CELL CYCLE(1).pptx 1st year registrar oncology

short look at cell cycle...summary

1. CELL CYCLE

2. CELL A CELL IS THE FUNDAMENTAL WORKING UNIT OF ALL LIVING ORGANISMS A CELL HAS 3 MAIN COMPONENTS CELL MEMBRANE CYTOPLASM NUCLEAS

3. WHAT IS A CELL CYCLE A CELL CYCLE IS A SERIES OF STEPS A CELL GOES THROUGH TO GROW AND REPLICATE IT SELF IT CAN BE DEVIDED INTO 2 MAJOR PHASES INTERPHASE MITOSIS

4. THE CELL CYCLE:

5. INTERPHASE INTERPHASE INCLUDED G1, S AND G2 PHASES OF THE CELL CYCLE THIS INVOLVES INCREASE IN THE THE CELLULAR COMPONENTS INCLUDING CYTOPLAM, ORGANELLS, RNA AND DNA IN PREPARATION FOR MITOSIS THE AVERAGE LENGTH OF A CELL CYCLE IS 24 HOURS AND INTERPHASE IS ON AVERAGE 15HOURS , BUT VARIABLE WITH DIFFERENT CELL TYPES

6. M PHASE M PHASE INVOLVES THE PARTIONING OF THE CELL TO PRODUCE 2 DAUGHTER CELLS AND INCLUDED MITOSES AND CYTOKINESIS M PHASES STEPS PROPHASE METAPHASE ANAPHASE TELOPHASE CYTOKINESIS

7. G1 PHASES G1 IS ALSO KNOWN AS GROWTH PHASES OR GAP 1 ABOUT 8 HOURS , longest stage , matter transportation, synthesis, lysis reactions, organelle production, RNA synthesis and tissue function at their highest levels. THIS IS WHEN THE CELL PREPARES FOR DNA REPLICATION THE CELL INCREASES IN SIZE G1 PHASE ALSO INVOLVES THE RESTRICTION POINT, WHICH WHEN THE CONDITIONS ARE FAVOURABLE THE CELL COMMITS TO GO INTO THE S PHASE. IF NOT THE CELL EXITS THE CYCLE AND INTO G0 CELLS THAT LOOSE ABILITY TO DIVIDE CONTINUE WITH THEIR FUNCTIONS AND LIFE ACTIVITIES E.G MUSCLE AND NERVE go into GO HAS A G1 CHECK POINT

8. G0 PHASE ALSO KNOWN AS THE QUISCENT,REST OR PERMANENT PHASE DURATION DEPENDS ON TYPES OF CELL AND AVAILABILITY OF STIMULUS SUCH AS MITOGENS, PROTEINS AND ENERGY STABLE CELLS WHICH REPLICATES ONLY WHEN THE STIMULUS IS ADEQUATE EG HEPATOCYTES, KIDNEY TUBLE EPITHELIAL CELLS AND ALVEOLAR LUNG CELLS PERMANE NT CELL STAY IN G0 PHASE EG NEURONS, MYOCARDIUM AND SKELETAL PHASE

9. CELL EXAMPLES SOME CELL DO NOT STAY IN G0 PHASE THESE ARE LABILE OR PROLIFERATIVE CELLS EG EPITHELIAL CELLS OF THE SKIN, GIT, GUS HAEMATOPOEITIC STEM CELL IN THE BONE MAROW

10. S PHASE SYNTHETIC PHASE ABOUT 6HOURS FOCUS ON DNA REPLICATION ALL 46 CHROMOSOMES(2n) ARE REPLICATED TO 92 CHROMATIDS(4n) A CHROMATID IS ONE OF THE TWO IDENTICAL HALVES OF A CHROMOSOME CHROMATIDS JOINED AT THE CENTOMERE

11. G2 PHASE CONTINUATION OF GROWTH OF THE CYTOPLASM AND PRODUCTION OF PROTEINS AND ORGANELLES DNA SYNTHESIS FINISHES BUT RNA SYNTHESIS CONTINUES G2 CHECK POINT CHECKS FOR READINESS OF CELL TO GO ON T O M PHASE

12. M PHASE THE PHASE DURING WHICH KARYOKINESIS OCCURS AND LEADS TO CYTOKINESIS EASILY SEEN VIA MICCROSCOPE AS THE CHROMOSOME IS CONDENSED AS COMPARED TO IN THE INTERPHASE KARYOKINESIS IS THE D I VISION OF THE NUCLEAS,DNA AND NUCLEOPLASM CYTOKINESIS FOLLOWS KARYOKINESIS AND IS THE D I VISION OF THE CYTOPLASM

