Cell Biology: The Cell Division Cylce

7/22/2019 Cell Biology: The Cell Division Cylce

1/56

Chapter 18The Cell Division Cycle

EssentialCell Biology

Third Edition

Copyright Garland Science 2010


2/56

Cell duplicates its contents and then dividesin two

Essential mechanism by which ALL living

things reproduce Bacteria and yeast - each cell division

produces new organism

Many rounds cell division required formulticellular organisms

Cell Cycle

Sarah E Golding PhD.


3/56

Figure 5-17 Essential Cell Biology ( Garland Science 2010)

One copy of a chromosome formed by DNA replication

that is still joined at the centromere to the other copy


Compact Mitotic Chromosome

During S-phase the chromosomesare copied

Each Early M-phase chromosome

has two sister chromatid (exact

copies)

The chromatids are joined

together at the centromere

Telomeresform caps at the ends

of each chromatid


4/56


Steps of Cell Division



5/56


Eukaryotic Cell Cycle Divided into Four Phases:

G1, S and G2 = Interphase

2.

3.

4.

Interphase: All the rest!



6/56


Eukaryotic Cell Cycle Divided into Four Phases:

M-Phase: Cell division- Mitosis



7/56

Events of cell cycle occur in proper orderand that each has been completed before

advancing to the next

Must have DNA Replication before Mitosis

Critical checkpoints = molecular brakes

Ensure each phase is completed properly beforestarting next phase

Cell-cycle control system



8/56


Nutrients and growth factors?

Cell cycle check points


Intra SThe DNA damaged

so badly that

replication needs to

be slowed for repair?


9/56

Cdks - kinases of the cell cycle control system

Activated at appropriate times in cell cycle & thenare quickly deactivated

Cyclins - no enzymatic activity but have to bind toCdks to make them enzymatically active

***Cyclin-Cdk complexes

Trigger entry into S phase or M phase

Cell cycle control mechanisms are highly conservedthrough evolution

Cyclin-dependent Protein Kinases- Cdks



10/56


Cdks bind cyclins


Cdksmust bind to the regulatory

cyclin proteins to become active

Once active the Cdk/Cyclin

complex phosphorylates proteins

required to drive the cell cycle

forward

This process acts as molecular

checks and balances ensuring all

is ready before the cell proceeds

Changes in cellular concentrations

of cyclins controls the cell cycle

(controlled by translation and

protein degradation)


11/56


Kinases drive the cell cycle


During interphase the cell makes cyclins

When the cell needs to transition to mitosis Cdksactivate cyclin activity

Changes in cellular concentrations of cyclins controls the cell cycle

(controlled by translation and protein degradation)


12/56


Phosphorylation controls cyclin-CdK activity


For a Cdk to be active it must be phosphorylated at one site to become primed for action

Think starting the engine of the car

While the cell is preparing 2 INHIBITORY phosphates are also places on the complex

Think putting the parking break on while you adjust your mirror, put on seat belt, put into

gear

At the correct moment the inhibitory phosphates are quickly removed by a phosphatase

and the cyclin-Cdk complex is active

The parking break comes off and the car moves forward


13/56

Table 18-2 Essential Cell Biology ( Garland Science 2010)

Different cyclinscontrol differentcell cycle phases


These complexes are formed in response to extra-cellular signals that tell the cell its

time to divide

Different cell types divide in response to different stimuli! What if we could

stimulate neurons to divide?You need to know these!


14/56

Figure 18-10 Essential Cell Biology ( Garland Science 2010) Sarah E Golding PhD.

Different cyclinscontrol differentcell cycle phases


15/56


Cyclin proteins are degraded by proteolysis tohelp regulate the timing of the cell cycle


Remember: Ubiquitination is the cellular signal to degrade a protein


16/56

G0 Phase

Terminal Differentiated State

Withdraw TEMPORARILY

The resting phase


Not all cells are actively growing and dividing all the time

Liver cells divide every year or so ---

Gut cells divide once every 12 hrs --- Actively growingSome cells never divide, such as neurons ---

(might not be as true as we first thought!)

What if we could stimulate this?

G0 also referred to as quiescence

Transition out of G0 requires accumulation of G1 cyclins (induced by signals from

the environment)


17/56

S-phase



18/56

Synthesis - DNA Replication

DNA Replication begins where??????

S-phase



19/56

Origin Recognition Complex (ORC) - remains bound to origins or

replication throughout the cell cycle - serves as a landing pad forregulatory proteins that bind before the S phase

Cdc6 - regulatory protein. Concentration increases in early G1binding of Cdc6 promotes binding of additional proteins to

form a pre-replicative complex

S-Cdk involved in initiating DNA replication!



