighlyElaborate Structures
Self-ReplicatingMoleculesUndergoNaturalSelection
HowDidProteinSynthesisEvolve?
AllPresent-DayCellsUseDNAasTheirHereditaryMaterial Summary Problems
References Chapter7 Controlof GeneExpression PathwayfromDNAto RNAto
Protein Summary AN OVERVIEWOFGENECONTROL 4'11
TheDifferentCellTypesof a MulticellularOrganismContainthe SameDNA
411 DifferentCellTypesSynthesizeDifferentSetsof proteins 412
ExternalSignalsCanCausea Cellto ChangetheExpressionof ItsGenes 413
GeneExpressionCanBeRegulatedat Manyofthe Stepsinthe 324 326 327 328
383 385 385 387 388 390 391 393 39s 552 5 5 5 335 336 338 339 340
342 343 401 402 403 404 407 408 408 409 410 411 353 J 5 5 355 5 t /
358 360 502 50J 366 415 415
DNA-BINDINGMOTIFSINGENEREGULATORYPROTEINS 416
GeneRegulatoryProteinsWereDiscoveredUsingBacterial Genetics
TheOutsideof the DNAHelixCanBeReadbyproteins
ShortDNASequencesAreFundamentalComponentsof Genetic Switches
GeneRegulatoryProteinsContainStructuralMotifsThatCan
ReadDNASeouences TheHelix-Turn-HelixMotiflsOneof theSimplestandMost
CommonDNA-B|ndingMotifs 416 416 418 418 419
12. HomeodomainProteinsConstitutea SpecialClassof Helix-Turn-
HelixProteins ThereAreSeveralTypesof DNA-B|ndingZincFingerMotifs p
sheetsCanAlsoRecognizeDNA
SomeProteinsUseLoopsThatEntertheMajorandMinorGroove to RecognizeDNA
TheLeucineZipperMotifMediatesBothDNABindingandProtein Dimerization
HeterodimerizationExpandstheRepertoireof DNASequencesThat
GeneRegulatoryProteinsCanRecognize
TheHelix-Looo-HelixMotifAlsoMediatesDimerizationandDNA Binding It
lsNotYetPossibleto PredicttheDNASequencesRecognized
byAllGeneRegulatoryProteins A
Gel-MobilityShiftAssayReadilyDetectsSequence-Specific
DNA-BindingProteins
DNAAffinityChromatographyFacilitatesthePurificationof
Sequence-SpecificDNA-BindingProteins TheDNASequenceRecognizedbya
GeneRegulatoryProtein CanBeDeterminedExperimentally
PhylogeneticFootprintingldentifiesDNARegulatorySequences
ThroughComparativeGenomics
ChromatinlmmunoprecipitationldentifiesManyof theSites
ThatGeneRegulatoryProteinsOccupyin LivingCells Summary
HOWGENETICSWITCHESWORK TheTryptophanRepressorlsa
SimpleSwitchThatTurnsGenes OnandOffin Bacteria
TranscriptionalActivatorsTurnGenesOn
ATranscriptionalActivatorandaTranscriptionalRepressor
ControltheLocOperon DNALoopingOccursDuringBacterialGeneRegulation
BacteriaUseInterchangeableRNAPolymeraseSubunitsto Help
RegulateGeneTranscription ComplexSwitchesHaveEvolvedto
ControlGeneTranscription in Eucaryotes A
EucaryoticGeneControlRegionConsistsof a PromoterPlus
RegulatoryDNASequences
EucaryoticGeneActivatorProteinsPromotetheAssemblyof RNA
PolymeraseandtheGeneralTranscriptionFactorsatthe
StartpointofTranscription
EucaryoticGeneActivatorProteinsAlsoModifyLocalChromatin Structure
GeneActivatorProteinsWorkSynergistically
EucaryoticGeneRepressorProteinsCanInhibitTranscription
inVariousWays EucaryoticGeneRegulatoryProteinsOftenBindDNA
Cooperatively
ComplexGeneticSwitchesThatRegulateDrosophilaDevelopment
AreBuiltUpfromSmallerModules fhe
DrosophilaEveGenelsRegulatedbyCombinatorialControls
ComplexMammalianGeneControlRegionsAreAlsoConstructed
fromSimpleRegulatoryModules
InsulatorsAreDNASequencesThatPreventEucaryoticGene
RegulatoryProteinsfromInfluencingDistantGenes
GeneSwitchesRapidlyEvolve Summary
THEMOLECULARGENETICMECHANISMSTHATCREATE SPECIALIZEDCELLTYPES
DNARearrangementsMediatePhaseVariationin Bacteria A Setof
GeneRegulatoryProteinsDeterminesCellTypein a BuddingYeast
TwoProteinsThatRepressEachOther! SynthesisDeterminethe
HeritableStateof BacteriophageLambda
SimpleGeneRegulatoryCircuitsCanBeUsedto MakeMemory Devices
TranscriptionalCircuitsAllowtheCellto CanyOutLogicOperations
SyntheticBiologyCreatesNewDevicesfromExistingBiologicalParts
CircadianClocksAreBasedon FeedbackLoopsin GeneRegulation A
SingleGeneRegulatoryProteinCanCoordinatethe Expression of a Setof
Genes Expressionof a CriticalGeneRegulatoryProteinCanTrigger the
Expressionof aWholeBatteryof DownstreamGenes
CombinatorialGeneControlCreatesManyDifferentCellTypes in Eucaryotes
A SingleGeneRegulatoryProteinCanTriggerthe Formation of
anEntireOrgan ThePatternof DNAMethylationCanBeInheritedWhen
VertebrateCellsDivide GenomiclmprintinglsBasedon DNAMethylation
CG-RichlslandsAreAssociatedwith ManyGenesin Mammals
EpigeneticMechanismsEnsureThatStablePatternsof
GeneExpressionCanBeTransmittedto DaughterCells
Chromosome-WideAlterationsin ChromatinStructure CanBeInherited
TheControlof GeneExpressionisIntrinsicallyNoisy Summary
POST-TRANSCRIPTIONALCONTROLS TranscriptionAttenuationCausesthe
PrematureTermination of SomeRNAMolecules
RiboswitchesMightRepresentAncientFormsof GeneControl
AlternativeRNASplicingCanProduceDifferentFormsof a
ProteinfromtheSameGene TheDefinitionof a GeneHasHadto
BeModifiedSincethe Discoveryof AlternativeRNASplicing
SexDeterminationinDrosophiloDependsona Regulated Seriesof
RNASplicingEvents A ChangeintheSiteof
RNATranscriptCleavageandPoly-A AdditionCanChangetheC-terminusof a
Protein RNAEditingCanChangetheMeaningoftheRNAMessage
RNATransportfromthe NucleusCanBeRegulated SomemRNAsAreLocalizedto
SpecificRegionsof theCytoplasm The5'and3'UntranslatedRegionsof
mRNAsControl TheirTranslation ThePhosphorylationof
anlnitiationFactorRegulatesProtein SynthesisGlobally
lnitiationatAUGCodonsUpstreamof theTranslationStart
CanRegulateEucaryoticTranslationInitiation
InternalRibosomeEntrySitesProvideOpportunitiesfor
TranslationControl Changesin mRNAStabilityCanRegulateGeneExpression
CytoplasmicPoly-AAdditionCanRegulateTranslation
SmallNoncodingRNATranscriptsRegulateManyAnimaland PlantGenes
RNAInterferencelsa CellDefenseMechanism
RNAInterferenceCanDirectHeterochromatinFormation
RNAlnterferenceHasBecomea PowerfulExperimentalTool Summory Problems
References Chapter8 ManipulatingProteins,DNA,and RNA
ISOLATINGCELLSANDGROWINGTHEMINCULTURE
CellsCanBelsolatedfromIntactTissues CellsCanBeGrownin Culture
EucaryoticCellLinesAreaWidelyUsedSourceof HomogeneousCells
EmbryonicStemCellsCouldRevolutionizeMedicine
SomaticCellNuclearTransplantationMayProvideaWayto
GeneratePersonalizedStemCells
HybridomaCellLinesAreFactoriesThatProduceMonoclonal Antibodies
Summary PURIFYINGPROTEINS
CellsCanBeSeparatedintoTheirComponentFractions 510
CellExtractsProvideAccessibleSystemsto StudyCellFunctions 511
ProteinsCanBeSeparatedbyChromatography 512
AffinityChromatographyExploitsSpecificBindingSiteson Proteins 513
Genetically-EngineeredTagsProvideanEasyWayto Purify Proteins 514
420 421 422 423 423 424 425 426 427 428 429 431 464 465 467 468 470
471 473 476 477 477 431 432 432 433 435 435 437 438 439 440 477 478
479 480 481 482 483 485 486 488 488 489 491 492 493 493 495 496 497
497 497 499 50r 501 502 s02 50s 505 s07 508 s 1 0 5 1 0 441 442 444
445 450 +)z 453 453 454 454 455 458 459 460 460 445 447 448
13.
