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CHAPTER 14
Cellular Reproduction
1
Overview of the cell cycle
DNA replicationDNA Damage and repair
Nuclear and Cell Division
Regulation of the Cell cycleGrowth Factors and Cell Proliferation
WILL NOT BEIncluded in the exam
2
Introduction
• Cells reproduce by the process of cell division.
• Mitosis leads to cells that are genetically identical to their parent.
• Meiosis leads to production of cells with half of the genetic content of the parent.
3
14.1 The Cell Cycle (1)
• The cell cycle is the series of stages that a cell goes through. It consists of the M phase and the interphase.
– The M phase includes the process of mitosis and cytokinesis.
– Mitosis last about an hour or so.
– Interphase constitutes the majority of the cell cycle and lasts longer than the M phase (~23 hrs);
– it may extend for days, week, or longer.
4
An overview of the eukaryotic cell cycle
5
The Eukaryotic Cell Cycle
Cell growth === Cell division=== Cell proliferation
-Duplication of DNA-Replication of DNA-DNA synthesis
---Mitosis/ Cytokinesis---Regulation of Cell cycle
Cell cycleMitosis ~0.5 hrs1-Starts--condension the chromatin2a-sister chromatids2b-nuclear envelop disorganize2c-mitotic spindle3-cytokinesis
G1 8 to 10 hrs
S 6 to 8 hrs
G2 4 to 6 hrs
~23.5 hrs
Go: the cell is out the cell cycle
GoTerminal differentiation
-Protein synthesis ?
6
The Cell Cycle (3)
• Cell cycles in vivo
– Three cell types are distinguished based on their capacity to grow and divide.
• Nerve cells have lost the ability to divide, but not all of them.
• Liver cells divides in function of stimulus
• Stem cells will divide frequently.
– Stem cells have asymmetric cell division in which the daughter cells have different fates.
7
The Cell Cycle (4)
• Control of the Cell Cycle
– Cell cycle is focused on initiation of DNA replication and initiation of mitosis.
– The cytoplasm contains factors that regulate the state of the nucleus.
• The cytoplasm of a replicating cell contains factors that stimulate initiation of DNA synthesis.
• The cytoplasm of a cell undergoing mitosis contains factors that trigger chromosomal condensation.
8
The stages of mitosis in animal and plants cells
9
Microtubule Polarity in the Mitotic Spindle
Polarity of MT
10
Microtubule Polarity in the Mitotic Spindle
Chromosome alignment and separation
Separated by microtubules, also requires additional proteins like Topoisomerase II, changes in adhesive proteins, (anaphase)and motor proteins (three different roles--mitotic motors-)
11
Mitotic Motors
1. Kinetochore microtubulesPlus & minus ends
Depolymerases binds MT and induces depolymerization(chromokinesin, C-terminal and bipolar kinesin)
2. Polar microtubules
ATP hydrolysis is require for MT sliding (C-terminal and bipolar kinesin)
3. Astral microtubules
MT associated (cytoplasmic dynein) with cell cortex at plasma membrane (actin microfilaments)Taxol: it blocks MT
depolymerization12
Cytokinesis and Cell Plate Formation in a Plant Cell
Youtube====50-year cell division puzzle solved
Vesicles from Golgi and ER
13
Typical eukaryotic cell cycle --- G1, S, G2, M
---Control / Regulation Systems:
1--Appropriate time and sequence of events2--Each event must be completed3--Respond to external conditions (nutrients and growth factors)
Cell cycle control: Key Transition Points in the Cell Cycle
1
2 3
Chromosome segregation
14
Cell Fusion Evidence for the Role of Cytoplasmic Chemical Signals in Cell Cycle Regulation
Specific moleculespresent in the cytoplasmthat induce the transformation
from S to G1(DNA replication genes=proteins)
from M to G1(cell cycle regulation genes=proteins)
Gene: cdc2=cell division cycle--regulate the transition from G2 to M--cdc2: protein kinase
Regulation by phosphorylation?
15
Experimental demonstration that cells contain factors that stimulate entry into mitosis
16
Cell Cycle Regulation
Mitotic M-cyclinsMitotic M-cdks
S cyclins
G1 cyclinsG1 cdks
http://www-rcf.usc.edu/~forsburg/cclecture.html
How is the cell cycle regulated?