13. PROPHASE PROPHASE IS THE FIRST STAGE OF THE M PHASE IT INVOLVES CHROMOSOME CONDENSATION NUCLEAR MEMBRANE DISSOLUTION DISSASEMBLY OF CYTOSKELETON CENTRIOLES FORM MICROTUBLE FORM FROM POLES TO THE CENTER CENTROSOMES MOVE TOWARDS OPPOSITE ENDS

14. METAPHASE CHROMOSOMES ALIGN SIDE TO SIDE IN A ROW IN EQUATORIAL PLANE METAPHASE PLATE HAS 4n(96 CHROMATIDS) CHROMOSOMES HOLD ONTO MICROTUBULES WITH THEIR CENTROMERES VIA THE KINETOCORE

15. ANAPHASE CONTRACTION AND RELAXATION MOVEMENTS OF MICROTUBULES BREAK THE CENTROMERES THAT LOCK CHROMATIDS TOGETHER SEPARATION OF SISTER CHROMATIDS TO OPPOSITE POLES MOVE ON MICROTUBLE VIA MOTOR PROTEINS CALLED DYNEIN AND KINESIN

16. TELOPHASE FORMATION OF NUCLEA MEMBRANE AROUND THE 2 SETS OF CHROMOSOMES DISSAPEARNACE OF THE M I TO TI C SPINDLE RNA AND PROTEIN SYNTHESIS STARTS FORMATION OF THE CLEAVAGE FARROW VIA CONTRACTILE PROTEINS LIKE THE ACTIN AND MYOSIN VITAL EVENTS RESTART IN CELL

17. CYTOKINESIS CYTOKINESIS IS THE SEPARATION OF THE TWO CYTOPLASM AND ITS CONTENTS AFTER CYTOKINESIS WE GO INTO G0 ALSO CALLED RESTING OR QUISCENT PHASE

18. CELL CYCLE REGULATION THE NORMAL REGULATION IS MEDIATED VIA CYCLINS CYCLIN DEPENDENT KINASES CELL CYCLE INHIBITORS E3 UBIQUITIN LIGASES PASSAGE OF THE CELL THROUGH AND INTO DIFFERENT PHASES IS REGULATED BY CYCLINS AND CDKS

19. CYCLINS THERE NAMED CYCLINS BECAUSE THEIR CONCENTRATION AT ANY GIVEN IS CYCLICAL DEPENDING ON THE CYCLE PHASE AND THE VAILABILITY OF STIMULANTS MORE THAN 15 CYCLINS HAVE BEEN IDENTIFIED CYCLIN D,E,A,B APPEAR SEQUENTIALLY DURING THE CELL CYCLE AND BIND TO AT LEAST 1 CDK THEIR FUNCTION IS TO ACTIVATE THE CDKS BY OPENING THE CATALYTIC CLEFT TO ALLOW FOR SUB STRATE DOCKING THEY HAVE NO CATALYTIC ACTIVITY

20. CDKS THESE ARE SERINE/THREONINE KINASES CDK ARE INACTIVE IN THE ABSENCE OF A CYCLINE CYCLIN BINDS TO CDK, PHOSPHORYLATING IT LEADING TO ACTIVATION OR INACTIVATION OF TARGET PROTEIN THEY ARE EXPRESSED CONSTITUTIVELY DURING THE CELL CYCLE BUT IN AN INACTIVE FORM

21. CYCLE REGULATION CYCLIN CONCENTRATION IS DEPENDEND ON MITOGENS OR GROWTH FACTORS EG VASCULAR ENDOTHELIAL GF, EPIDERMAL GF AND PLATELET DERIVED GF

22. CYC LIN D CYCLIN D IS THE FIRST CYCLIN IT APPEARS WHEN QUIESCENT CELLS ARE ACTIVATED BY GFS GFS ACT VIA SEVERAL PATHAWAYS TO ACTIVATE TRANSCRPTION OF CYCLIN PROTEINS 1) JAK STAT PATHWAY 2) RAS-MAPK PATHWAY 3) G PROTEIN PATHWAY

