CELL CYCLE

Dr. JUSUF FANTONI, SpPA, MSc. PATH

CELL CYCLECELL CYCLECELL CYCLE = “ PROGRAM “ FOR CELL GROWTH CELL CYCLE = “ PROGRAM “ FOR CELL GROWTH

AND CELL DIVISION ( PROLIFERATION) AND CELL DIVISION ( PROLIFERATION)

4 BROAD PHASES OF CELL CYCLE : 4 BROAD PHASES OF CELL CYCLE : G1, S, G2, G1, S, G2, AND AND MM

G1

Cell CycleCell Cycle

Eric NiederhofferEric Niederhoffer

SIU-SOMSIU-SOM

G0

6-8 h

DNA, RNA, Protein

3-4 h

RNA, Protein

1 h

Mitosis, Cytokinesis

S

G2 Cyc D’sCDK4,6

Cyc B/ACDK1

Cyc ACDK2

M

Cyc ECDK2

6-12 h RNA, Protein

p53pRb

LaminH1Abl

THE THE G1G1 ( GAP 1 ) PHASE IS CHARACTERIZED BY ( GAP 1 ) PHASE IS CHARACTERIZED BY GENE GENE

EXPRESSION AND PROTEIN SYNTHESIS. EXPRESSION AND PROTEIN SYNTHESIS. REGULATED PRIMARILY BY REGULATED PRIMARILY BY

EXTRACELLULAR EXTRACELLULAR STIMULI. STIMULI. THE CELL GROWS AND PRODUCES ALL THE CELL GROWS AND PRODUCES ALL

THE THE NECESSARY PROTEINS FOR DNA NECESSARY PROTEINS FOR DNA

SYNTHESIS.SYNTHESIS.

THE THE S PHASE : S PHASE : THE CELL REPLICATES ITS DNA, THE CELL REPLICATES ITS DNA, SO ITSO IT

NOW HAS 2 COMPLETE SETS OF DNA. NOW HAS 2 COMPLETE SETS OF DNA. THIS ALLOWS THE CELL TO DIVIDE INTO THIS ALLOWS THE CELL TO DIVIDE INTO

22 DAUGHTER CELLS DAUGHTER CELLS

DURING THEDURING THE G2G2 PHASE , THE CELL UNDERGOES PHASE , THE CELL UNDERGOES GROWTH AND PROTEIN SYNTHESIS --- GROWTH AND PROTEIN SYNTHESIS ---

PRIMING PRIMING IT TO BE ABLE TO DIVIDE.IT TO BE ABLE TO DIVIDE. ONCE THIS IS COMPLETE , THE CELL ONCE THIS IS COMPLETE , THE CELL

FINALLYFINALLY ENTERS THE FOURTH & FINAL PHASE, M ENTERS THE FOURTH & FINAL PHASE, M

PHASE PHASE

DURING THE DURING THE M PHASE M PHASE, THE CELL SPLITS APART, THE CELL SPLITS APART INTO 2 DAUGHTER CELLS.INTO 2 DAUGHTER CELLS. NOW THE CYCLE HAS BEEN COMPLETED.NOW THE CYCLE HAS BEEN COMPLETED.

WHAT DO THE CELLS DO NOW ?WHAT DO THE CELLS DO NOW ?THERE ARE 2 CHOICES : EITHER……… START THERE ARE 2 CHOICES : EITHER……… START

THE CYCLE AGAIN BY ENTERING THE CYCLE AGAIN BY ENTERING G1G1, OR IT CAN, OR IT CANBE QUIESCENT BY ENTERING BE QUIESCENT BY ENTERING Go.Go.

THE INHERRENT PROBLEM WITH THIS CYCLE ;THE INHERRENT PROBLEM WITH THIS CYCLE ;

IF IT WASN’T CONTROLLED, THE CELLS WOULD IF IT WASN’T CONTROLLED, THE CELLS WOULD CONTINUE TO GROW AND DIVIDE…OVER AND CONTINUE TO GROW AND DIVIDE…OVER AND OVER AGAIN, SO THERE ARE A NUMBER OFOVER AGAIN, SO THERE ARE A NUMBER OFPROTEINS THAT REGULATE AND CONTROL THEPROTEINS THAT REGULATE AND CONTROL THECELL CYCLE.CELL CYCLE.THESE CONTROL MECHANISMS ARE DEFECTIVE THESE CONTROL MECHANISMS ARE DEFECTIVE IN MALIGNANT CANCER CELLS.IN MALIGNANT CANCER CELLS.