PurifiedCell-FreeSystemsAreRequiredforthepreciseDissectionof
MolecularFunctions Summory ANALYZINGPROTEINS
ProteinsCanBeSeparatedbySDSpolyacrylamide-Gel Electrophoresis
SpecificProteinsCanBeDetectedbyBlottingwithAntibodies
MassSpectrometryProvidesa HighlySensitiveMethod for
ldentifyingUnknownproteins
Two-DimensionalSeparationMethodsareEspeciallypowerful
HydrodynamicMeasurementsRevealtheSizeandShapeof a Proteincomolex
Setsof InteractingProteinsCanBeldentifiedbyBiochemical Methods
Protein-ProteinInteractionsCanAlsoBeldentifiedbya
Two-HybridTechniqueinyeast
CombiningDataDerivedfromDifferentTechniquesproduces
ReliableProtein-lnteractionMaDs
OpticalMethodsCanMonitorProteinInteractionsin RealTime
SomeTechniquesCanMonitorSingleMolecules
ProteinFunctionCanBeSelectivelyDisruptedwithSmall Molecules
ProteinStructureCanBeDeterminedUsingX-RayDiffraction NMRCanBeUsedto
DetermineproteinStructurein Solutron
ProteinSequenceandStructureprovideCluesAboutprotein Function
Summory ANALYZINGAND MANIPULATINGDNA
RestrictionNucleasesCutLargeDNAMoleculesintoFragments
GelElectrophoresisSeparatesDNAMoleculesof DifferentSizes
PurifiedDNAMoleculesCanBeSpecificallyLabeledwith
RadioisotopesorChemicalMarkersin yitro
NucleicAcidHybridizationReactionsprovidea SensitiveWayof
DetectingSpecificNucleotideSequences
NorthernandSouthernBlottingFacilitateHybridizationwith
ElectrophoreticallySeparatedNucleicAcidMolecules
GenesCanBeClonedUsingDNALibraries TwoTypesof
DNALibrariesServeDifferentpurooses
cDNAClonesContainUninterruptedCodingSequences
GenesCanBeSelectivelyAmplifiedbypCR CellsCanBeUsedAsFactoriesto
produceSoecificproteins
ProteinsandNucleicAcidsCanBeSynthesizedDirectlyby ChemicalReactions
DNACanBeRapidlySequenced NucleotideSequencesAreUsedto
predicttheAminoAcio Sequencesof Proteins TheGenomesof
ManyOrganismsHaveBeenFullySequenceo Summary
STUDYINGGENEEXPRESSIONAND FUNCTION
ClassicalGeneticsBeginsbyDisruptingaCellprocessbyRanoom Mutagenesis
GeneticScreensldentifyMutantswith SpecificAbnormalirres
MutationsCanCauseLossor Gainof proteinFunction
ComplementationTestsRevealWhetherTwoMutationsAre intheSameGeneor
DifferentGenes GenesCanBeOrderedin Pathwaysby EpistasisAnalysis
GenesldentifiedbyMutationsCanBeCloned
HumanGeneticsPresents5pecialproblemsandSpecial Opportunities
HumanGenesAreInheritedin HaplotypeBlocks,WhichCan Aidin
theSearchforMutationsThatCauseDisease
ComplexTraitsAreInfluencedbyMultipleGenes
ReverseGeneticsBeginswitha KnownGeneandDetermines
WhichCellProcessesRequireltsFunction GenesCanBeRe-Engineeredin
SeveralWays EngineeredGenesCanBeInsertedintotheGermLineof
ManyOrganisms AnimalsCanBeGeneticallyAltered
TransgenicPlantsArelmportantfor BothCellBiologyand Agriculture
LargeCollectionsofTaggedKnockoutsProvideaToolfor
ExaminingtheFunctionof EveryGeneinanOrganism RNAInterferencelsa
SimpleandRapidWayto TestGeneFunction
ReporterGenesand/nSituHybridizationRevealWhenano
WhereaGenelsExpressed Expressionof
IndividualGenesCanBeMeasuredUsino QuantitativeRT-PCR Lipidsin
CellMembranes PhospholioidsSoontaneouslvFormBilavers
MicroarraysMonitorthe ExpressionofThousandsof Genesat Once 574
5ingle-CellGeneExpressionAnalysisRevealsBiological"Noise" 575
Summary 576 Problems 576 References 579 Chapter 9 Visualizing Cells
LOOKINGATCELLSINTHELIGHTMICROSCOPE
TheLightMicroscopeCanResolveDetails0.2pm Apart
LivingCellsAreSeenClearlyin a Phase-Contrastora Differential-
Interference-ContrastMicroscooe
lmagesCanBeEnhancedandAnalyzedbyDigitalTechniques
IntactTissuesAreUsuallyFixedandSectionedbeforeMicroscopy
SpecificMoleculesCanBeLocatedinCellsbyFluorescence Microscopy
AntibodiesCanBeUsedto DetectSpecificMolecules lmagingof
ComplexThree-DimensionalObjectslsPossible withtheOpticalMicroscope
TheConfocalMicroscopeProducesOpticalSectionsbyExcluding 579 579 s80
583 583 585 586 588 589 Out-of-FocusLight 590
FluorescentProteinsCanBeUsedtoTagIndividualproteinsin
LivingCellsandOrganisms 592 ProteinDynamicsCanBeFollowedin
LivingCells 593 Light-EmittingIndicatorsCanMeasureRapidlyChanging
IntracellularlonConcentrations 596
SeveralStrategiesAreAvailablebyWhichMembrane-lmpermeant
SubstancesCanBeIntroducedintoCells 597 LightCanBeUsedto
ManipulateMicroscopicObjectsAsWell Asto lmageThem 598
SingleMoleculesCanBeVisualizedbyUsingTotalInternal
ReflectionFluorescenceMicroscopy 5gg
IndividualMoleculesCanBeTouchedandMovedUsingAtomic ForceMicroscopy
600 MoleculesCanBeLabeledwithRadioisotopes 600
RadioisotopesAreUsedtoTraceMoleculesinCellsandOrganisms602 Summary
603 LOOKINGATCELLSANDMOLECULESINTHEELECTRON MtcRoScoPE 604
TheElectronMicroscopeResolvesthe FineStructureofthe Cell 604
BiologicalSpecimensRequireSpecialPreparationfortheElectron
Microscope 605
SpecificMacromoleculesCanBeLocalizedbylmmunogoldElectron Microscopy
606 lmagesof SurfacesCanBeObtainedbyScanningElectron Microscopy 607
MetalShadowingAllowsSurfaceFeaturesto BeExaminedat
HighResolutionbyTransmissionElectronMicroscopy 60g
NegativeStainingandCryoelectronMicroscopyBothAllow Macromoleculesto
BeViewedat HighResolution 6l O MultiplelmagesCanBeCombinedto
IncreaseResolution 610 DifferentViewsof a
SingleObjectCanBeCombinedto Givea Three-DimensionalReconstruction
Summary Problems References Chapter10MembraneStructure 612 o t 2
614 o t ) 6",7 THELIPIDBILAYER 617
Phosphoglycerides,Sphingolipids,andSterolsAretheMajor ) t o ) t o
517 517 5 1 8 5 1 9 5 2 1 522 523 523 524 524 526 J 2 / i l l 529
530 ) J l 532 s32 534 s35 ) J ) s38 540 541 544 544 546 569 571 572
573 548 548 550 5 5 1 ))z 553 553 556 558 558 s59 s63 564 s60 561
s63 565 foo )oaJ 6 1 8 A)6
14. TheLipidBilayerlsaTwo-DimensionalFluid TheFluidityof a
LipidBilayerDependson ltsComposition
DespiteTheirFluidity,LipidBilayersCanFormDomainsof
DifferentCompositions LipidDropletsAreSurroundedbya
PhospholipidMonolayer TheAsymmetryof
theLipidBilayerlsFunctionallylmportant
GlycolipidsAreFoundontheSurfaceof AllPlasmaMembranes Summary
MEMBRANEPROTEINS MembraneProteinsCanBeAssociatedwiththe
LipidBilayerin VariousWays
LipidAnchorsControltheMembraneLocalizationof Some SignalingProteins
InMostTransmembraneProteinsthePolypeptideChainCrosses
theLipidBilayerin ano-HelicalConformation
TransmembranecrHelicesOftenlnteractwithOneAnother Somep
BarrelsFormLargeTransmembraneChannels
ManyMembraneProteinsAreGlycosylated
MembraneProteinsCanBeSolubilizedandPurifiedin Detergents
Bacteriorhodopsinlsa Light-DrivenProtonPumpThatTraverses the
LipidBilayerasSevens Helices
MembraneProteinsOftenFunctionasLargeComplexes
ManyMembraneProteinsDiffuseinthePlaneof theMembrane
CellsCanConfineProteinsandLipidsto SpecificDomainsWithin a Membrane