20/56 Sarah E Golding PhD.

How is S-phase initiated?

S-Cdk triggers S-phase by

facilitating the activation ofthe replication machine

Cdc6 helping assemble the

machinary

S-Cdk also stops re-

replication at the same originby inducing the degradation

of cdc6

You need to know this!


21/56


Hold together sister chromatids

Vital to correct division of the chromosomes

** Assemble along the length as DNA is replicated

Cleaved in late mitosis

What would happen if cohesin rings were defective?

ERRORS in chromosome segregation

Cohesins tie together the replicated chromosome



22/56

M-phase


http://www.youtube.com/watch?v=ZEwddr9ho-4
http://www.youtube.com/watch?v=ZEwddr9ho-4http://www.youtube.com/watch?v=ZEwddr9ho-4http://www.youtube.com/watch?v=ZEwddr9ho-4http://www.youtube.com/watch?v=ZEwddr9ho-4http://www.youtube.com/watch?v=ZEwddr9ho-4


23/56


M-phase is triggered by M-Cdk


M-Cdk triggers the condensation of the chromosomes (tightens the chromatin)

Similar regulation to S-Cdk, receives an activating phosphate and an inhibitoryphosphate keeping the complex INACTIVE (again starting engine but with

parking break on!)

Complex activity is induced by the phosphatase Cdc25 removing a phosphate



24/56


M-Cdk positively feeds back to further increasemitotic signals


Active M-Cdk can positively feed

back on itself by activatingadditional cdc25 to AMPLIFY the

mitotic response

Cdc25 activity can be influenced

by signals from the environmentvia MAPK cascades to increase or

decrease mitotic events!


25/56


M-Cdk triggers the assembly of condensin complexes

onto DNA phosphorylating some of the condensin

subunits

Condensins assemble on each individual chromatid at the

start of M phase - coil up the DNA to help chromatids

condense

Condensins help condense chromatin



26/56


You should have this memorized


27/56




28/56



Form metaphase plate


29/56




30/56


cytokinesismitosis

Two transient cytoskeletal structures mediate

M-phase in animal cells



31/56


Chromosomal segregation is facilitated by thecytoskeleton


3 different types of Microtubules are involved


32/56


Cohesion rings are cleaved allowing sisterchromatids to separate to the opposite poles of the

cell



33/56


The centrosome cycle


REMEMBER? Centrosome is themajor micro-tubule organizing

center

It must be duplicated to allow each

cell to receive a centrosome

Forms the two poles of the cell

As the 2 centrosomes separate they

produce an array of microtubles the

aster


34/56


Mitotic spindle assembly


REMEMBER?Microtubules continuously

growing and shrinking Dynamic

Instability

During M-phase microtubules are very

actively growing/shrinking from both

centrosome forming spindle poles

At some point microtubules interact with

tubules from the opposite centrosome and

stabilize

This forms interpolar microtubules

Interpolar microtubules assembly is driven

by large motor proteins that crosslink and

stabilize


35/56


Prometaphasenuclear membrane degrades and Kinetochoresattach chromosomes to the mitotic spindle


Prometaphase begins with

the breakdown of nuclearpores and the nuclear

lamina

The spindle microtubles

are already being formed

As the nuclear membrane

breaks down the spindle

gain access to the

chromosomes and capture

them

Spindle bind via

Kinetochores at the

centromeres (one on each

chromatid)


36/56


Metaphasechromosomes line up halfway between poles

Anaphase - Sister chromatids separate


Chromosomes lines up halfway between the spindle during metaphase

Chromosomes then oscillate back and forth in a tug of war towards the opposite

spindles


37/56


Chromosome separation is triggered by APC


APCAnaphasepromoting complex

Anaphase is initiated by

the release of cohesins

Catalyzed by Separase

APC degrades securin

which allows separase to

become active which

degrades the cohesin

rings



38/56


Breakdown and reformation of the nuclear membrane


During prometaphase

nuclear pore proteins and

lamins are phosphorylated

causing them to separate the

membrane is broken down

into vesicles

During telophase thevesicles reform the

membrane and pore proteins

and lamins are

dephosphorylated to reform

the nuclear membrane

Once reformed nuclear

proteins are pumped in and

the chromosomes

decondense allowing

transcription to occur again


39/56


The cell is divided in 2 by the contractile ring



40/56

Figure 18-35ac Essential Cell Biology ( Garland Science 2010)

Cytokinesis in plant cells involves formation of the a few cell wall



41/56

Organelles must be divided too!