Cdc2 (Cell Division Cycle ) =kinase
Kinase
PhosphataseSubstrate(P1)
Substrate(P2)
(Cyclins)=substrate
(Cyclin-dependent kinase)-CDK-
Cdc=cdk 17
Evidence for the Existence of MPF
Maturation promoting factor=MPF=mitotic cdk-cyclin complex
----control the G2 to M transition
18
Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
Maximal Enzymatic Activity during the G2-M transition
Substrate: degradation or synthesis?
Regulation: phosphorylation or de-phosphorylation?
CDK Rel
ativ
e ac
tivity
19
Phosphorylation and Dephosphorylation in the Activation of a Cdk-Cyclin Complex
Ser= variableThr= 161Tyr=15
MPF-i
mitotic cdk-cyclin complex=MPF
MPF-a
20
Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
Maximal Enzymatic Activity during the G2-M transition
Substrate: degradation or synthesis?
Regulation:?
Rel
ativ
e ac
tivity
CDK
21
The Mitotic Cdk Cycle
1-Phosphorylation of lamin in the nuclear lamina induces depolarization
2-Phosphorylation of condensin induces chromosome condensation
3-Phosphorylation of MT induces polymerization
4-Phosphorylation of Anaphase promoting degradation complex.-APC-(ubiquitin ligase)
Cell Cycle Control-I
22
The Anaphase-Promoting Complex and the Spindle Checkpoint
Mitotic CDK-cyclin
Anaphase promoting complex(ubiquitin ligase)
23
The Anaphase-Promoting Complex and the Spindle Checkpoint
Regulation of the anaphase promoting complex:Binding with cdc20
APC cdc20
24
APC cdh1
-degradate mitotic cyclins
SCF controls G1/S through G2/M transitionsUbiquitin ligase-degradation.
SCF
complex
complex
p27 and p21 (cyclin-dependent-kinase inhibitors (CKIs) G1/S cyclin, Cyclin E
25
Role of the Rb (Retinoblastoma) Protein in Cell Cycle Control
Cell Cycle Control-II
G1 cdk cyclin
26
Cell Cycle Regulation
Mitotic M-cyclinsMitotic M-cdks
S cyclins
G1 cyclinsG1 cdks
How is the cell cycle regulated?
, 6
/A
27
DNA Damage: p53-dependent and independent pathways
---DNA damage: ?? can not be repaired--
Cell Cycle Control-III
ATM kinase=ataxia telangiectasia mutated/mutation
ATM=Ionizing radiation
28
ATR= UV radiation
ATR kinase: Inactivation of cyclin
DNA Damage: p53-dependent and independent pathways
29
http://www.epa.gov
30
1. Spindle checkpoint
Kinetochore attachmentMad, Bub, Cdc20
2. DNA replication checkpoint
Completion of DNA synthesisG2/M transitionPhosphorylation of mitotic cyclin
3. DNA damage checkpoint
Cell cycle halted at various stagesp53 – guardian of the genome
Checkpoints=Cell Cycle Control
TimerCdkCyclins
A. DNA integrity (DNA damage)
B. Processes(complete)
31
General Model for Cell Cycle Regulation
RegulationNutrients
MitogensEGFPDGF
APC complex
Growth factorsExtra-cellular signals
APC / SCF complex
32
Growth Factor Signaling via the Ras Pathway
-bacteria and yeast cell proliferation/division
-mammalian cells cell proliferation/division
Nutrients
Glucose
Growth factor = mitogens
33
Growth Factor Signaling via the Ras Pathway
34
Growth Factor Signaling via the Ras Pathway
Raf=MAPkkk
MEK=MAPkk
ERK=MAPk
Mitogenic Activated Protein
Serine/Threonine
PM or endosomes
Tyrosine
35
The PI3K-Akt Signaling Pathway
Insulin (I) and Insulin-like growth factor (IGF)
36
EGF/ PDGF TGF-
(+) (-)
Cell Growth / Proliferation
Mothers Against Decapentaplegic (MAD)Small Mothers Against paralysis (SMA)
Phosphorylation of Smad
Activation of p27, p21 and p15 (Cdk inhibitors)
MAPK
37
38