TheCorticalCytoskeletonGivesMembranesMechanicalStrength
andRestrictMembraneProteinDiffusion Summary Problems References
Patch-ClampRecordingIndicatesThatIndividualGatedChannels Openin
anAll-or-NothingFashion 680
Voltage-GatedCationChannelsAreEvolutionarilyandStructurally Related
682 TransmittercatedlonChannelsConvertChemicalSignalsinto
ElectricalOnesatChemicalSynapses 682
ChemicalSynapsesCanBeExcitatoryor Inhibitory 684
TheAcetylcholineReceptorsatthe NeuromuscularJunctionAre
Transmitter-GatedCationChannels 684
TransmitterGatedlonChannelsAreMajorTargetsfor Psychoactive Drugs
686 NeuromuscularTransmissionInvolvestheSequentialActivation of
FiveDifferentSetsof lonChannels
SingleNeuronsAreComplexComputationDevices
NeuronalComputationRequiresa Combinationof at Least ThreeKindsof
K+Channels Long-TermPotentiation(LTP)intheMammalianHippocampus
DependsonCa2+EntryThroughNMDA-ReceptorChannels Summary Problems
References Chapter12IntracellularCompartmentsand ProteinSorting 695
THECOMPARTMENTALIZATIONOFCELLS 695
AllEucaryoticCellsHavetheSameBasicSetofMembrane- EnclosedOrganelles
695 EvolutionaryOriginsExplaintheTopologicalRelationshipsof
Organelles ProteinsCanMoveBetweenCompartmentsin DifferentWays
SignalSequencesDirectProteinsto theCorrectCellAddress
MostOrganellesCannotBeConstructedDeNovo:TheyRequire Informationin
theOrganelleltself Summary THETRANSPORTOF
MOLECULESBETWEENTHENUCLEUS ANDTHECYTOSOL
NuclearPoreComplexesPerforatethe NuclearEnvelope
NuclearLocalizationSignalsDirectNuclearProteinsto theNucleus
NuclearlmportReceptorsBindto BothNuclearLocalization
SignalsandNPCProteins NuclearExportWorksLikeNuclearlmport,Butin
Reverse TheRanGTPaselmposesDirectionalityonTransportThrough NPCs
TransportThroughNPCsCanBeRegulatedbyControlling Accessto
theTransPortMachinerY DuringMitosisthe NuclearEnvelopeDisassembles
Summary THETRANsPORTOF PROTEINSINTOMITOCHONDRIA AND CHLOROPLASTS
713 TranslocationintoMitochondriaDependson SignalSequences
andProteinTranslocators 7'13
MitochondrialPrecursorProteinsArelmportedasUnfolded
PolypeptideChains 715 ATPHydrolysisanda
MembranePotentialDriveProteinlmport IntotheMatrixSpace 716
BacteriaandMitochondriaUseSimilarMechanismsto lnsert
PorinsintotheirOuterMembran2 717 TransDortIntothe
InnerMitochondrialMembraneand
IntermembraneSpaceOccursViaSeveralRoutes 717
TwoSignalSequencesDirectProteinsto theThylakoid o l l 622 624
ot> 626 628 629 629 629 630 631 632 634 o5f 636 640 642 642 645
646 648 648 650 6s3 654 654 656 o)t 658 oou 661 663 667 687 688 689
691 692 693 694 697 699 701 702 704 Chapter11MembraneTransportof
SmallMolecules and the ElectricalPropertiesof Membranes 651
PRINCIPLESOFMEMBRANETRANSPORT 651
Protein-FreeLipidBilayersAreHighlylmpermeableto lons 652
ThereAreTwoMainClassesof MembraneTransportProteins:
TransportersandChannels 652
ActiveTransportlsMediatedbyTransportersCoupledto an EnergySource
Summary TRANSPORTERSAND ACTIVEMEMBRANETRANSPORT
ActiveTransportCanBeDrivenbylonGradients Transportersin
thePlasmaMembraneRegulateCytosolicpH
AnAsymmetricDistributionofTransportersin EpithelialCells
UnderliestheTranscellularTransportof Solutes ThereAreThreeClassesof
ATP-DrivenPumps TheCa2+PumplstheBest-UnderstoodP-typeATPase
ThePlasmaMembraneP-typeNa+-K+PumpEstablishesthe
Na+GradientAcrossthePlasmaMembrane
ABCTransportersConstitutetheLargestFamilyof Membrane
TransoortProteins Summary IONCHANNELSANDTHEELECTRICALPROPERTIESOF
MEMBRANES 667 lonChannelsArelon-SelectiveandFluctuateBetweenOpenand
closedStates 667 TheMembranePotentialin AnimalCellsDependsMainlyon
K+Leak ChannelsandtheK+GradientAcrossthePlasmaMembrane 669
TheRestingPotentialDecaysOnlySlowlyWhenthe Na+-K+Pump lsStopped 669
TheThree-DimensionalStructureof a BacterialK+ChannelShows
HowanlonChannelCanWork AquaporinsArePermeableto
WaterButlmpermeableto lons TheFunctionofa NeuronDependson
ltsElongatedStructure
Voltage-GatedCationChannelsGenerateActionPotentialsin
ElectricallyExcitableCells
MyelinationIncreasestheSpeedandEfficiencyof ActionPotential
Propagationin NerveCells MembraneinChloroplasts Summary PEROXISOMES
PeroxisomesUseMolecularOxygenandHydrogenPeroxideto
PerformOxidativeReactions A ShortSignalSequenceDirectsthe lmportof
Proteinsinto Peroxisomes Summary 704 705 705 671 673 675 676 o / 6
707 708 708 709 7't0 712 719 720 721 721 722 t 2 5
15. THEENDOPLASMICRETICULUM 723
TheERlsStructurallyandFunctionallyDiverse 724
SignalSequencesWereFirstDiscoveredin proteinslmoorteo
intotheRoughER 726 A
Signal-RecognitionParticle(SRp)DirectsERSignalSequences to a
SpecificReceptorintheRoughERMembrane 727
ThePolypeptideChainPassesThroughanAqueousporeinthe Translocator 730
TranslocationAcrossthe ERMembraneDoesNotAlwaysRequire
OngoingPolypeptideChainElongation 731
InSingle-PassTransmembraneProteins,a SingleInternalERSignal
SequenceRemainsintheLipidBilayerasa Membrane-spanning o Helix 732
Combinationsof Start-TransferandStop-TransferSignalsDetermine
theTopologyof MultipassTransmembraneproteins 734
TranslocatedPolypeptideChainsFoldandAssemblein theLumen
oftheRoughER n6 MostProteinsSynthesizedin
theRoughERAreGlycosylatedby theAdditionofa
CommonN-LinkedOligosaccharide 736 OligosaccharidesAreUsedasTagsto
MarktheStateof protein Folding 738
lmproperlyFoldedProteinsAreExportedfromthe ERand Degradedin
theCytosol 739 MisfoldedProteinsintheERActivateanUnfoldedprotein
TRANSPORTFROMTHEIRANSGOLGINETWORK TO LYSOSOMES 779 LysosomesArethe
PrincipalSitesof IntracellularDigestion 779
LysosomesAreHeterogeneous 780
PlantandFungalVacuolesAreRemarkablyVersatileLysosomes 781
MultiplePathwaysDeliverMaterialsto Lysosomes 792 A
Mannose6-PhosphateReceptorRecognizesLysosomalProteins in
thelronsGolgiNetwork TheM6PReceptorShuttlesBetweenSpecificMembranes
A SignalPatchinthe HydrolasePolypeptideChainProvides theCuefor
M6PAddition Defectsin theGlcNAcPhosphotransferaseCausea Lysosomal
StorageDiseasein Humans SomeLysosomesUndergoExocytosis Summary
TRANSPORTINTOTHECELLFROMTHEPLASMA MEMBRANE:ENDOCYTOSIS
SpecializedPhagocyticCellsCanIngestLargeParticles
PinocyticVesiclesFormfromCoatedPitsinthePlasmaMemorane
NotAllPinocyticVesiclesAreClathrin-Coated
CellsUseReceptor-MediatedEndocytosisto lmportSelected
ExtracellularMacromolecules
EndocytosedMaterialsThatAreNotRetrievedfromEndosomes EndUpin
Lysosomes SpecificProteinsAreRetrievedfromEarlyEndosomesand
Returnedto thePlasmaMembrane MultivesicularBodiesFormonthe
Pathwayto LateEndosomes
TranscytosisTransfersMacromoleculesAcrossEpithelial CellSheets
EpithelialCellsHaveTwoDistinctEarlyEndosomalCompartments buta
CommonLateEndosomalComoartment Summory
TRANSPORTFROMTHEIRANSGOLGINETWORK TOTHECELLEXTERIOR:EXOCYTOSIS