THE CONTROL MECHANISMS ARE THE THE CONTROL MECHANISMS ARE THE CHECK-CHECK-POINTSPOINTS..THERE 2 CHECKPOINTS FOR THE CELL CYCLE :THERE 2 CHECKPOINTS FOR THE CELL CYCLE :

* AT THE END OF THE * AT THE END OF THE G1 PHASEG1 PHASE,,* AT THE END OF THE * AT THE END OF THE G2 PHASEG2 PHASE

WHEN THE DIVIDING CELLS ARE IN CONTACTWHEN THE DIVIDING CELLS ARE IN CONTACTWITH OTHER CELLS ----- STOP DIVIDINGWITH OTHER CELLS ----- STOP DIVIDING

IF THE CELLS ARE SURROUNDED BY LOTS OFIF THE CELLS ARE SURROUNDED BY LOTS OF OTHER OTHER CELLS, IT MAY FAIL TO PASS THE CHECKPOINT CELLS, IT MAY FAIL TO PASS THE CHECKPOINT BECAUSE IT COULDN’T DIVIDE IT IS ALREADY BECAUSE IT COULDN’T DIVIDE IT IS ALREADY CROWDED.CROWDED.

THE CHECKPOINTS ARE OUR DEFENSE AGAINST THE CHECKPOINTS ARE OUR DEFENSE AGAINST TUMORS.TUMORS.

CONTROL OF THE CELL CYCLECONTROL OF THE CELL CYCLE

AMONG THE MAIN PLAYERS ARE :AMONG THE MAIN PLAYERS ARE :

** CYCLINS CYCLINS. THERE ARE 3 GROUPS :. THERE ARE 3 GROUPS :- G1 CYCLINS- G1 CYCLINS- S-PHASE CYCLINS- S-PHASE CYCLINS- M-PHASE CYCLINS- M-PHASE CYCLINS

THEIR LEVELS IN THE CELL RISE AND FALL THEIR LEVELS IN THE CELL RISE AND FALL WITH THE STAGES OF THE CELL CYCLE.WITH THE STAGES OF THE CELL CYCLE.

* * CYCLIN-DEPENDENT KINASESCYCLIN-DEPENDENT KINASES ( ( CDKs CDKs ).).

HERE ARE 3 GROUPS : - G1 HERE ARE 3 GROUPS : - G1 CDKsCDKs

- S-PHASE - S-PHASE CDKsCDKs

- M-PHASE - M-PHASE CDKsCDKs

THEIR LEVELS IN THE CELL REMAIN STABILE, THEIR LEVELS IN THE CELL REMAIN STABILE, BUT EACH MUST BEHIND THE APPROPRIATE BUT EACH MUST BEHIND THE APPROPRIATE

CYCLIN IN ORDER TO BE CYCLIN IN ORDER TO BE ACTIVATED.ACTIVATED.

* * THE ANAPHASE-PROMOTING COMPLEX THE ANAPHASE-PROMOTING COMPLEX ( ( APC APC )) AND OTHER PROTEOLYTIC AND OTHER PROTEOLYTIC

ENZYMES.ENZYMES.

Variation in Cell Cycle Cyclins

M G1 G2S M G1

Start

Cell cycle phases

Cyclin-dependent kinases

D E A B(A)cyclins

Cdk4 Cdk2 Cdk1

pRbpRb

Cell Cycle Regulation

CDK2

CE

E2FEnzymes for DNA synthesis

Passage from G1 to S

DNA damage1. CDK phosphorylation

2. C degradation

3. C & CDK synthesis

4. CDK inhibition

pRb P

Active p53

p21

pRb

THE APC :THE APC :- TRIGGERS THE EVENTS LEADING TO - TRIGGERS THE EVENTS LEADING TO DESTRUCTION OF THE COHESINS AND DESTRUCTION OF THE COHESINS AND THUS ALLOWING THE SISTER CHROMA-THUS ALLOWING THE SISTER CHROMA- TIDS TO SEPARATETIDS TO SEPARATE- DEGRADES THE MITOTIC ( M-PHASE)- DEGRADES THE MITOTIC ( M-PHASE) CYCLINS.CYCLINS.

