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

Mitosis, Cytokinesis

Cyc B/A CDK1

G2 M 3-4 h 1 h S 6-8 h G1 6-12 h

Cyc Ds G0 CDK4,6 RNA, Protein Cyc E CDK2

p53 pRb

DNA, RNA, Protein

Cyc A CDK2

Eric Niederhof fer

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 2 DAUGHTER CELLS

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 THE CHECKPOINTS. THERE 2 CHECKPOINTS FOR THE CELL CYCLE : * AT THE END OF THE G1 PHASE, * AT THE END OF THE G2 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 ). HERE ARE 3 GROUPS : - G1 CDKs - S-PHASE CDKs - M-PHASE CDKs

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

Cyclin-dependent kinases

Cdk4
cyclins

Cdk2
D E A

Cdk1
B(A)

G1 Start

G2

M G1

Cell cycle phases

Cell Cycle Regulation

1. CDK phosphorylation 2. C degradation DNA damage

3. C & CDK synthesis

4. CDK inhibition CDK2 CE p21

Active p53

pRb
pRb E2F Enzymes for DNA synthesis

Passage from G1 to S

THE APC :
- TRIGGERS THE EVENTS LEADING TO DESTRUCTION OF THE COHESINS AND THUS ALLOWING THE SISTER CHROMATIDS TO SEPARATE - DEGRADES THE MITOTIC ( M-PHASE) CYCLINS. 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. CDKs ARE EXPRESSED DURING THE CELL CYCLE IN AN INACTIVE FORM. THEY ARE ACTIVATED BY PHOSPHORYLATION AFTER BINDING

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 CYCLIN IS STIMULATED WHICH BINDS TO CDK2.

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. THE OTHER FAMILY OF CDKIS HAS SELECTIVE 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, SARCOMAS AND GLIOBLASTOMAS.

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 NEGATIVE REGULATOR OF p53 IS Mdm2 WHICH IS ACTUALLY A p53 RESPONSIVE GENE. p53 ACTIVATED, THEN INCREASED THE Mdm2 LEVELS 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 TO CYCLIN E OR CYCLIN A ) IS INCREASED AT THE END OF G1 WHICH CAN PHOSPHORYLATE p53 AND GET IT OUT OF THE NUCLEUS SO IT DOES NOT INTERFERE WITH DNA SYNTHESIS.