ManyProteinsandLipidsSeemto BeCarriedAutomaticallv
fromtheGolgiApparatusto theCellSurface
SecretoryVesiclesBudfromthefuonsGolgiNetwork
ProteinsAreOftenProteolyticallyProcessedDuringthe Formationof
SecretoryVesicles SecretoryVesiclesWaitNearthePlasmaMembraneUntil
Signaledto ReleaseTheirContents RegulatedExocytosisCanBea
LocalizedResponseofthe PlasmaMembraneandltsUnderlyingCytoplasm
SecretoryVesicleMembraneComponentsAreeuicklyRemoved
fromthePlasmaMembrane SomeRegulatedExocytosisEventsServeto
Enlargetheplasma Membrane
PolarizedCellsDirectProteinsfromthelransGolgiNetworkto
theAppropriateDomainofthePlasmaMembrane
DifferentStrategiesGuideMembraneProteinsandLipidsSelectively to
theCorrectPlasmaMembraneDomains
SynapticVesiclesCanFormDirectlyfromEndocyticVesicles >ummary
Problems References Chapter14EnergyConversion:Mitochondria and
Chloroplasts 813 THEMITOCHONDRION 815
TheMitochondrionContainsanOuterMembrane,anInner
Membrane,andTwoInternalCompartments 916
TheCitricAcidCycleGeneratesHigh-EnergyElectrons 817
AChemiosmoticProcessConvertsOxidationEnergyintoATp 917
NADHTransfersitsElectronsto OxygenThroughThreeLarge
RespiratoryEnzymeComplexes gl9 AsElectronsMoveAlongthe
RespiratoryChain,EnergylsStored
asanElectrochemicalProtonGradientAcrossthe lnner 783 784 785 785
786 786 Resoonse SomeMembraneProteinsAcquireaCovalentlyAttached
Glycosylphosphatidylinositol(Gpl)Anchor
TheERAssemblesMostLipidBilayers Summory Problems References Chapter
13 IntracellularVesicularTraffic THEMOLECULARMECHANISMSOFMEMBRANE
TRANSPORTANDTHEMAINTENANCEOF COMPARTMENTALDIVERSITY
ThereAreVariousTypesofCoatedVesicles
TheAssemblyofaClathrinCoatDrivesVesicleFormation
NotAllCoatsFormBasket-likeStructures
PhosphoinositidesMarkOrganellesandMembraneDomarns
CytoplasmicProteinsRegulatethepinching-OffandUncoarrng of
CoatedVesicles MonomericGTPasesControlCoatAssembly
NotAllTransportVesiclesAreSpherical
RabProteinsGuideVesicleTargeting SNAREsMediateMembraneFusion
InteractingSNAREsNeedto BepriedApartBeforeTheyCan FunctionAgain
ViralFusionProteinsandSNAREsMayUseSimilarFusion 740 742 743 745 746
748 749 750 751 754 757 t ) I 758 760 760 toz 764 787 787 789 790
791 792 793 795 797 798 799 800 801 803 803 804 799 805 806 807 809
8 1 0 812 820 a2'l 805 80s Mechanisms 764 Summary 766
TRANSPORTFROMTHEERTHROUGHTHEGOLGI APPARATUS 766
ProteinsLeavetheERin COPII-CoatedTransportVesicles 767
OnlyProteinsThatAreproperlyFoldedandAssembledCanLeave theER 767
VesicularTubularClustersMediateTransportfromtheERto the
GolgiApparatus 768 TheRetrievalPathwayto theERUsesSortingSignals
769 ManyProteinsAreSelectivelyRetainedintheCompartmentsin
WhichTheyFunction 771 TheGolgiApparatusConsistsof anOrderedSeriesof
Compartments 771
OligosaccharideChainsAreProcessedintheGolgiApparatus 773
ProteoglycansAreAssembledin theGolgiApparatus 775
WhatlsthePurposeof Glycosyfationt 776
TransportThroughtheGolgiApparatusMayOccurbyVesicular
TransportorCisternalMaturation 777
GolgiMatrixProteinsHelpOrganizetheStack 77g Summory 77g Membrane
TheProtonGradientDrivesATPSynthesis
16. TheProtonGradientDrivesCoupledTransportAcrosstheInner
Membrane 822 ProtonGradientsProduceMostof theCell'sATP 822
MitochondriaMaintaina HighATP:ADPRatioinCells 823 A
LargeNegativeValueof AGforATPHydrolysisMakesATP Usefulto theCell
824 ATPSynthaseCanFunctionin Reverseto HydrolyzeATPand PumoHr 826
Summary 827 ELECTRON-TRANSPORTCHAINSANDTHEIRPROTOI' PUMPS 827
ProtonsAreUnusuallyEasyto Move 827 TheRedoxPotentiallsa Measureof
ElectronAffinities 828 EfectronTransfersReleaseLargeAmountsofEnergy
829 SpectroscopicMethodsldentifiedManyElectronCarriersinthe
RespiratoryChain 829
TheRespiratoryChainIncludesThreeLargeEnzymeComplexes
EmbeddedintheInnerMembrane 831 Anlron-CopperCenterin
CytochromeOxidaseCatalyzesEfficient 02 Reduction 832
ElectronTransfersinthe InnerMitochondrialMembraneAreMediated
byElectronTunnelingduringRandomCollisions 834 A LargeDropin
RedoxPotentialAcrossEachoftheThreeRespiratory
EnzymeComplexesProvidesthe Energyfor H+Pumping 835
TheH+PumpingOccursbyDistinctMechanismsintheThreeMajor
EnzymeComplexes 835
H+lonophoresUncoupleElectronTransportfromATPSynthesis 836
RespiratoryControlNormallyRestrainsElectronFlowThrough theChain 837
NaturalUncouolersConverttheMitochondriain BrownFatinto
Heat-GeneratingMachines 838
TheMitochondrionPlaysManyCriticalRolesin CellMetabolism 838
BacteriaAlsoExploitChemiosmoticMechanismsto Harness Energy 839
Summary 840 CHLOROPLASTSAND PHOTOSYNTHESIS 840
TheChloroplastlsOneMemberof the PlastidFamilyof Organelles 841
ChloroplastsResembleMitochondriaButHaveanExtra Compartment 842
ChloroplastsCaptureEnergyfromSunlightandUselt to Fix Carbon 843
CarbonFixationlsCatalyzedbyRibuloseBisphosphate Carboxylase 844
EachCO2MoleculeThatlsFixedConsumesThreeMolecules
ofATPandTwoMoleculesofNADPH 845 CarbonFixationin
SomePlantslsCompartmentalizedto Facilitate Growthat
LowCO2Concentrations 846 PhotosynthesisDependsonthe
Photochemistryof Chlorophyll Molecules 847 A
PhotochemicalReactionCenterPlusanAntennaComplex Forma Photosystem
848 Ina ReactionCenter,LightEnergyCapturedbyChlorophyll Createsa
StrongElectronDonorfromaWeakOne 849
NoncyclicPhotophosphorylationProducesBothNADPHandATP 850
ChloroplastsCanMakeATPbyCyclicPhotophosphorylation
WithoutMakingNADPH 853 PhotosystemsI andll
HaveRelatedStructures,andAlsoResemble BacterialPhotosystems
TheProton-MotiveForcelstheSamein Mitochondriaand Chloroplasts
CarrierProteinsintheChloroplastInnerMembraneControl
MetaboliteExchangewiththeCytosol
ChloroplastsAlsoPerformOtherCrucialBiosyntheses Summary
THEGENETICSYSTEMSOFMITOCHONDRIAAND PLASTIDS
MitochondriaandChloroplastsContainCompleteGeneticSystems
OrganelleGrowthandDivisionDeterminetheNumberof
MitochondriaandPlastidsina Cell 8s3 6 f J 854 855 855
MitochondriaandChloroplastsHaveDiverseGenomes 859
MitochondriaandChloroplastsProbablyBothEvolvedfrom
EndosymbioticBacteria 859 MitochondriaHavea
RelaxedCodonUsageandCanHavea VariantGeneticCode
AnimalMitochondriaContaintheSimplestGeneticSystemsKnown
SomeOrganelleGenesContainIntrons TheChloroplastGenomeof
HigherPlantsContainsAbout 120Genes
MitochondrialGenesAreInheritedbya Non-Mendelian Mechanism
OrganelleGenesAreMaternallyInheritedin ManyOrganisms
PetiteMutantsinYeastsDemonstratetheOverwhelming
lmportanceoftheCellNucleusforMitochondrialBiogenesis
MitochondriaandPlastidsContainTissue-SpecificProteinsthat
AreEncodedintheCellNucleus
MitochondrialmportMostofTheirLipids;ChloroplastsMake MostofTheirs
MitochondriaMayContributeto theAgingof CellsandOrganisms
WhyDoMitochondriaandChloroplastsHaveTheirOwnGenetic Systems?