- Mitochondria and chloroplasts duplicate by division similar to cell division

- They are present in large enough numbers to be equally distributed when the newcell is formed

- The ER is continuous with the nuclear membrane it is released from the nuclear

membrane but remains intact

- It is cut in two during cytokinesis

- The Golgi is fragmented during M and the fragments associate with the spindle

microtublesby motor proteins hitching a ride! to the poles

- Soluble proteins in the cytoplasm are inherited randomly during cytokinesis


42/56

But how is cell size and number controlled?


????????????????????????????

Dynamic balance between, cell growth, cell division and cell death

A i d ll d h


43/56


Apoptosisprogramed cell death


Cell suicide Controlleddeath process

Initiates a regulated death process in response to cell signals

Amount of normal apoptosis astonishing

of nerve cells de during development

Billions of gut and bone marrow cells die in humans each day

Why?????????

Separate structure?

A i d ll d h


44/56




Cell suicide Controlleddeath process

Initiates a regulated death process in response to cell signals

Amount of normal apoptosis astonishing

of nerve cells de during development

Billions of gut and bone marrow cells die in humans each day

Why?????????

Because those cells arent needed anymore?

A i d ll d h


45/56




To perfectly control organ size?

Can resect the liver and it will regrow

Expose human liver to phenobarbital liver

will enlarge

Remove drug and the liver will return to its

natural size (within a week or so)

Organ size is regulated by a balance between

the rate of cell birth and the rate of cell death

A i i k d l


46/56


Apoptosisquick and clean


Necrosismessy!The result of injury

Causes inflammation and

damage to neighbors

Apoptosisquick, clean, environmentally safe!

No effect on surrounding cells

cleaned up by phagocytes

Organic material can be recycled


47/56


Apoptosis regulated by intracellular proteolytic cascade


Conserved

Caspases = family of proteases

Inactive precaspases cleaved in

response to cellular signals

Initiate caspase cascades amplifyingthe response

They then break down nuclear lamina

and other cytosolic proteins to

dismantle the cell

Irreversible! And tightly controlled


48/56


Apoptosis is regulated by Bcl-2 family of proteins


The grim reapers! pro-deathActivated by death signals

Release cytochrome C from mitochondria

which activates caspases

Bear Grylles of the cell! Pro-survival!

Block caspase activation

By blocking release of Cytochrome C

Know some of these!


49/56


Bak and Bax stimulate formation of the apoptosome




50/56

But where do the life verses death signals comefrom?


Dynamic balance between, cell growth, cell division and cell death

Life/growth

Cell Death


51/56

Cell must receive signals from their environment!


Unicellular organisms such as Bacteria and yeast grow as fast as they canProliferation rate is controlled by:

- Availability of nutrients

- Space

In multi-cellular organisms growth is controlled- Nutrients are needed by are not enough to cause cell division

- Must receive signals, usually from surrounding cells in the form of soluble proteins

(Pro) Survival factorssuppress apoptosis

Mitogensstimulate cell division by overriding cell cycle checkpoints

Growth Factors stimulate cell growth (increase in size and mass) by promoting geneexpression and suppressing protein degradation

Not mutually exclusive many signaling molecules often stimulate more than one

C ll d h dj h b f d l i


52/56


Cell death adjusts the number of developing neurons toensure sufficient target cells


Similar strategies used in other tissues during development and adulthood

Survival factors from other cells influence cell fate by


53/56


Survival factors from other cells influence cell fate bybinding to cell surface receptors


Mitogens stimulate cell division


54/56


Mitogens stimulate cell division


Mitogens usually secreted proteins that bind to cell surface receptors and initiate cell

signaling pathways to release cell cycle checkpoints (usually G1/S)

Rb acts as transcriptional repressor

Activated G1/S-CdK phosphorylates Rb releasing inhibition allowing transcription, translation and

cell proliferation to occur

You need to know

this!

Growth factors stimulate cells to grow


55/56


Growth factors stimulate cells to grow



Facilitate the growth of the cell by

promoting protein synthesis andblocking degradation

Some growth factors can

stimulate growth and cell division

Eg EGF PDGF NGF FGF


Growth factors can also tell cells to stop growing!


56/56

Growth factors can also tell cells to stop growing!

Myostatin is an inhibitory growth factor that tells our muscles when to stop growing!

These show cows breed for muscles mass where shown to have mutations of their

myostatin genes

Documents

Cell Biology: The Cell Division Cylce