CYCLINS & CYCLIN-DEPENDENT KINASES ( CDK )CYCLINS & CYCLIN-DEPENDENT KINASES ( CDK )

THE ORDERLY PROGRESSION OF CELLS THROUGH THE ORDERLY PROGRESSION OF CELLS THROUGH THE CELL CYCLE IS ORCHESTRATED BY CYCLINS AND THE CELL CYCLE IS ORCHESTRATED BY CYCLINS AND CDKs AND THEIR INHIBITORS.CDKs AND THEIR INHIBITORS.

CDKs DRIVE THE CELL CYCLE BY CDKs DRIVE THE CELL CYCLE BY PHOSPHORYLATING CRITICAL TARGET PROTEINS.PHOSPHORYLATING CRITICAL TARGET PROTEINS.

CDKs ARE EXPRESSED DURING THE CELL CYCLE CDKs ARE EXPRESSED DURING THE CELL CYCLE IN AN INACTIVE FORM. THEY ARE ACTIVATED BY IN AN INACTIVE FORM. THEY ARE ACTIVATED BY PHOSPHORYLATION AFTER BINDING TO CYCLINS.PHOSPHORYLATION AFTER BINDING TO CYCLINS.

CYCLINS ARE SYNTHESIZED DURING SPECIFIC PHASES CYCLINS ARE SYNTHESIZED DURING SPECIFIC PHASES

OF THE CELL CYCLE, AND THEIR FUNCTION IS TO OF THE CELL CYCLE, AND THEIR FUNCTION IS TO

ACTIVATE THE CDKs.ACTIVATE THE CDKs.

THE TRANSITION FROM G1 TO S IS AN EXTREMELY THE TRANSITION FROM G1 TO S IS AN EXTREMELY

IMPORTANT CHECKPOINT IN THE CELL CYCLE IMPORTANT CHECKPOINT IN THE CELL CYCLE

BECAUSE ONCE CELLS CROSS THIS BARRIER THEY BECAUSE ONCE CELLS CROSS THIS BARRIER THEY

ARE COMMITED TO PROGRESS INTO S PHASE.ARE COMMITED TO PROGRESS INTO S PHASE.

WHEN A CELL RECEIVES GROWTH-PROMOTING WHEN A CELL RECEIVES GROWTH-PROMOTING

SIGNALS, THE SYNTHESIS OF D TYPE CYCLINS THAT SIGNALS, THE SYNTHESIS OF D TYPE CYCLINS THAT

BIND TO CDK4 AND CDK6 IS STIMULATED IN THE BIND TO CDK4 AND CDK6 IS STIMULATED IN THE

EARLY PART OF G1.EARLY PART OF G1.

LATER IN THE G1 PHASE, THE SYNTHESIS OF LATER IN THE G1 PHASE, THE SYNTHESIS OF

E CYCLIN IS STIMULATED WHICH BINDS TO CDK2.E CYCLIN IS STIMULATED WHICH BINDS TO CDK2.

PROGRESSION FROM S PHASE INTO G2 PHASE IS PROGRESSION FROM S PHASE INTO G2 PHASE IS FASCILITATED BY CYCLINS WHICH BINDS TO FASCILITATED BY CYCLINS WHICH BINDS TO

CDK2 AND TO CDK1.CDK2 AND TO CDK1.EARLY IN THE G2 PHASE, B CYCLIN TAKES EARLY IN THE G2 PHASE, B CYCLIN TAKES OVER FORMING COMPLEXES WITH CDK1, OVER FORMING COMPLEXES WITH CDK1,

WHICH WHICH HELPS THE CELL MOVE FROM G2 TO M.HELPS THE CELL MOVE FROM G2 TO M.