Summary THEEVOLUTIONOFELECTRON-TRANSPORTCHAINS
TheEarliestCellsProbablyUsedFermentationto ProduceATP
Electron-TransoortChainsEnabledAnaerobicBacteriato Use
NonfermentableMoleculesasTheirMajorSourceof Energy
ByProvidinganInexhaustibleSourceof ReducingPower,
PhotosyntheticBacteriaOvercamea MajorEvolutionary Obstacle
ThePhotosyntheticElectron-TransportChainsof Cyanobacteria
ProducedAtmosphericOxygenandPermittedNewLife-Forms Summary Problems
References Chapter 15 Mechanisms of Cell Communication 879
GENERALPRINCIPLESOFCELLCOMMUNICATION 879
ExtracellularSignalMoleculesBindto SpecificReceptors 880
ExtracellularSignalMoleculesCanActOverEitherShortor Long Distances
881 GapJunctionsAllowNeighboringCellsto ShareSignaling lnformation
884 EachCelllsProgrammedto Respondto SpecificCombinationsof
ExtracellularSignalMolecule5 884 DifferentTypesof
CellsUsuallyRespondDifferentlyto theSame
ExtracellularSignalMolecule 885 TheFateof
SomeDevelopingCellsDependsonTheirPositionin MorphogenGradients 886
A CellCanAltertheConcentrationof anlntracellularMolecule
QuicklyOnlylf theLifetimeof the MoleculelsShort 886
NitricOxideGasSignalsbyDirectlyRegulatingtheActivityof
SpecificProteinsInsidetheTargetCell 887
NuclearReceptorsAreLigand-ModulatedGeneRegulatory Proteins 889
TheThreeLargestClassesof Cell-SurfaceReceptorProteinsArelon-
Channel-Coupled,G-Protein-Coupled,andEnzyme-Coupled Receptors 891
MostActivatedCell-SurfaceReceptorsRelaySignalsViaSmall
Moleculesanda Networkof IntracellularSignalingProteins 893
ManyIntracellularSignalingProteinsFunctionasMolecularSwitches
ThatAreActivatedbyPhosphorylationorGTPBinding 895
IntracellularSignalingComplexesEnhancetheSpeed,Efficiency,
andSpecificityofthe Response 897
ModularInteractionDomainsMediatelnteractionsBetween
IntracellularSignalingProteins 897 CellsCanUseMultipleMechanismsto
RespondAbruptlyto a GraduallyIncreasingConcentrationofan
ExtracellularSignal 899
IntracellularSignalingNetworksUsuallyMakeUseof 861 862 863 863 864
866 866 867 867 606 868 870 870 870 871 872 873 875 877 878 85s 856
857 FeedbackLoops CellsCanAdjustTheirSensitivityto a Signal Summary
901 902 903
17. SIGNALINGTHROUGHG-PROTEIN-COUPLEDCELL-
sURFACERECEPTORS(GPCRs)ANDSMALL INTRACELLULARMEDIATORS
TrimericGProteinsRelaySignalsfromGpCRs
SomeGProteinsRegulatetheProductionof CyclicAMp
Cyclic-AMP-DependentProteinKinase(pKA)MediatesMosr of theEffectsof
CyclicAMP SomeG ProteinsActivateAnInositolPhospholipidSignaling
PathwaybyActivatingPhospholipaseC-p Ca2+Functionsasa
UbiquitousIntracellularMediator TheFrequencyof
Ca2+OscillationslnfluencesaCell!Response
Ca2+/Calmodulin-DependentproteinKinases(CaM-Kinases)
MediateManyoftheResponsesto Ca2+SignalsinAnimalCells
SomeGProteinsDirectlyRegulatelonChannels
SmellandVisionDependonGPCRsThatRegulateCyclic-
Nucleotide-GatedlonChannels
IntracellularMediatorsandEnzymaticCascadesAmplify
ExtracellularSignals GPCRDesensitizationDependson
Receptorphosphorylation Summory
SIGNALINGTHROUGHENZYME-COUPLEDCELL-SURFACE RECEPTORS
ActivatedReceptorTyrosineKinases(RTKs)phosphorylate Themselves
PhosphorylatedTyrosineson RTKsServeasDockingSitesfor
IntracellularSignalingProteins ProteinswithSH2DomainsBindto
phosphorylatedTyrosines RasBelongsto a LargeSuperfamilyof
MonomericGTpases RTKsActivateRasViaAdaptorsandGEFs:Evidencefromthe
DevelopingDrosophilaEye RasActivatesa MAPKinaseSignalingModule
ScaffoldProteinsHelpPreventCross-TalkBetweenparallelMAp
KinaseModules
RhoFamilyGTPasesFunctionallyCoupleCell-SurfaceReceptors to
theCytoskeleton
Pl3-KinaseProducesLipidDockingSitesintheplasmaMemorane
ThePl-3-Kinase-AktSignalingPathwayStimulatesAnimalCellsto
SurviveandGrow
TheDownstreamSignalingPathwaysActivatedByRTKsandGpCRs Overlao
Tyrosine-Kinase-AssociatedReceptorsDependonCytoplasmic
TyrosineKinases
CytokineReceptorsActivatetheJAK-STATSignalingpathway, Providinga
FastTrackto theNucleus
ProteinTyrosinePhosphatasesReverseTyrosinephosphorylations
SignalProteinsof theTGFBSuperfamilyActThroughReceptor
Serine/ThreonineKinasesandSmads
Serine/ThreonineandTyrosineproteinKinasesAreStructurally Related
BacterialChemotaxisDependson aTwo-ComponentSignaling
PathwayActivatedbyHistidine-Kinase-AssociatedReceptors
ReceptorMethylationlsResponsibleforAdaptationin Bacterial
Chemotaxis Summory SIGNALINGPATHWAYSDEPENDENTON REGULATED
PROTEOLYSISOF LATENTGENEREGULATORYPROTEINS
TheReceptorProteinNotchlsa LatentGeneRegulatoryprotein
WntProteinsBindto FrizzledReceptorsandInhibitthe Degradationof
p-Catenin HedgehogProteinsBindto patchedRelievingltsInhibition of
Smoothened ManyStressfulandInflammatoryStimuliActThroughan
NFrB-DependentSignalingPathway Summory SIGNALINGIN PLANTS
MulticellularityandCellCommunicationEvolvedIndependently in
PlantsandAnimals ReceptorSerine/ThreonineKinasesArethe
LargestClassof Cell-SurfaceReceptorsin Plants
EthyleneBlockstheDegradationof SpecificGeneRegulatory Proteinsin
theNucleus 957 RegulatedPositioningof
AuxinTransportersPatternsPlantGrowth 959
PhytochromesDetectRedLight,andCryptochromesDetectBlue Light Summory
Problems References Chapter16 TheCytoskeleton 960 961 964 965
THESELF-AssEMBLYAND DYNAMICSTRUCTUREOF CYTOSKELETALFILAMENTS 965
CytoskeletalFilamentsAreDynamicandAdaptable 966
TheCytoskeletonCanAlsoFormStableStructures 969 EachTypeof
CytoskeletalFilamentlsConstructedfromSmaller ProteinSubunits 970
FilamentsFormedfromMultipleProtofilamentsHave
AdvantageousProperties 971
NucleationlstheRate-LimitingStepintheFormationof
aCytoskeletalPolymer 973
TheTubulinandActinSubunitsAssembleHead-to-Tailto
CreatePolarFilaments 973
MicrotubulesandActinFilamentsHaveTwoDistinctEnds ThatGrowat
DifferentRates 975
FilamentTreadmillingandDynamicInstabilityAreConsequences of
NucleotideHydrolysisbyTubulinandActin 976
TreadmillingandDynamicInstabilityAidRapidCytoskeletal Rearrangement
980 TubulinandActinHaveBeenHighlyConservedDuring
EucaryoticEvolution 982
IntermediateFilamentStructureDependsonTheLateral
BundlingandTwistingof CoiledCoils 983
IntermediateFilamentslmpartMechanicalStabilityto AnimalCells 985
DrugsCanAlterFilamentPolymerization 987
BacterialCellOrganizationandCellDivisionDependon Homologsofthe
EucaryoticCytoskeleton 999 Summary 991
HOWCELLSREGULATETHEIRCYTOSKELETALFILAMENTS 992 A
ProteinComplexContainingyTubulinNucleatesMicrotubules 992
MicrotubulesEmanatefromtheCentrosomeinAnimalCells 992
ActinFilamentsAreOftenNucleatedatthe PlasmaMembrane 996
TheMechanismof NucleationInfluencesLarge-ScaleFilament Organization
999 ProteinsThatBindto theFreeSubunitsModifyFilamentElongation999
SeveringProteinsRegulatetheLengthandKineticBehaviorof
ActinFilamentsandMicrotubules 1000 ProteinsThatBindAlongtheSidesof
FilamentsCanEitherStabilize or DestabilizeThem 1OO1
ProteinsThatInteractwithFilamentEndsCanDramaticallyChange
FilamentDynamics 1OO2 DifferentKindsof ProteinsAlterthe
Propertiesof RapidlyGrowing MicrotubuleEnds
FilamentsAreOrganizedintoHigher-OrderStructuresin Cells
IntermediateFilamentsAreCross-LinkedandBundledlnto StrongArrays
Cross-LinkingProteinswith DistinctPropertiesOrganizeDifferent 1003
1005 1005 AssembliesofActinFilaments 1006
FilaminandSpectrinFormActinFilamentWebs l OOg
CytoskeletalElementsMakeManyAttachmentsto Membrane 1009 Summary
l0l0 MOLECULARMOTORS Actin-BasedMotorProteinsAreMembersof theMvosin
Superfamily ThereAreTwoTypesof MicrotubuleMotorProteins:Kinesinsand
Dyneins rc14 TheStructuralSimilarityof MyosinandKinesinIndicatesa
CommonEvolutionaryOrigin 1015
MotorProteinsGenerateForcebyCouplingATPHydrolysisto
ConformationalChanqes 1016 904 90s 90s 908 909 912 912 914 916 917
919 920 921 921 922 923 924 926 927 928 930 931 932 934 v5) 935 937
938 939 941 941 943 944 946 946 948 950 952 954 955 1 0 1 0 1 0 11
955 vf,o
18. MotorProteinKineticsAreAdaptedto CellFunctions 1020
MotorProteinsMediatethe IntracellularTransportof Membrane-
Microtubule-DependentMotorProteinsGovernSpindle AssemblyandFunction
1077 TwoMechanismsCollaborateintheAssemblyof a
BipolarMitoticEnclosedOrganelles
TheCytoskeletonLocalizesSpecificRNAMolecules
CellsRegulateMotorProteinFunction Summary THECYTOSKELETONAND
CELLBEHAVIOR Slidingof Myosinll andActinFilamentsCausesMusclesto
Contract A SuddenRisein CytosolicCa2+ConcentrationInitiatesMuscle
Contraction HeartMusclelsa PreciselyEngineeredMachine of
theActinCytoskeleton
ExtracellularSignalsCanActivatetheThreeRhoProtein FamilyMembers
ExternalSignalsCanDictatetheDirectionof CellMigration
CiliaandFlagellaAreMotileStructuresBuiltfromMicrotubules andDyneins
1031 Constructionof theMitoticSpindleRequiresMicrotubule
DynamicsandtheInteractionsof ManyMotorProteins
ManyCellsCanCrawlAcrossA SolidSubstratum
ActinPolymerizationDrivesPlasmaMembraneProtrusion
CellAdhesionandTractionAllowCellsto PullThemselves Forward 1040
Membersof the RhoProteinFamilyCauseMajorRearrangements Soindle
CentrosomeDuplicationOccursEarlyin theCellCycle
M-CdkInitiatesSpindleAssemblyin Prophase TheCompletionof
