Cell Cycle 2010cj

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Regulation ofCell cycle

J uan Chen

2010.10


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The cell cycle is the series

of events that take place in a

cell leading to its division andduplication. We also call it

cell-division cycle.

Whats the cell cycle?


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In eukaryotes, the cell cycle can be divided in two brief periods:

interphaseduring which the cell grows, accumulating nutrients

needed for mitosis and duplicating its DNA

mitosis phase (M), during which the cell splits itself into twodistinct cells, often called "daughter cells".

G1 - first gap

S - DNA synthesis

(replication)

G2 - second gap

M - mitosis


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Section 1

History of cell cycle


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1RaoJohnson(1970) discovered prematurelycondensed chromosomePCC)

Figure: Micrographs of chromosomes from hybrid cellsleft panel S-phase cell + M-phase cell;right panel M-phase cell + G1 phase cell.

Conclusion: there are diffusible factors

that can promote S or M phase. The S phase

promoting factor only works on G1 nuclei. The M phase promoter works on everything.


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2 Lohka MJ, Hayes MK, Maller JL (1988)Purification of maturation-promoting factorMPF,an intracellular regulator of early mitotic events.

Maturation-promoting factor consists of 45 kDa and 32 kDa subunits.


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Nurse P (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene c d c 2.Nature 327: 31-5

Hartwell LH, et. al. (1974) Genetic control of the cell divisioncycle in yeast----

CDC28 gene . Science 183: 46-51

Hunt T (1983) Cycl in: a protein specified by maternal mRNA

in sea urchin()

eggs that is destroyed at each cleavage

division. Cell 33: 389-96


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MPF=CDC2(CDK1)+Cyclin B


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Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse

won the 2001 Nobel

Prize in Physiology or Medicine

for their discovery of these central molecules.
http://en.wikipedia.org/wiki/Leland_H._Hartwellhttp://en.wikipedia.org/wiki/R._Timothy_Hunthttp://en.wikipedia.org/wiki/Paul_M._Nursehttp://en.wikipedia.org/wiki/Paul_M._Nursehttp://en.wikipedia.org/wiki/Paul_M._Nursehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicinehttp://en.wikipedia.org/wiki/Paul_M._Nursehttp://en.wikipedia.org/wiki/R._Timothy_Hunthttp://en.wikipedia.org/wiki/Leland_H._Hartwell


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Section 2

Cell Phases


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The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (known as interphase) and M phase (mitosis).
http://en.wikipedia.org/wiki/G1_phasehttp://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/G2_phasehttp://en.wikipedia.org/wiki/G2_phasehttp://en.wikipedia.org/wiki/Interphasehttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Interphasehttp://en.wikipedia.org/wiki/G2_phasehttp://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/G1_phase


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Activation of each phase is dependent

on the proper progression. Cells that have

temporarily or reversibly stopped dividing

are said to have entered a state of

quiescence called G0 phase.

Abb i ti


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State Phase Abbreviation Description

quiescent/

senescent

Gap 0 G0 A resting phase where the cell has left the cycle and has stopped

dividing.

Interphase Gap 1 G1 Cells increase in size in Gap 1. The G1 checkpointcontrol

mechanism ensures that everything is ready for DNA synthesis.

Synthesis S DNA replication occurs during this phase.

Gap 2 G2 During the gap between DNA synthesis and mitosis, the cell will

continue to grow. The G2 checkpointcontrol mechanism ensures

that everything is ready to enter the M (mitosis) phase and

divide.

Cell division Mitosis M Cell growth stops at this stage and cellular energy is focused on

the orderly division into two daughter cells. A checkpoint in the

middle of mitosis (Metaphase Checkpoint) ensures that the cell

is ready to complete cell division.


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After cell division, each of the daughter

cells begin a new cycle. Although the

various stages of interphase

are not

usually morphologically distinguishable,

each phase of the cell cycle has a set of

specialized biochemical processes

that

prepare the cell for initiation of cell

division.


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Interphase

G1 phase

S phase

G2 phase


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G1 phase

The first phase within interphase, from the end of theprevious M phase until the beginning of DNA synthesis is

called G1. It is also called the growth phase.

