CELL CYCLE

Dr. JUSUF FANTONI, SpPA, MSc.

PATH

CELL CYCLE
CELL CYCLE = PROGRAM FOR CELL GROWTH
AND CELL DIVISION ( PROLIFERATION)
4 BROAD PHASES OF CELL CYCLE : G1, S, G2, AND
M

Cell Cycle
RNA, Protein

Lamin
H1
Abl

Cyc B/A
CDK1
DNA, RNA,
Protein
Cyc A
CDK2

Mitosis, Cytokinesis

G2 M
3-4 h 1 h
S
6-8 h

Cyc Ds G0
CDK4,6
G1

6-12 h

RNA, Protein
Cyc E
CDK2

Eric
Niederho
ffer

p53
pRb

THE G1 ( GAP 1 ) PHASE IS CHARACTERIZED BY

GENE
EXPRESSION AND PROTEIN SYNTHESIS.
REGULATED PRIMARILY BY
EXTRACELLULAR
STIMULI.
THE CELL GROWS AND PRODUCES ALL
THE
NECESSARY PROTEINS FOR DNA
SYNTHESIS.
THE S PHASE : THE CELL REPLICATES ITS DNA,
SO IT
NOW HAS 2 COMPLETE SETS OF DNA.
THIS ALLOWS THE CELL TO DIVIDE INTO

DURING THE G2 PHASE , THE CELL UNDERGOES

GROWTH AND PROTEIN SYNTHESIS --PRIMING
IT TO BE ABLE TO DIVIDE.
ONCE THIS IS COMPLETE , THE CELL
FINALLY
ENTERS THE FOURTH & FINAL PHASE, M
PHASE
DURING THE

M PHASE, THE CELL SPLITS APART

INTO 2 DAUGHTER CELLS.
NOW THE CYCLE HAS BEEN COMPLETED.

WHAT DO THE CELLS DO NOW ?

THERE ARE 2 CHOICES :

EITHER START
THE CYCLE AGAIN BY ENTERING G1, OR IT CAN
BE QUIESCENT BY ENTERING Go.

THE INHERRENT PROBLEM WITH THIS CYCLE ;

IF IT WASNT CONTROLLED, THE CELLS WOULD
CONTINUE TO GROW AND DIVIDEOVER AND
OVER AGAIN, SO THERE ARE A NUMBER OF
PROTEINS THAT REGULATE AND CONTROL THE
CELL CYCLE.
THESE CONTROL MECHANISMS ARE DEFECTIVE
IN MALIGNANT CANCER CELLS.
THE CONTROL MECHANISMS ARE
POINTS.
THERE 2 CHECKPOINTS FOR THE
* AT THE END OF THE G1
* AT THE END OF THE G2

THE CHECKCELL CYCLE :

PHASE,
PHASE

WHEN THE DIVIDING CELLS ARE IN CONTACT

WITH OTHER CELLS ----- STOP DIVIDING

IF THE CELLS ARE SURROUNDED BY LOTS OF OTHER

CELLS, IT MAY FAIL TO PASS THE CHECKPOINT
BECAUSE IT COULDNT DIVIDE IT IS ALREADY
CROWDED.
THE CHECKPOINTS ARE OUR DEFENSE AGAINST
TUMORS.
CONTROL OF THE CELL CYCLE
AMONG THE MAIN PLAYERS ARE :

CYCLINS.

THERE ARE 3 GROUPS :

G1 CYCLINS
S-PHASE CYCLINS
M-PHASE CYCLINS

THEIR LEVELS IN THE CELL RISE AND FALL

WITH THE STAGES OF THE CELL CYCLE.
* CYCLIN-DEPENDENT KINASES ( CDKs ).

CDKs
CDKs

HERE ARE 3 GROUPS :

- G1 CDKs
- S-PHASE
- M-PHASE

THEIR LEVELS IN THE CELL REMAIN STABILE,

BUT EACH MUST BEHIND THE APPROPRIATE
CYCLIN IN ORDER TO BE ACTIVATED.
* THE ANAPHASE-PROMOTING COMPLEX ( APC )
AND OTHER PROTEOLYTIC ENZYMES.

Variation in Cell Cycle Cyclins

Cdk4

Cyclin-dependent kinases
Cdk2
Cdk1

cyclins

G1

S
Start
Cell cycle phases

B(A)

G2

M G1

Cell Cycle Regulation

1. CDK phosphorylation

DNA damage

2. C degradation
Active p53

3. C & CDK synthesis

4. CDK inhibition

CDK2
CE

p21
P
pRb

pRb
E2F

Enzymes for
DNA synthesis

Passage from
G1 to S

THE APC :
TO
AND
CHROMAPHASE)

- TRIGGERS THE EVENTS LEADING

DESTRUCTION OF THE COHESINS
THUS ALLOWING THE SISTER
TIDS TO SEPARATE
- DEGRADES THE MITOTIC ( MCYCLINS.

CYCLINS & CYCLIN-DEPENDENT KINASES ( CDK )

THE ORDERLY PROGRESSION OF CELLS
THROUGH THE CELL CYCLE IS ORCHESTRATED BY
CYCLINS AND CDKs AND THEIR INHIBITORS.
CDKs DRIVE THE CELL CYCLE BY
PHOSPHORYLATING CRITICAL TARGET PROTEINS.