SpindleAssemblyin AnimalCellsRequires NuclearEnvelopeBreakdown
MicrotubuleInstabilityIncreasesGreatlyin Mitosis
MitoticChromosomesPromoteBipolarSpindleAssembly
KinetochoresAttachSisterChromatidsto theSpindle
Bi-OrientationlsAchievedbyTrialandError
MultipleForcesMoveChromosomesontheSpindle
TheAPC/CTriggersSister-ChromatidSeparationandthe Completionof
Mitosis UnattachedChromosomesBlockSister-ChromatidSeparation:
TheSpindleAssemblYCheckPoint ChromosomesSegregatein AnaphaseA andB
Reproduction Summory CYTOKINESIS ActinandMyosinll
intheContractileRingGeneratethe Forcefor Cytokinesis
SegregatedChromosomesArePackagedin DaughterNucleiat Teloohase 1o9o
Meiosislsa SoecialFormof NuclearDivisionInvolvedin Sexual 1021 1022
1023 1025 1025 1026 1028 1031 1077 l 078 1078 1079 1080 1081 1082
1083 1085 1087 1088 1089 1034 1036 1037 1041 1043 1045 1090 1092
1092 1093CommunicationBetweentheMicrotubuleandActinCytoskeletons
CoordinatesWhole-CellPolarizationandLocomotion 1046
TheComplexMorphologicalSpecializationof NeuronsDepends
ontheCytoskeleton Summary Problems References Chapter17TheCellCycle
OVERVIEWOFTHECELLCYCLE
TheEucaryoticCellCyclelsDividedintoFourPhases
Cell-CycleControllsSimilarinAllEucaryotes
Cell-CycleControlCanBeDissectedGeneticallybyAnalysisof YeastMutants
Cell-CycleControlCanBeAnalyzedBiochemicallyin Animal Embryos
Cell-CycleControlCanBeStudiedin CulturedMammalianCells
Cell-CycleProgressionCanBeStudiedinVariousWays Summary
THECELL-CYCLECONTROLSYSTEM
TheCell-CycleControlSystemTriggerstheMajorEventsofthe CellCycle
1060 TheCell-CycleControlSystemDependsonCyclicallyActivated
Cyclin-DependentProteinKinases(Cdks) 1062
InhibitoryPhosphorylationandCdkInhibitoryProteins(CKls)
CanSuppressCdkActivity
TheCell-CycleControlSystemDependsonCyclicalProteolysis
Cell-CycleControlAlsoDependsonTranscriptionalRegulation
TheCell-CycleControlSystemFunctionsasa Networkof
BiochemicalSwitches Summaty 5 PHASE
S-CdkInitiatesDNAReplicationOncePerCycle
ChromosomeDuplicationRequiresDuplicationof Chromatin Structure
CohesinsHelpHoldSisterChromatidsTogether Summory MITOSIS
M-CdkDrivesEntryIntoMitosis
DephosphorylationActivatesM-CdkattheOnsetof Mitosis
CondensinHelpsConfigureDuplicatedChromosomesfor Separation
TheMitoticSpindlelsa Microtubule-BasedMachine LocalActivationof
RhoATriggersAssemblyandContractionof the ContractileRing 1094
TheMicrotubulesof theMitoticSpindleDeterminethe Planeof1047 1050
1050 1052 1053 1054 1054 1056 1056 1057 1059 1059 1060 1060
AnimalCellDivision ThePhragmoplastGuidesCytokinesisin HigherPlants
Membrane-EnclosedOrganellesMustBeDistributedto Daughter
CellsDuringCytokinesis SomeCellsRepositionTheirSpindleto
DivideAsymmetrically MitosisCanOccurWithoutCytokinesis
TheG1Phaselsa StableStateof Cdklnactivity Summary
CONTROLOFCELLDIVISIONAND CELLGROWTH MitogensStimulateCellDivision
CellsCanDelayDivisionbyEnteringa SpecializedNondividing
AbnormalProliferationSignalsCauseCell-CycleArrestor
Apoptosis,Exceptin CancerCells OrganismandOrganGrowthDependon
CellGrowth
ProliferatingCellsUsuallyCoordinateTheirGrowthandDivision
NeighboringCellsCompetefor ExtracellularSignalProteins
AnimalsControlTotalCellMassbyUnknownMechanisms Summary Problems
References Chapter18APoPtosis State 1103
MitogensStimulateGr-CdkandGrlS-CdkActivities 1103
DNADamageBlocksCellDivision:TheDNADamageResponse 1105
ManyHumanCellsHavea Built-lnLimitationontheNumber
ofTimesTheyCanDivide 1oo7 1095 1097 1098 1099 1099 1100 1101 11 0 1
1102 1107 r 108 1108 1 1 1 0 1 1 1 1 1112 1112 1 1 1 3 1115 1 1 1 8
1063 1064 I uof, 1065 't067 't067 1067 1069 1070 1071 1071 1071
1074 1075 1075 ProgrammedCellDeathEliminatesUnwantedCells 1115
ApoptoticCellsAreBiochemicallyRecognizable 1117
ApoptosisDependsonanIntracellularProteolyticCascade
ThatlsMediatedbYCasPases Cell-SurfaceDeathReceptorsActivatethe
ExtrinsicPathway ofApoptosis 1120 TheIntrinsicPathwayof
ApoptosisDependsonMitochondria 1121
Bcf2ProteinsRegulatetheIntrinsicPathwayof Apoptosis 1121
lAPsInhibitCaspases 1124
ExtracellularSurvivalFactorsInhibitApoptosisinVariousWays '1126
EitherExcessiveor InsufficientApoptosisCanContributeto Disease1127
Summary 1128 problems 1128 References 1129
19. Chapter19CellJunctions,CellAdhesion,and the
ExtracellularMatrix CADHERINSANDCELL-CELLADHESION
CadherinsMediateCa2+-DependentCell-CellAdhesionin AllAnimals
TheCadherinSuperfamilyinVertebratesIncludesHundredsof
DifferentProteins,IncludingManywithSignaling Functions
CadherinsMediateHomophilicAdhesion
5electiveCell-CellAdhesionEnablesDissociatedVertebrare Cellsto
ReassembleintoOrganizedTissues
CadherinsControltheSelectiveAssortmentof Cells
TwistRegulatesEpithelial-MesenchymaITransitions
CateninsLinkClassicalCadherinsto theActinCytoskeleton
AdherensJunctionsCoordinatetheActin-BasedMotilityof AdjacentCells
DesmosomeJunctionsGiveEpitheliaMechanicalStrenqth
Cell-CellJunctionsSendSignalsintotheCellInterior
SelectinsMediateTransientCell-CellAdhesionsinthe Bloodstream
Membersofthelmmunoglobulin5uperfamilyof proteins
MediateCa2+-lndependentCell-CellAdhesion ManyTypesof
CellAdhesionMoleculesActin parallelto Create a Synapse
ScaffoldProteinsOrganizeJunctionalComplexes Summary
TIGHTJUNCTIONSANDTHEORGANIZATIONOF EPITHELIA TightJunctionsForma
SealBetweenCellsanda FenceBetween MembraneDomains
ScaffoldProteinsinJunctionalComplexesplaya KeypartIn theControlof
CellProliferation
Cell-CellJunctionsandtheBasalLaminaGovernAoico-Basal Polarityin
Epithelia A SeparateSignalingSystemControlsplanarCellpolarity
Summary PASSAGEWAYSFROMCELLTOCELL:GApJUNCT|ONS AND PLASMODESMATA
GapJunctionsCoupleCellsBothElectricallyandMetabolically A
Gap-JunctionConnexonlsMadeUpof SixTransmembrane ConnexinSubunits
GapJunctionsHaveDiverseFunctions
CellsCanRegulatethePermeabilityofTheirGapJunctions In
Plants,PlasmodesmataperformManyof theSameFunctions asGapJunctions
Summary THEBASALLAMINA
BasalLaminaeUnderlieAllEpitheliaandSurroundSome
NonepithelialCellTypes Lamininlsa PrimaryComponentoftheBasalLamina
TypelVCollagenGivestheBasalLaminaTensileStrenoth
BasalLaminaeHaveDiverseFunctions Summary
INTEGRINSANDCELL-MATRIXADHESION
IntegrinsAreTransmembraneHeterodimersThatLinkto tne Cytoskeleton
IntegrinsCanSwitchBetweenanActiveandanInactive Conformation
IntegrinDefectsAreResponsiblefor ManyDifferentGenetic Diseases
IntegrinsClusterto FormStrongAdhesions
ExtracellularMatrixAttachmentsActThroughIntegrinsto
ControlCellProliferationandSurvival
IntegrinsRecruitIntracellularSignalingproteinsatSitesofCell-
SubstratumAdhesion IntegrinsCanProduceLocalizedIntracellularEffects
Summory THEEXTRACELLULARMATRIXOFANIMALCONNECTIVE TlsSuES 1178
TheExtracellularMatrixlsMadeandOrientedbytheCells Withinlt j179
Glycosaminoglycan(GAG)ChainsOccupyLargeAmountsof
SpaceandFormHydratedGels 1179 HyaluronanActsasa SpaceFilleranda
FacilitatorofCellMigration DuringTissueMorphogenesisandRepair 1180
ProteoglycansAreComposedof GAGChainsCovalentlyLinked to a
CoreProtein ProteoglycansCanRegulatetheActivitiesof
SecretedProterns Cell-SurfaceProteoglycansActasCo-Receptors
CollagensAretheMajorProteinsof theExtracellularMatrix
CollagenChainsUndergoa Seriesof Post-Translational Modifications
PropeptidesAreClippedOffProcollagenAfterltsSecretion to
AllowAssemblyof Fibrils
SecretedFibril-AssociatedCollagensHelpOrganizetheFibrils
CellsHelpOrganizetheCollagenFibrilsTheySecreteby
ExertingTensiononthe Matrix ElastinGivesTissuesTheirElasticitv
FibronectinlsanExtracellularProteinThatHelpsCellsAttach to
theMatrix 1191 TensionExertedbyCellsRegulatesAssemblyof Fibronectin
Fibrils FibronectinBindsto IntegrinsThroughanRGDMotif CellsHaveto
BeAbleto DegradeMatrix,asWellasMakeit
MatrixDegradationlsLocalizedto theVicinityof Cells Summary
THEPLANTCELLWALL TheCompositionof theCellWallDependsontheCellType
TheTensileStrengthof theCellWallAllowsPlantCellsto
DevelopTurgorPressure
ThePrimaryCellWalllsBuiltfromCelluloseMicrofibrils Interwovenwitha
Networkof PecticPolysaccharides
OrientedCell-WallDepositionControlsplantCellGrowth
MicrotubulesOrientCell-WallDeposition Summary Problems References
Chapter20 Cancer CANCERA5AMICROEVOLUTIONARYPROCESS
CancerCellsReproduceWithoutRestraintandColonize OtherTissues
MostCancersDerivefroma SingleAbnormalCell
CancerCellsContainSomaticMutations A SingleMutationlsNotEnoughto
CauseCancer CancersDevelopGraduallyfromIncreasinglyAberrantCells
CervicalCancersArePreventedbyEarlyDetection
TumorProgressionInvolvesSuccessiveRoundsof Random
InheritedChangeFollowedbyNaturalSelection
TheEpigeneticChangesThatAccumulatein CancerCellsInvolve
InheritedChromatinStructuresandDNAMethylation
HumanCancerCellsAreGeneticallyUnstable
CancerousGrowthOftenDependson DefectiveControlof
CellDeath,CellDifferentiation,or Both
CancerCellsAreUsuallyAlteredinTheirResponsesto DNA
DamageandOtherFormsof Stress HumanCancerCellsEscapea
Built-lnLimitto Cellproliferation A SmallPopulationof
CancerStemCellsMaintainsMany Tumors HowDoCancerStemCellsArise?