This phase is marked by synthesis of various enzymes that

are required in S phase, mainly those needed for DNA

replication.
http://en.wikipedia.org/wiki/G1_phasehttp://en.wikipedia.org/wiki/G1_phase


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S phase

The ensuing S phase

starts when DNA

synthesis commences;

when it is complete, all of the chromosomes have beenreplicated.During this phase, the amount of DNA in the cell haseffectively doubled, though the ploidy of the cell remainsthe same. Rates of RNA transcription

and protein synthesis

are very low during this phase. An exception to this ishistone production, most of which occurs during the S phase.
http://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/S_phasehttp://en.wikipedia.org/wiki/S_phase


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G2 phase

The cell then enters the G2 phase, which lasts until the

cell enters mitosis.

Significant protein synthesis occurs during this phase,

mainly involving the production of microtubules,

which are required during the process of mitosis.

Inhibition of protein synthesis during G2 phase prevents

the cell from undergoing mitosis.
http://en.wikipedia.org/wiki/G2_phasehttp://en.wikipedia.org/wiki/G2_phase


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Mitosis (M Phase)

M phase

consists of nuclear division and cytoplasmic

division

(cytokinesis).

It is generally followed by cytokinesis, which divides the nuclei,

cytoplasm, organelles

and cell membrane into two daughter cells

containing roughly equal shares of these cellular components.

Mitosis and cytokinesis

together define the M phase

of the cell cycle

- the division of the mother cell into two daughter cells, geneticallyidentical to each other and to their parent cell.
http://en.wikipedia.org/wiki/M_phasehttp://en.wikipedia.org/wiki/M_phasehttp://en.wikipedia.org/wiki/M_phasehttp://en.wikipedia.org/wiki/M_phase


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Section 3

Regulation of eukaryotic cell cycle


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Regulation of the cell cycle involves processes crucial to the survival of a cell,

including the detection and repair of genetic damage.The molecular events that control the cell cycle are ordered and directional.


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Two key classes of regulatory molecules

determine a cell's progress through the cell

cycle:

cyclins

cyclin-dependent kinases (CDKs),.
http://en.wikipedia.org/wiki/Cyclinhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin


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Cyclins

are a family of proteins

which control the

progression of cells through the cell cycle byactivating cyclin-dependent kinase (Cdk)enzymes.

Whats the Cyclins?
http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Protein


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St ruc tu re

Cyclins contain two domains of similar fold, the first located atthe N-terminus and the second at the C-terminus.


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Cyclins form the regulatory subunits and CDKs thecatalytic subunits of an activated heterodimer;

When activated by a bound cyclin, CDKs perform acommon biochemical reaction called phosphorylation

that activates or inactivates target proteins into thenext phase of the cell cycle.

Mec hanism of Cyc l ins
http://en.wikipedia.org/wiki/Heterodimerhttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Heterodimer


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Ex press ion o f cyc l ins in ce l l c yc le


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Cyclin-dependent kinases (CDK) belong to a group ofprotein kinases originally discovered as being involvedin the regulation of the cell cycle.

CDKs

phosphorylate

proteins on serine

and threonineamino acid residues: they are serine/threonine

kinases.

A cyclin-dependent kinase is activated by associationwith a cyclin, forming a cyclin-dependent kinase

complex.

Whats the Cyclin-dependent kinases

(CDKs)?
http://en.wikipedia.org/wiki/Protein_kinasehttp://en.wikipedia.org/wiki/Protein_kinasehttp://en.wikipedia.org/wiki/Protein_kinasehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Serinehttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Serinehttp://en.wikipedia.org/wiki/Threoninehttp://en.wikipedia.org/wiki/Threoninehttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclinhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinase_complexhttp://en.wikipedia.org/wiki/Cyclinhttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Serine/threonine_kinaseshttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Threoninehttp://en.wikipedia.org/wiki/Serinehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Protein_kinase


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Main groups of cyclins and CDKsmammalian yeast