CYCLINS ARE SYNTHESIZED DURING SPECIFIC PHASES

OF THE CELL CYCLE, AND THEIR FUNCTION IS TO
ACTIVATE THE CDKs.
THE TRANSITION FROM G1 TO S IS AN EXTREMELY
IMPORTANT CHECKPOINT IN THE CELL CYCLE
BECAUSE ONCE CELLS CROSS THIS BARRIER THEY
ARE COMMITED TO PROGRESS INTO S PHASE.
WHEN A CELL RECEIVES GROWTH-PROMOTING
SIGNALS, THE SYNTHESIS OF D TYPE CYCLINS THAT
BIND TO CDK4 AND CDK6 IS STIMULATED IN THE
EARLY PART OF G1.
LATER IN THE G1 PHASE, THE SYNTHESIS OF E

PROGRESSION FROM S PHASE INTO G2 PHASE IS

FASCILITATED BY CYCLINS WHICH BINDS TO
CDK2 AND TO CDK1.
EARLY IN THE G2 PHASE, B CYCLIN TAKES
OVER FORMING COMPLEXES WITH CDK1,
WHICH
HELPS THE CELL MOVE FROM G2 TO M.
THE ACTIVITY OF CDKs IS REGULATED BY 2
FAMILIES OF CDK INHIBITORS ( CDKIS ).
ONE FAMILY OF CDKIS, COMPOSED OF P21,
P27, AND P 57, INHIBITS THE CDKs BROADLY.

SELECTIVE
/

THE OTHER FAMILY OF CDKIS HAS

EFFECTS ON CYCLIN D / CDK4 AND CYCLIN D
CDK6.

THE FOUR MEMBERS OF THIS FAMILY ( P15, P16,

P18, P19 ) ARE SOMETIMES CALLED INK4
BECAUSE THEY ARE INHIBITOR OF CDK4 AND
CDK6.
WITH THIS BACKGROUND, IT COULD BE
UNDERSTOOD THAT MUTATIONS THAT DYSREGULATE
THE ACTIVITY OF CYCLINS AND CDKs WOULD
FAVOR CELL RPOLIFERATION.
MISHAPS AFFECTING THE EXPRESSION OF
CYCLIN D OR CDK4 SEEM TO BE A COMMON
EVENT IN NEOPLASTIC TRANSFORMATION.

THE CYCLIN D GENES ARE EXPRESSED IN

MANY CANCERS, INCLUDING THOSE
AFFECTING THE BREAST, ESOPHAGUS AND
LIVER AND IN A SUBSET OF

LYMPHOMAS.

AMPLIFICATION OF THE CDK4 GENE

OCCURS IN
MELANOMAS,
GLIOBLASTOMAS.

SARCOMAS AND

p53 PATHWAY
p53 IS THE TUMOR SUPPRESSOR PROTEIN
THAT REGULATES THE CELL CYCLE.
p53 IS THE MOST FREQUENTLY DISRUPTED
GENE IN CANCER, ILLUSTRATING ITS IMPORTANCE.
P53 IS A DNA-BINDING PROTEIN INVOLVED IN
REGULATING THE EXPRESSION OF GENES
INVOLVED IN CELL CYCLE ARREST AND
APOPTOSIS.
p53 RECOGNIZES WHEN SOMETHING IN THE
CELL HAS GONE WRONG AND EITHER TELLS THE
CELL TO STOP GROWING OR IF ALL ELSE FAILS,
TELLS THE CELL TO KILL ITS

p53 PROTEIN LEVELS ARE NORMALLY KEPT VERY

LOW WITHIN THE CELL; ONCE STIMULATED, THE
LEVELS ARE RAPIDLY INCREASED ALONG WITH ITS
HALF-LIFE.

THE
WHICH
p53
LEVELS

NEGATIVE REGULATOR OF p53 IS Mdm2

IS ACTUALLY A p53 RESPONSIVE GENE.
ACTIVATED, THEN INCREASED THE Mdm2
WHICH INACTIVATES p53, TURNING IT OFF.

ONE MECHANISM THAT INHIBITS Mdm2 IS BY

ONCOGENES BY INDUCING THE EXPRESSION OF A
TUMOR SUPPRESOR PROTEIN CALLED p19ARF.

TWO CDKs ARE ACTIVATED NEAR THE END OF G1

AND S PHASE : CDK2 AND cdc2 ( CDK1 ).
ONCE THE CELL HAS BEGUN TO CYCLE THESE 2
CDKs CAN ALSO INHIBIT p53.
CDK2 AND cdc2 ARE THOUGHT TO KEEP p53 IN
THE CYTOPLASM.
WHEN THE CELL IS NOT IN G1, CDK2 ACTIVITY (
BY

BINDING

INCREASED

TO

AT

PHOSPHORYLATE

CYCLIN

OR

CYCLIN

THE

END

OF

G1

p53

AND

GET

IT

WHICH
OUT

OF

IS

CAN
THE

NUCLEUS SO IT DOES NOT INTERFERE WITH DNA

SYNTHESIS.