ToMetastasize,MalignantCancerCellsMustSurviveand Proliferateina
ForeignEnvlronment TumorsInduceAngiogenesis
TheTumorMicroenvironmentInfluencesCancer Development
ManyPropertiesTypicallyContributeto CancerousGrowth Summary I 131
1133 11 3 5 t t 5 0 1137 1 3 9 140 141 142 1142 1143 1"t45 1145
1146 1147 1148 1149 11 5 0 11 5 0 11 5 3 11 5 5 1157 11 5 8 11 5 8
11 5 8 11 5 9 11 6 1 11 6 1 1162 11 6 3 ^t't64 1164 11 6 5 't166
1167 1169 1169 1170 1"170 "1172 1174 1175 1176 11 7 7 1178 11 8 1
1182 1183 1184 1186 1187 't187 1189 1189 't't91 1193 1193 1194 1195
11 9 5 1195 't't97 1197 1199 1200 1202 1202 1204 1205 1205 1206
1207 I208 1209 1210 1211 1212 1213 1214 1215 1216 12'.t7 1217 1218
1220 1220 1222 1223 1223
20. THEPREVENTABLECAU5E5OFCANCER
Many,ButNotAll,Cancer-CausingAgentsDamageDNA
TumorInitiatorsDamageDNA;TumorPromotersDoNot
VirusesandOtherInfectionsContributeto a Significant Proportionof
HumanCancers ldentificationof CarcinogensRevealsWaysto Avoid Cancer
Summary FINDINGTHECANCER-CRITICALGENES Theldentificationof
Gain-of-FunctionandLoss-of-Function
MutationsRequiresDifferentMethods
RetrovirusesCanActasVectorsforOncogenesThatAlter CellBehavior
DifferentSearchesforOncogenesHaveConvergedonthe SameGene-Ras
Studiesof RareHereditaryCancerSyndromesFirstldentified
TumorSuppressorGenes
TumorSuopressorGenesCanAlsoBeldentifiedfromStudies ofTumors
BothGeneticandEpigeneticMechanismsCanInactivateTumor
SuppressorGenes GenesMutatedinCancerCanBeMadeOveractivein Many Ways
TheHuntforCancerCriticalGenesContinues Summary
THEMOLECULARBASISOFCANCER-CELLBEHAVIOR Studiesof
BothDevelopingEmbryosandGenetically EngineeredMiceHaveHelpedto
UncovertheFunctionof Cancer-CriticalGenes
ManyCancer-CriticalGenesRegulateCellProliferation
DistinctPathwaysMayMediatetheDisregulationof Cell-Cycle
ProgressionandtheDisregulationof CellGrowthin CancerCells
MutationsinGenesThatRegulateApoptosisAllowCancerCells to
SurviveWhenTheyShouldNot
Mutationsinthep53GeneAllowManyCancerCellsto Survive
andProliferateDespiteDNADamage DNATumorVirusesBlocktheActionof
KeyTumorSuppressor Proteins TheChangesinTumorCellsThatLeadto
MetastasisAreStill Largelya Mystery
ColorectalCancersEvolveSlowlyViaa SuccessionofVisible Changes A
FewKeyGeneticLesionsAreCommonto a LargeFractionof ColorectalCancers
SomeColorectalCancersHaveDefectsin DNAMismatchRepair
TheStepsofTumorProgressionCanOftenBeCorrelatedwith
SDecificMutations EachCaseof CancerlsCharacterizedbyltsOwnArrayof
Genetic Lesions Summary CANCERTREATMENT:PRESENTANDFUTURE
TheSearchforCancerCureslsDifficultbutNotHopeless
TraditionalTherapiesExploittheGeneticInstabilityandLossof
Cell-CycleCheckpointResponsesinCancerCells
NewDrugsCanExploittheSpecificCauseof aTumor'sGenetic Instability
GeneticInstabilityHelpsCancersBecomeProgressivelyMore
ResistanttoTherapies NewTherapiesAreEmergingfromOurKnowledgeof
Cancer Biology SmallMoleculesCanBeDesignedto
InhibitSpecificOncogenic Proteins
TumorBloodVesselsAreLogicalTargetsforCancerTherapy
ManyCancersMayBeTreatablebyEnhancingthelmmune ResponseAgainsta
SpecificTumor TreatingPatientswithSeveralDrugsSimultaneouslyHas
PotentialAdvantagesforCancerTherapy
GeneExpressionProfilingCanHelpClassifyCancersinto
ClinicallyMeaningfulSubgroups TherelsStillMuchMoreto Do 1264
Summory 1265 problems 1265 References 1267 Chapters21-25availableon
MediaDVD-ROM Chapter2t SexualReproduction:Meiosis,
GermCells,andFertilization OVERVIEWOFSEXUALREPRODUCTIOII 1269
TheHaploidPhasein HigherEucaryoteslsBrief 1269
MeiosisCreatesGeneticDiversity 1271
SexualReproductionGivesOrganismsa CompetitiveAdvantage 1271 Summary
1272 ME|OS|S 1272 GametesAreProducedbyTwoMeioticCellDivisions 1272
DuplicatedHomologs(andSexChromosomes)PairDuringEarly proohase1 1274
1224 1225 1226 1 2 2 7 1229 1230 1230 1231 1232 1233 1234 I l 5
> 1235 1237 1239 1240 1240 1241 1242 1244 1245 1246 1247 1249
1250 1251 1254 1254 I z)o Iz>o 1256 1257 1257 1257 1259 1260
1260 I loz | 202 | 205 1264 1269
HomologPairingCulminatesintheFormationof a Synaptonemal Complex
HomologSegregationDependson Meiosis-Specific,Kinetochore-
AssociatedProteins MeiosisFrequentlyGoesWrong
Crossing-OverEnhancesGeneticReassortment
Crossing-OverlsHighlyRegulated MeiosislsRegulatedDifferentlyin
MaleandFemaleMammals Summary PRIMORDIALGERMCELLSAND
sEXDETERMINATIONIN MAMMALS 1275 1276 1278 1279 1280 1280 1281 1282
SignalsfromNeighborsSpecifyPGCsin MammalianEmbryos 1282
PGCSMigrateintotheDevelopingGonads 1283
TheSryGeneDirectstheDevelopingMammalianGonadto BecomeaTestis 1283
ManyAspectsof SexualReproductionVaryGreatlybetween AnimalsPecies
1285 Summary 1286 EGGS 1287 AnEgglsHighlySpecializedfor
IndependentDevelopment 1287 EggsDevelopinStages 1288
OocytesUseSpecialMechanismsto Growto TheirLargeSize 1290
MostHumanOocytesDieWithoutMaturing 1291 Summary 1292 SPERM 't292
SpermAreHighlyAdaptedfor DeliveringTheirDNAto anEgg 1292
SpermAreProducedContinuouslyin theMammalianTestis 1293
SpermDevelopasa SYncYtium 1294 Summary 1296 FERTILIZATION 1297
EjaculatedSpermBecomeCapacitatedinthe FemaleGenitalTract 1297
CapacitatedSpermBindto theZonaPellucidaandUndergoan
AcrosomeReaction 1298 TheMechanismof Sperm-EggFusionlsStillUnknown
1298 SpermFusionActivatestheEggbyIncreasingCa2+intheCytosol 1299
Ti'reCorticalReactionHelpsEnsureThatOnlyOneSpermFertilizes theEgg
1300 TheSoermProvidesCentriolesasWellasltsGenometo theZygote1301
IVFandlCSlHaveRevolutionizedtheTreatmentof Human Infertility
Summary References Chapter22Developmentof Multicellular Organisms
UNIVERSALMECHANISMSOFANIMALDEVELOPMENT 1305
AnimalsShareSomeBasicAnatomicalFeatures 1307 1301 1303 1304
1305
21. MulticellularAnimalsAreEnrichedin proteinsMediatinoCell
InteractionsandGeneRegulation RegulatoryDNADefinestheprogramof
Development Manipulationof theEmbryoRevealstheInteractionsBetween
ItsCells Studiesof MutantAnimalsldentifytheGenesThatControl
DevelopmentalProcesses A
CellMakesDevelopmentalDecisionsLongBeforelt Shows aVisibleChange
CellsHaveRememberedPositionalValuesThatReflectTheir Locationin
theBody InductiveSignalsCanCreateOrderlyDifferencesBetween
InitiallyldenticalCells
SisterCellsCanBeBornDifferentbyanAsymmetricCell Division
PositiveFeedbackCanCreateAsymmetryWhereThereWas NoneBefore
PositiveFeedbackGeneratespatterns,CreatesAll-or-None
Outcomes,andProvidesMemory A SmallSetof
SignalingPathways,UsedRepeatedly,Controls DevelopmentalPatterning
MorphogensAreLong-RangeInducersThatExertGradedEffects
ExtracellularInhibitorsof SignalMoleculesShapetheResponse to