THE ACTIVITY OF CDKs IS REGULATED BY 2 THE ACTIVITY OF CDKs IS REGULATED BY 2 FAMILIES OF CDK INHIBITORS ( CDKIS ).FAMILIES OF CDK INHIBITORS ( CDKIS ).ONE FAMILY OF CDKIS, COMPOSED OF ONE FAMILY OF CDKIS, COMPOSED OF

P21, P27, P21, P27, AND P 57, AND P 57, INHIBITS THE CDKs BROADLY.INHIBITS THE CDKs BROADLY.

THE OTHER FAMILY OF CDKIS HAS THE OTHER FAMILY OF CDKIS HAS SELECTIVE SELECTIVE

EFFECTS ON CYCLIN D / CDK4 AND CYCLIN D EFFECTS ON CYCLIN D / CDK4 AND CYCLIN D / /

CDK6.CDK6.

THE FOUR MEMBERS OF THIS FAMILY ( THE FOUR MEMBERS OF THIS FAMILY ( P15, P16,P15, P16,

P18, P19 )P18, P19 ) ARE SOMETIMES CALLED INK4 ARE SOMETIMES CALLED INK4

BECAUSE THEY ARE INHIBITOR OF CDK4 AND BECAUSE THEY ARE INHIBITOR OF CDK4 AND

CDK6.CDK6.

WITH THIS BACKGROUND, IT COULD BE WITH THIS BACKGROUND, IT COULD BE

UNDER-UNDER-

STOOD THAT MUTATIONS THAT DYSREGULATE STOOD THAT MUTATIONS THAT DYSREGULATE

THE ACTIVITY OF CYCLINS AND CDKs WOULDTHE ACTIVITY OF CYCLINS AND CDKs WOULD

FAVOR CELL RPOLIFERATION.FAVOR CELL RPOLIFERATION.

MISHAPS AFFECTING THE EXPRESSION OF MISHAPS AFFECTING THE EXPRESSION OF

CYCLIN D OR CDK4 SEEM TO BE A COMMONCYCLIN D OR CDK4 SEEM TO BE A COMMON

EVENT IN NEOPLASTIC TRANSFORMATION.EVENT IN NEOPLASTIC TRANSFORMATION.

THE CYCLIN D GENES ARE EXPRESSED IN THE CYCLIN D GENES ARE EXPRESSED IN

MANY CANCERS, INCLUDING THOSE MANY CANCERS, INCLUDING THOSE

AFFECTING THE BREAST, ESOPHAGUS AND AFFECTING THE BREAST, ESOPHAGUS AND

LIVER AND IN A SUBSET OF LYMPHOMAS.LIVER AND IN A SUBSET OF LYMPHOMAS.

AMPLIFICATION OF THE CDK4 GENE AMPLIFICATION OF THE CDK4 GENE

OCCURS IN OCCURS IN

MELANOMAS, SARCOMAS AND MELANOMAS, SARCOMAS AND

GLIOBLASTOMAS.GLIOBLASTOMAS.

p53 p53 PATHWAYPATHWAY

p53p53 IS THE TUMOR SUPPRESSOR PROTEIN IS THE TUMOR SUPPRESSOR PROTEIN

THAT REGULATES THE CELL CYCLE.THAT REGULATES THE CELL CYCLE.

pp53 IS THE MOST FREQUENTLY DISRUPTED 53 IS THE MOST FREQUENTLY DISRUPTED

GENE IN CANCER, ILLUSTRATING ITS IMPORTANCE.GENE IN CANCER, ILLUSTRATING ITS IMPORTANCE.