23. 1) G PROTEIN RECEPTOR MEDIATED Gq MITOGEN BINDS TO Gq RECEPTOR Gq RECEPTOR ACTIVATES PHOSPHOLIPASE C PHOSPHOLIPASE CONVERTS PHOSPHOTIDYL INOSITOL DIPHOSPHATE(PIP2) INTO DIACYLGLYCEROL(DAG) AND INOSITOL TRIPHOSPHATE(IP3) DAG ACTIVATES PKC WHICH ACTIVATES TRANSCRIPTION FACTORS THAT LEASD TO PRODUCTION OF CYCLIN PROTEINS IP3 INCREASES FREE INTRACELLULAR CA2+ WHICH ACTIVATES CALMODULIN WHICH ACTIVATE CYCLIN D TRANSCRPTION FACTORS

24. G STIMULATORY(GS) RECEPTOR Gs MITOGEN BINDS GS RECEPTORS WHICH ACTIVATE ADENALATE CYCLASE(AC) AC THEN CONVERTS ATP INTO CYCLIC AMP CAMP ACTIVATES PROTEIN KINASE A PKA THEN PHOSPHORYLATES CYCLIN TRANSCRIPTION FACTORS

25. 2) TYROSINE KINASE RECEPTOR MITOGEN BINDS TO TK RECEPTORS AND THEY DIMERISE WHICH PHOSPHORYLATES THEM THIS LEADS TO ACTIVATION OF RAS PROTEIN RAS ACTIVATES RAF WHICH ACTIVATES MAP KINASES WHICH PHOSPHORYLATES TRANSCRIPTION FACTORS

26. 3) JANUS KINASES RECEPTOR MITOGEN BINDS AND ACTIVATES THE JANUS KINASE JANUS KINASE STIMULATES SIGNAL TRANSDUCER ACTIVATOR OF TRANSCRIPTION(STAT) WHICH BIND THE CYCLIN GENE

27. RETINOBLASTOMA PROTEIN GENE ON CHROMOSME 13q14 DNA BINDING PROTEIN G1/S CHECKPOINT AS A NEGATIVE REGULATOR OF CELL CYCLE IN G1, RB IS HYPOPHOSPHORYLATED AND BOUND TO E2F FAMILY OF TRANSCRIPTION FACTORS (prevents transcription of cyclin E) HYPOPHOSPHORYLATED RB BLOCKS E2F IN 2 WAYS 1) BOUND TO IT AND PREVENTS ITS INTERACTION WITH OTHER TRANSCRIPTION FACTORS 2) THROUGH HISTONE DEACETYLASES AND HISTONE METHYLTRANSFERASES WHICH BIND TO PROMOTERS OF E2F-RESPONSIVE GENES (CYCLINE E)

28. G1 CYCLIN D IS THE FIRST CYCLIN TO BE PRODUCED STIMULATED BY GFs BIND TO CDK4/6 CYCLIN D CDK4/6 CO M PLEX THEN PHOSPHORYLATES RETINOBLASTOMA E2F COMPLEX PHOSPHORYLATION OF RB THEREFORE LEADS TO INACTIVATION OF THE HISTONE DEACYTELASE WHICH ALLOWS THE DNA TO RELAXE AND BE TRANSCRIBED E2F LEADS TO TRANSCRIPTION OF CYCLIN E WHICH IS THE NEXT CYCLIN AND CYCLIN E LEADS TO S PHASE BY BINDING CDK2 CYCLINE E COMBINES WITH CDK2 IN LATE G1 TO ASSIST WITH MOVEMENT TO S PHASE

29. S CYCLINE E/CDK2 COMPLEXES THEN STIMULATES DNA REPLICATION AND PROGRESSION THROUGH THE CELL CYCLE WHEN CELLS ENTER S PHASE THEY ARE COMMITTED TO DIVIDE WITHOUT ADDITIONAL GROWTH FACTOR STIMULATION DURING M PHASE, THE PHOSPHATE GROUPS ARE REMOVED FROM RB BY PHOSPHATSES, REGENERATING THE HYPOPHOSPHORYLATED FORM OF RB CYCLINE E/CDK2 AND CYCLINE A/CDK2 REGULATE PROCESSES IN S PHASE BY PHOSPHORYLATING AND ACTIVATING PROTEINS AND ENZYMES THAT ARE INVOLVED IN DNA SYNTHESIS