theInducer DevelopmentalSignalsCanSpreadThroughTissuein Severar
DifferentWays ProgramsThatAreIntrinsicto a
CellOftenDefinetheTime-Course of itsDevelooment
InitialPatternsAreEstablishedinSmallFieldsof Cellsano
RefinedbySequentialInductionastheEmbrvoGrows Summory
CAENORHABDITISELEGANS:DEVELOPMENTFRoMTHE
PERSPECTIVEOFTHEINDIVIDUALCELL
CaenorhabditiseleganslsAnatomicallySimple CellFatesinthe
DevelopingNematodeAreAlmostperfectly Predictable Productsof
Maternal-EffectGenesOrganizetheAsymmetric DivisionoftheEgg
ProgressivelyMoreComplexpatternsAreCreatedbyCell-Cell Interactions
MicrosurgeryandGeneticsRevealtheLogicof Developmental
Control;GeneCloningandSequencingRevealltsMolecular Mechanisms
CellsChangeOverTimeinTheirResponsivenessto DevelopmentalSignals
HeterochronicGenesControltheTimingof Development
CellsDoNotCountCellDivisionsinTimingTheirInternal Programs
SelectedCellsDiebyApoptosisaspartof theproqramof Development
Summary DROSOPHILAANDTHEMOLECULARGENETICSOF
PATTERNFORMATION:GENESISOFTHEBODYPLAN TheInsectBodylsConstructedasa
Seriesof SegmentalUnits DrosophiloBeginsltsDevelopmentasa Syncytium
GeneticScreensDefineGroupsofGenesRequiredforSpecific Aspectsof
EarlyPatterning Interactionsof
theOocyteWithltsSurroundingsDefinethe Axesof theEmbryo:theRoleof
theEgg-polarityGenes TheDorsoventralSignalingGenesCreatea
Gradientof a NuclearGeneRegulatoryprotern DppandSogSetUpa
SecondaryMorphogenGradientto RefinethePatternof theDorsalpartof the
Embrvo TheInsectDorsoventralAxisCorrespondsto theVeriebrate
VentrodorsalAxis ThreeClassesof
SegmentationGenesRefinetheAnterior_posterior
MaternalPatternandSubdividethe Embrvo TheLocalizedExpressionof
SegmentationGeneslsRegulated bya Hierarchyof PositionalSignals
TheModularNatureof RegulatoryDNAAllowsGenesto Have
MultipleIndependentlyControlledFunctions
HomeoticSelectorGenesCodeforDNA-BindingproteinsThat
lnteractwithOtherGeneRegulatoryProteins 1342
TheHomeoticSelectorGenesAreExpressedSequentially Accordingto
TheirOrderin theHoxComplex TheHoxComplexCarriesa PermanentRecordof
Positional Information
TheAnteroposteriorAxislsControlledbyHoxSelectorGenesIn
vertebratesAlso Summary ORGANOGENESISANDTHEPATTERNINGOF APPENDAGES
ConditionalandInducedSomaticMutationsMakeit possibleto
AnalyzeGeneFunctionsLatein Development BodyPartsof
theAdultFlyDevelopFromlmaginalDiscs
HomeoticSelectorGenesAreEssentialfortheMemoryof
PositionalInformationin lmaginalDiscCells
SpecificRegulatoryGenesDefinetheCellsThatWillForman Appendage
TheInsectWingDisclsDividedintoCompartments
FourFamiliarSignalingPathwaysCombineto Patternthe
WingDisc:Wingless,Hedgehog,Dpp,andNotch TheSizeof
EachCompartmentlsRegulatedbyInteractions AmongltsCells
SimilarMechanismsPatterntheLimbsofVertebrates LocalizedExpressionof
SpecificClassesof GeneRegulatory
ProteinsForeshadowsCellDifferentiation
LateralInhibitionSinglesOutSensoryMotherCellsWithin
ProneuralClusters
LateralInhibitionDrivestheProgenyoftheSensoryMotherCell
TowardDifferentFinalFates 857
PlanarPolarityofAsymmetricDivisionsisControlledbySignaling viathe
ReceptorFrizzled 1359
AsymmetricStem-CellDivisionsGenerateAdditionalNeurons
intheCentralNervousSystem 1359
AsymmetricNeuroblastDivisionsSegregateanInhibitorof Cell
Egg-Polarity,Gap,andPair-RuleGenesCreateaTransient
PatternThatlsRememberedbvOtherGenes Summary
HOMEOTICSELECTORGENESANDTHEPATTERNINGOF THEANTEROPOSTERIORAXIS The
Hox Code SpecifiesAnterior-PosteriorDifferences
DivisionintoJustOneoftheDaughterCells
NotchSignalingRegulatestheFine-Grainedpatternof
DifferentiatedCellTypesin ManyDifferentTissues
SomeKeyRegulatoryGenesDefinea CellType;OthersCan
ActivatetheProgramforCreationof anEntireOrgan Summary
CELLMOVEMENTSANDTHESHAPINGOFTHE VERTEBRATEBODY
ThePolarityoftheAmphibianEmbryoDependsonthepolarity of theEgg
CleavageProducesManyCellsfromOne GastrulationTransformsa
HollowBallof CellsintoaThree-Lavered Structurewitha PrimitiveGut
TheMovementsof GastrulationArePreciselypredictable
ChemicalSignalsTriggertheMechanicalProcesses ActiveChangesof
CellPackingProvidea DrivingForcefor Gastrulation ChangingPatternsof
CellAdhesionMoleculesForceCells IntoNewArrangements
TheNotochordElongates,WhiletheNeuralplateRollsUpro Formthe
NeuralTube A Gene-ExpressionOscillatorControlsSegmentationof the
MesodermlntoSomites
DelayedNegativeFeedbackMayGeneratetheOscillations
oftheSegmentationClock 1308 1309 13 1 0 1 3 11 1 3 11 1312 13 1 3 1
3 1 3 1314 t 5 t ) 13 1 6 13 1 6 1317 13 1 8 1 3 1 9 13 1 9 1320 13
2 1 't321 1322 1323 1324 | 5l) 1325 1326 1327 1327 1328 1328 1329
1330 1332 1333 1334 1336 1336 1336 1337 I 339 1340 1341 1341 1342
1343 1344 1344 1347 1347 1348 1349 t S f l 1351 1352 I 353 13s3
1355 1356 1357 1361 1362 1362 1363 1363 1364 l 365 I J O ) | 500
1367 1368 1369 1370 't371 1373 EmbryonicTissuesAreInvadedina
StrictlyControlledFashion byMigratoryCells 1373 TheDistributionof
MigrantCellsDependsonSurvivalFactors asWellasGuidanceCues 1375
22. Left-RightAsymmetryof theVertebrateBodyDerivesFrom
MolecularAsymmetryintheEarlyEmbryo Summary THEMOUSE
MammalianDevelopmentBeginsWitha SpecializedPreamble
TheEarlyMammalianEmbryolsHighlyRegulative
TotipotentEmbryonicStemCellsCanBeObtainedFroma MammalianEmbryo
InteractionsBetweenEpitheliumandMesenchymeGenerate
BranchingTubularStructures Summary NEURALDEVELOPMENT
NeuronsAreAssignedDifferentCharactersAccordingto the
TimeandPlaceWhereTheyAreBorn TheCharacterAssignedto a Neuronat
ltsBirthGovernsthe Connectionslt WillForm EachAxonor
DendriteExtendsbyMeansof aGrowthConeat ItsTip
TheGrowthConePilotstheDevelopingNeuriteAlonga Precisely
DefinedPath/nVlvo
GrowthConesCanChangeTheirSensibilitiesasTheyTravel
TargetTissuesReleaseNeurotrophicFactorsThatControlNerve
CellGrowthandSurvival NeuronalSpecificityGuidestheFormationof
OrderlyNeural Maps AxonsFromDifferentRegionsofthe
RetinaRespondDifferently to aGradientof
ReoulsiveMoleculesintheTectum DiffusePatternsof
SynapticConnectionsAreSharpenedby Activity-DependentRemodeling
ExperienceMoldsthePatternof SynapticConnectionsinthe Brain
AdultMemoryandDevelopmentalSynapseRemodelingMay
DependonSimilarMechanisms Summary PLANTDEVELOPMENT
ArabidopsisServesasa ModelOrganismforPlantMolecular Genetics fhe
ArabidopsisGenomelsRichin DevelopmentalContro Genes
EmbryonicDevelopmentStartsbyEstablishinga Root-Shoot
AxisandThenHaltsInsidetheSeed ThePartsof a
PlantAreGeneratedSequentiallybyMeristems De
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