PP53 IS A DNA-BINDING PROTEIN INVOLVED 53 IS A DNA-BINDING PROTEIN INVOLVED

IN REGULATING THE EXPRESSION OF GENES IN REGULATING THE EXPRESSION OF GENES

INVOLVED IN CELL CYCLE ARREST AND INVOLVED IN CELL CYCLE ARREST AND

APOPTOSIS.APOPTOSIS.

pp53 RECOGNIZES WHEN SOMETHING IN THE 53 RECOGNIZES WHEN SOMETHING IN THE

CELL HAS GONE WRONG AND EITHER TELLS THE CELL HAS GONE WRONG AND EITHER TELLS THE

CELL TO STOP GROWING OR IF ALL ELSE FAILS, CELL TO STOP GROWING OR IF ALL ELSE FAILS,

TELLS THE CELL TO KILL ITSTELLS THE CELL TO KILL ITS

pp53 PROTEIN LEVELS ARE NORMALLY KEPT VERY 53 PROTEIN LEVELS ARE NORMALLY KEPT VERY

LOW WITHIN THE CELL; ONCE STIMULATED, THE LOW WITHIN THE CELL; ONCE STIMULATED, THE

LEVELS ARE RAPIDLY INCREASED ALONG WITH ITS LEVELS ARE RAPIDLY INCREASED ALONG WITH ITS

HALF-LIFE.HALF-LIFE.

THE NEGATIVE REGULATOR OF THE NEGATIVE REGULATOR OF pp53 IS Mdm2 53 IS Mdm2

WHICH IS ACTUALLY A WHICH IS ACTUALLY A pp53 RESPONSIVE GENE. 53 RESPONSIVE GENE.

pp53 ACTIVATED, THEN INCREASED THE Mdm2 53 ACTIVATED, THEN INCREASED THE Mdm2

LEVELS WHICH INACTIVATES LEVELS WHICH INACTIVATES pp53, TURNING IT OFF.53, TURNING IT OFF.

ONE MECHANISM THAT INHIBITS Mdm2 IS BY ONE MECHANISM THAT INHIBITS Mdm2 IS BY

ONCOGENES BY INDUCING THE EXPRESSION OF A ONCOGENES BY INDUCING THE EXPRESSION OF A

TUMOR SUPPRESOR PROTEIN CALLED p19ARF.TUMOR SUPPRESOR PROTEIN CALLED p19ARF.

TWO CDKs ARE ACTIVATED NEAR THE END OF G1 TWO CDKs ARE ACTIVATED NEAR THE END OF G1

AND S PHASE : CDK2 AND cdc2 ( CDK1 ).AND S PHASE : CDK2 AND cdc2 ( CDK1 ).

ONCE THE CELL HAS BEGUN TO CYCLE THESE ONCE THE CELL HAS BEGUN TO CYCLE THESE

2 CDKs CAN ALSO INHIBIT 2 CDKs CAN ALSO INHIBIT pp53.53.

CDK2 AND cdc2 ARE THOUGHT TO KEEP CDK2 AND cdc2 ARE THOUGHT TO KEEP pp53 53

IN THE CYTOPLASM.IN THE CYTOPLASM.

WHEN THE CELL IS NOT IN G1, CDK2 WHEN THE CELL IS NOT IN G1, CDK2

ACTIVITY ( BY BINDING TO CYCLIN E OR CYCLIN A ACTIVITY ( BY BINDING TO CYCLIN E OR CYCLIN A

) IS INCREASED AT THE END OF G1 WHICH CAN ) IS INCREASED AT THE END OF G1 WHICH CAN

PHOSPHORYLATE PHOSPHORYLATE pp53 AND GET IT OUT OF THE 53 AND GET IT OUT OF THE

NUCLEUS SO IT DOES NOT INTERFERE WITH DNA NUCLEUS SO IT DOES NOT INTERFERE WITH DNA

SYNTHESIS.SYNTHESIS.