Cyclin CDK Cyclin CDKG1

-CDK Cyclin

D* CDK4 6 Cln

3 CDK1(CDC28)

G1

/S-CDK Cyclin E CDK2 Cln 12 CDK1(CDC28)S-CDK Cyclin A CDK2 Clb 56 CDK1(CDC28)M-CDK Cyclin B CDK1(CDC2) Clb 1-4 CDK1(CDC28)CDK3we dont know the function;CDK5 occur in neurons= CDK1CDK7 can regulate TFIIH activity


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Role of cyclins and CDKs in cell cycle


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1. G1 phaseG0

Growth factors stimulate

CyclinD and CDK4/6 expression

Mid G1

Across restriction site

Late G1

S

CDK2-CyclinE expression and across G1/S

checkpoint

Phosphorylation ofRbrelease E2Finitiatestructure genes expression such as cyc l i nEA andCDK1


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2. S phase

Cyclin A and CDK2 form a complex.

Function DNA replication


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4. M phase

In the late M phase , CyclinB was

degradedMPFwas inactivated.

CDK1-CyclinB complex


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Cyclin B degradation in M phase

()

()

()

()

anaphase-promoting complexAPC

APC

CDK1


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Growth

Facto r

CDK1

CDK1

CDK2

CDK2


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Mec han ism of Regu la t ion

1. A cyclin-CDK complex can be regulated by

the protein synthesis .


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CDK1Thr14Tyr15Thr161

P34CDK1

cyclinB

P34CDK1

cyclinB

T14 Y15T161

P34CDK1

cyclinB

T14 Y15T161

P

P34CDK1

cyclinB

T14 Y15T161

CAK

P P P

P80CDC25

weel

MPF MPF MPF

CDC25


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Regulation of CDK1 activity


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CKIsCDK-Inhibitors

Ink4 (Inhibitor of cdk 4):P16ink4aP15ink4bP18ink4cP19ink4d

The INK4

binds to CDK4 and arrests the cell

cycle in G1 phase.


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The cip/kipfamily includes the genes p21, p27 andp57. They stop cell cycle in G1 phase, by binding to,and inactivating, cyclin-CDK complexes.

p21 is activated by p53

(which, in turn, is triggered

by DNA damage eg. due to radiation). p27 is

activated by Transforming Growth Factor (TGF

), a growth inhibitor.

Cip(CDK-interacting protein )/ K ip(Kinaseinhibition protein)
http://en.wikipedia.org/wiki/P21http://en.wikipedia.org/wiki/TGF_%CE%B2http://en.wikipedia.org/wiki/TGF_%CE%B2http://en.wikipedia.org/wiki/TGF_%CE%B2http://en.wikipedia.org/wiki/TGF_%CE%B2http://en.wikipedia.org/wiki/P21


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Function of CKIs

P16 P18 P15 P27 P21

D

CDK

4/6 CDK2 CDK2E A

TGF- DNAp53

DNA dam ageDi f ferent ia t ionSerum def ic ienc y


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synthes isdegradat ion


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PLK1

PLK1 P

CDK1

T14

Y15T161

CyclinB

Pi

inactive

active

active

CDC25C

P

CDK1

T14

Y15T161

CyclinB

P

P

P

2Pi

CDC25CP

low activity

Pi

CDC25CP

High activity

P

Pi

PLKpolo-like KinaseCDK1/cyclinBPLKcdc25cCDK1/cyclinB

inactive

inactive


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Checkpo in ts

Cell cycle checkpoints

are used by the cell to

monitor and regulate the progress of the cell cycle.

Checkpoints prevent cell cycle progression at

specific points, allowing verification of necessaryphase processes and repair of DNA damage.

Two main checkpoints exist:

the G1/S checkpoint and the G2/M checkpoint.
http://en.wikipedia.org/wiki/Cell_cycle_checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpointhttp://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#Restriction_Checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#Restriction_Checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#Restriction_Checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#G2_Checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#G2_Checkpointhttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint#Restriction_Checkpointhttp://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/Cell_cycle_checkpoint


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Cell Cycle 2010cj

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