30. CYCLE REGULATION OTHER E2F GENE PRODUCTS CYCLIN E /CDK2 -G1 INTO S PHASE VIA CDK2 AND INITIATES DNA REPLICATION DNA POLYMERASE REPLICATES DNA THYMIDINE KINASE KEY ENZYME FOR PYRIMIDINE SYNTHESIS DEHYDROFOLATE REDUCTASE INVOLVED IN DENOVO SYNTHESES OF PURINES CYCLIN A / CDK2 T RANSTIONS THE CELL THROUGH S PHASE INTO G2/M1 RESTRICTION POINT AND REGULATES MITOTIC PROPHASE

31. CYCLE REGULATION CYCLIN B-CDK1 PROPELS THE CELL BEYOND PROPHASE ACTIVATED BY CDC25 PHO S PHATASES AND BEGIN TO ACCUMULATE IN EARLY PROPHASE FUNCTIONS ARE NUCLEAR ENVELOPE BREAKDOWN, CHROMOSONE CONDENSATION. GOLGI APPARATUS FRAGMENTATION AND SPINDLE FORMATION TO EXIT FROM MITOSIS THE CYCLIN B CDK1 NEED TO BE DOWN REGULATED CDK1 IS ALSO KNOWN AS CDC2 SEPARATION OF CHROMOSOME AT ANAPHASE REQUIRES THE ANAPHASE-PROMOTING COMPLEX (APC), WHICH CONSIST OF E3 UBIQUITIN LIGASE CAUSING THE DEGRADATION OF CYCLINE B TO ALLOW EXIT FROM M PHASE.

32. REQUIREMENTS TO EXIT CYCLE DISMANTLING OF THE CELL CYCLE MACHINERY LACK OF MITOGENS DOWNREGULATION AND DEGRADATION OF CYCLINS CYCLINS ARE DEGRADED BY PROTEOSOMES VIA BINDING OF UBIQUITING WHICH IS A DEGRADATION MARKER FOR PROTEOSOMES ACCUMULATION OF CYCLIN INHIBITORS P16, P15, P18

33. CELL CYCLE INHIBITORS ANTIMITOGENS EG TRANSFORMING GROWTH FACTOR B CIP/KIP FAMILY INK4/ARF FAMILY

34. CELL CYCLE INHIBITORS THE CIP AND INK4 FUNCTION AS TUMOR SUPPRESSORS AND ARE ALTERED IN TUMORS THE CIP/KIP FAMILY HAS P21, P27, P57 WHICH BIND AND INACTIVATE CYCLIN-CDK COMPLEXES P21 IS ALSO ACTIVATED VIA P53 THE INK4 FAMILY ENCODED 2 PROTEINS P16INK4A COMPETETIVE INHIBITOR FOR CYCLIN D P14ARF PREVENTS p53 DEGRADATION

35. P53 TRANSCRIPTION FACTOR THAT BLOCKS NEOPLASTIC TRANSFORMATION VIA 1) TEMPORARY CELL CYCLE ARREST (QUIESCENCE) 2) PERMANENT CELL CYCLE ARREST (SENESCENCE) 3) APOPTOSIS TRIGGERS OF P53 1) ANOXIA 2) INAPPROPRIATE PRO-GROWTH STIMULI 3) DNA DAMAGE

36. P53 IS TARGETED BY MDM2 (GIVES IS A HALF LIFE OF 20MIN) ATM (ATAXIA TELANGIECTASIA) IS ACTIVATED IN RESPONSE TO DNA DAMAGE WHICH WILL RELEASE P53 FROM MDM2, INCREASING ITS HALF LIFE AND ABILITY TO DRIVE TRANSCRIPTION OF TARGET GENES 1) CELL CYCLE ARREST P53 CAUSES TRANSCRIPTION OF CDK1 GENE CDKN1A (P21) WHICH INHIBITS CYCLINE CDK COMPLEX AND PREVENTS PHOSPHORYLATION OF RB ALSO INDUCES EXPRESSION OF DNA DAMAGE REPAIR GENES IF DNA IS REPAIRED SUCCESSFULLY P53 UPREGULATES TRANSCRIPTION OF MDM2 LEADING TO ITS DESTUCTION AND CONTINUATION OF CELL CYCLE

37. IF DAMAGE CNT BE REPAIRED- 2) SENESCENCE REQUIRES ACTIVATION OF P53 AND OR RB MECHA NOT KNOW 3) P53 INDUCED APOPTOSIS