CELL DEATHIN 1972 KERR, WYLLIE AND CURRIE DISTINGUISHED BETWEEN TWO FORMS OF CELL DEATH, NECROSIS AND APOPTOSIS. NECROSIS IS THE FORM OF DEATH WHICH RESULTS FROM CELLULAR METABOLIC COLLAPSE, WHEN A CELL CAN NO LONGER MAINTAIN IONIC HOMEOSTASIS. NECROSIS IS NOT SEEN IN NORMAL DEVELOPMENT, BUT IS INVARIABLY THE RESPONSE TO INURY OR TOXIC DAMAGE.APOPTOSIS, OR PROGRAMMED CELL DEATH , IS A CENTRAL PART OF NORMAL DEVELOPMENT. IT IS A GENETICALLY MEDIATED FORM OF CELL DEATH, WHICH IS INVOLVED IN ORGANOGENESIS, TISSUE HOMEOSTASIS AND THE EDITING OF THE IMMUNE SYSTEM TO REMOVE AUTOREACTIVE CLONES. IN TISSUE, APOPTOSIS CHARACTERISTICALLY AFFECTS SCATTERED INDIVIDUAL CELLS IN CONTRAST TO NECROSIS WHICH USUALLY INVOLVES TRACTS OF CONTIGUOUS CELLS. INFLAMMATION IS TYPICLLY ABSENT IN AREAS OF TISSUE UNDERGOING APOPTOSIS.APOPTOTIC CELLS LOSE CONTACT WITH THEIR NEIGHBORS, DECREASE IN SIZE AND SHOW CONDENSATION OF CHROMATIN. THE CELLULAR DNA IS DEGRADED .THE CELL MEMBRANE PROTIENS ARE CROSS LINKED MAKING THE MEMBRANE MORE RIGID AND THE APOPTOTIC CELLS ARE TYPICALLY PHAGOCYTOSED BY ADJACENT CELLS OR MACROPHAGES.UNDER SOME CIRCUMSTANCES, HOWEVER, APOPTOSIS CAN ALSO BE SEEN IN RESPONSE TO A NUMBER OF ABNORMAL STIMULI WHICH INCLUDE HORMONAL OR GROWTH FACTOR MANIPULATIONS, ABERRANT GENE EXPRESSION, PARTICULARLY OF ONCOGENES, OR ANTI-ONCOGENES, AND IN RESPONSE TO A NUMBER OF TOXIC AGENTS INCLUDING CHEMOTHERAPEUTIC DRUGS AND XRAYS.

THEREFORE, APOPTOSIS IS MAINLY THE RESULT OF A PHYSIOLOGICAL PROCESS BY WHICH CELLS ARE ELIMINATED WHEN THEY ARE NO LONGER REQUIRED BY THE BODY.APOPTOSIS ( LITERAALY “ FALLING OFF” AS OF LEAVES IN AUTUMN ) IS CHARACTERIZED BY SHRINKAGE AND COMPACTION OF THE DYING CELL. IT RAPIDLY BREAKS UP TO FORM “ APOPTOTIC BODIES “ . CELLS APPEAR AS INCONSPICUOUS ROUND OR OVAL EOSINOPHILIC STRUCTURES WITH DENSE CHROMATIN INCLUSIONS.APOPTOSIS REQUIRES CONTINUING SYNTHESIS OF RNA AND PROTEIN AND A SUPPLY OF ATP, FEATURES SUGGESTING THAT THE PROCESS IS ONE OF THE ACTIVE SELF DESTRUCTION.REGULATION OF CELL PROLIFERATION AND THE CONTROL OF APOPTOSISTHERE ARE SEVERAL INSTANCES WHERE CONTROL OF APOPTOSIS SEEMS TO BE LINKED TO SOME OF THE GENES WHICH ALSO REGULATE CELL CYCLE PROGRESSION.THYMOCYTES UNDERGO APOPTOSIS AT THE G0- TRANSITION IN RESPONSE TO GLUCOCORTICOIDS OR XRAYS.p53 GENE WHICH IS STRONGLY IMPLICATED IN HUMAN AND ANIMAL CARCINOGENESIS CAN ALSO BE A SIGNIFICANT REGU;ATOR OF THE PROCESS OF APOPTOSIS.ALTERATIONS IN CELL PROLIFERATIVE ACTIVITY ARE ALSO INTIMATELY LINKED TO THE CONTROL OF APOPTOSIS. THIS LINKAGE HAS BEEN RECOGNIZED BOTH FOR THE TUMOR SUPPRESSOR GENES p53 AND RETINOBLSTOMA AND FOR THE DOMINANT ONCOGENE Myc. IN VIRUSES WITH ANTI-APOPTOTIC FUNCTIUONS PRESUMABLY EVOLVED TO PERMIT VIRAL REPLICATION, PROMOTE THE UNCONTROLLED CELLULAR PROLIFERATION.