38. TRANSFORMING GROWTH FACTOR B POTENT INHIBITOR OF PROLIFERATION BINDS TO TGF-B RECEPTORS 1 AND II, DIMERIZATION AND LEADS TO A CASCADE OF EVENTS THAT RESULT IN TRANSCRIPTIONAL ACTIVATION OF CDKIs CDKI HAVE GROWTH SUPPRESSING ACTIVITY TGF-B CAUSES REPRESSION OF GROWTH PROMOTING GENES SUCH AS MYC AND CDK4 TGF-B BINDS TO TRANSMEMBRANE RECEPTOR WHICH ACTIVATES TRANSCRIPTION FACTORS CALLED SMADS SMADS ACTIVATE GENES THAT PRODUCE P15 WHICH INHIBITS CDK4 AND CDK6 THAT LEADS TO G1 ARREST

39. CELL CYCLE CHECK POINTS A CHECK POINT IS A SERIES OF PATHWAYS THAT MAINTAIN THE GENOME INTEGRITY BY SENSING AND INDUCING A RESPONSE TO DNA DAMAGE Checkpoints monitor and modulate the progression of cells through the cell cycle in response to intracellular or environmental signals. THERE ARE 3 CHECK POINTS IN THE CELL CYCLE G1 CHECK POINT G2 CHECK POINT METAPHASE TO ANAPHASE CHECK POINT

40. G1/S CHECK POINT THIS LEADS TO CYCLE ARREST IF THERE IS DNA DAMAGE NOTED BEFORE THE S PHASE THIS HELPS PREVENT CARRYING OVER DNA DAMAGE TO THE NEXT PROGENY IT ALSO LOOKS FOR AVAILABILITY OF INTERNAL STRUCTURES LIKE GROWTH FACTORS AND OTHER PROTEINS

41. G1/S CHECK POINT DNA DAMAGE IS SENSED VIA ATM/ATR KINASES IF THERE IS DAMAGE THEY PHOSPHORYLATE CHK2 WHICH ACTIVATES P53 P53 THEN ACTIVATES P21 WHICH INHIBITS CDK AND PAUSE THE CYCLE INORDER TO ALLOW REPAIR OF DAMAGE IF REPAIR FAILS P53 ACTIVATES APOPTOSIS VIA THE CASPASE CASCADE FROM THE MITCHONDRIA RB IS ACTIVATED VIA CDK4/6, IF P53 IS INHIBITING CDK4/6 VIA P16 THE RB WILL NOT ALLOW E2F TO BIND TO THE DNA ALSO IF GF IS ABSENT THE CYCLINS WILL NOT BE TRANSCRIBED THERFORE THE RB WILL NOT BE SEPARATED FROM THE E2F p16, p21, p27 INHIBIT CDK4/6 CDC25A PHOSPHATASE IS ALSO CABLE OF REMOVING INHIBITORY PHOSPHORYLATION RESIDUES ON CDK2 IN LATER G1 PHASE, RESULTING IN ADDITIONAL PHOSPHORYLATION OF RB1 AND RELEASE OF E2F, THERE PROMOTING G1/S TRANSITION

42. G2/M CHECKPOINT MONITORS COMPLETION OF DNA REPLICATION IMPORTANT IN CELLS EXPOSED TO IONISING RADIATION, DAMAGE WILL LEAD TO ARREST IN G2 PHASE DEFECTS LEAD TO CHROMOSOMAL ABNORMALITIES DNA DAMAGE SENSED BY ATM/ATR KINASES WHICH ACTIVATE CHK1 CHK1 INHIBITS CDC25 THAT IS SUPPOSED TO ACTIVATE CYCLIN B-CDK1 CHK1 ALSO ACTIVATES P53

43. METAPHASE ANAPHASE CHECK POINT CDELL ENSURE CHROMOSOMES ARE PROPERLY ALGNED AND ATTACHED TO SPINDLES IN LATE METAPHASE THE ANAPHASE PROMOTING COMPLEX INHIBITS SECURIN AND ALLOWS SEPARASE TO SEPARATE THE CHROMOSOMES SENSORS ARE WITHIN THE KINETOCHORES UNEVEN TENSION ON THE KINETOCHORES TRIGERS MOLECULES SUCH AS MAD 1 AND MAD 2 WHICH INHIBIT THE APC UNTIL THERE IS EVEN TENSION HELPS TO PREVENT CHROMOSOME DISTRIBUTION ERRORS WHICH LEAD TO ANEUPLOIDY

44. THANK YOU