p53 AND APOPTOSIS

p53 MUTATIONS ARE NOW RECOGNIZED TO BE THE MOST COMMON GENETIC CHANGES IN HUMAN CANCER. P53 IS NOW MORE PROPERLY THOUGHT OF AS A TUMOR SUPPRESSOR GENE.THE ACTION OF p53 IS COMPLEX. IT BINDS TO MANY IMPORTANT CELLULAR PROTEINS AND IS INVOLVED IN THE CONTROL OF GENE EXPRESSION. NOW MORE FOCUSING ON ITS ROLES IN CEL CYCLE DELAY IN G1 PHASE AND IN APOPTOSIS.IT IS NOW RECOGNIZED THAT p53 CAN REGULATE BOTH CELL PROLIFERATION AND INDUCES APOPTOSIS DEPENDING ON THE CIRCUMSTANCES AND CELLULAR BACKGROUND.RECENT STUDIES DEMOSTRATED THAT, IN THE ABSENCE OF RETINOBLASTOMA GENE FUNCTION, THE APOPTOTIC ACTION OF p53 CAN COMPENSATE FOR THIS LOSS AND THUS PREVENT MALIGNANT TRANSFORMATION.THE Rb PROTEIN PREVENTS CELL CYCLE PROGRESSION AT G1 / S BY INHIBITING MEMBERS OF THE E2F FAMILY OF TRANSRIPTIONAL FACTORS THEREBY INHIBITING THE EXPRESSION OF MANY GENES IMPLICATED IN S PHASE, INCLUDING TK, Myc, DHFR AND DNA POLYMERASE. THUS , THE Rb GENE PRODUCT IN THE DEVELOPING LENS CAUSES THE CELLS TO UNDERGO GROWTH ARREST AND TO TERMINALLY DIFFERENTIATE.

THE FUNCTIONS OF p53 AND Rb GENE PRODUCTS ARE TIGHTLY LINKED TO CELL CYCLE EVENTS IN THE G1 PHASE OF THE CELL CYCLE. p53 IS KNOWN TO INDUCE G1 ARREST AS WELL AS APOPTOSIS.XRAYS OR OTHER DNA-DAMAGING AGENTS HAVE BEEN SHOWN TO INCREASE THE LEVELS OF p53 BY A POST-TRANSLATIONAL MECHANISM. INCREASED p53 IS KNOWN TO RESULT IN A G1 ARREST WHICH IS MEDIATED BY INDUCTION OF TWO IDENTIFIED GENES WAF1 / CIP 1, A POTENT INHIBITOR OF SEVERAL CYCLIN DEPENDENT KINASES ( cdks ), PARTICULARLY OF G1 Cdks WHICH ARE ESSENTIAL FOR THE G1/S TRANSITON

Bcl-2 and APOPTOSISBcl-2 WAS DISCOVERED AS A GENE WHOSE EXPRESSION WAS INCREASED BY CHROMOSOMAL TRANSLOCATIONS IN B-CELL MALIGNANCIES. IT IS FOUND TO BE ACTIVATED IN THE M AJORITY OF FOLLICULAR NON-HODGKIN’S LYMPHOMAS AND LESS COMMONLY OIN PROSTATE CANCER.ITS ACTIVATION HAS ALSO BEEN SEEN IN SOME BENIGN CONDITIONS SUCH AS FOLLICULAR HYPERTROPHY OF LYMPH NODES AND TONSILS.RECENT YEARS Bcl-2 HAS BEENNFOCUSED ON ITS FUNCTION AS OPPONENT OF APOPTOSIS.IN MULTIPLE SYSTEMS, LYMPHOCYTES, FIBROBLASTS, NEURONS, HEMATOPOIETIC CELLS ETC, EXPRESSION OF Bcl-2 SHOWN TO ABLE TO DELAY OR EVEN PREVENT APOPTOSIS.