CELL DEATH: THE ROLE OF PARP
CONTENTS G1 PHASE: COMPONENTS, CONUNDRUMS, CONTEXT INTRODUCTION ARRIVAL OF THE CYCLE DISCRETE EVENTS DURING DIVISION MAINTAINING ORDER CELL CYCLE MACHINERY G1 PROGRESSION IN CULTURED CELLS COORDINATING CELL GROWTH AND DIVISION INFORMATION INTEGRATION THE CYCLIN-CDK ENGINE REMOVING IMPEDIMENTS: INACTIVATING RB REMOVING IMPEDIMENTS: INACTIVATING P27KIP1 PREPARING FOR THE FUTURE ABLATING G1 REGULATORS IN MICE CYCLIN D-CDK4/6 CYCLIN E/CDK2 G1 TARGETS IMPLICATIONS AND FUTURE DIRECTIONS CONUNDRUMS G1 IN CONTEXT CONCLUSIONS REFERENCES REGULATION OF S PHASE ORIGINS OF REPLICATION GENOME REPLICATOR SEQUENCES PRE-REPLICATION COMPLEX ORC CDT1 CDC6 MCM2-7 GEMININ SUMMARY PRE-INITIATION COMPLEX MCM10 CDC45 GINS DPB11 S-PHASE REGULATION AND CANCER CONCLUSION CHECKPOINT AND COORDINATED CELLULAR RESPONSES TO DNA DAMAGE SENSING DNA DAMAGE AND DNA REPLICATION STRESS RECRUITMENT OF ATR TO DNA DNA DAMAGE RECOGNITION BY THE RFC- AND PCNA-LIKE CHECKPOINT COMPLEXES PROCESSING OF DNA LESIONS MRN COMPLEX AND ACTIVATION OF ATM AND ATR TRANSDUCTION OF DNA DAMAGE SIGNALS REGULATION OF DOWNSTREAM CELLULAR PROCESSES REGULATION OF THE CELL CYCLE REGULATION OF DNA REPLICATION FORKS REGULATION OF DNA REPAIR REGULATION OF TELOMERES INTERPLAY BETWEEN CHECKPOINT SIGNALING AND CHROMATIN PERSPECTIVES PROTEIN KINASES INVOLVED IN MITOTIC SPINDLE CHECKPOINT REGULATION THE SPINDLE ASSEMBLY CHECKPOINT REGULATION OF THE SPINDLE CHECKPOINT BY PROTEIN KINASES BUB1 BUBR1 AURORA B MPS1 MITOGEN-ACTIVATED PROTEIN KINASE THE SPINDLE CHECKPOINT AND CANCER THE CENTROSOME CYCLE HISTORY MICROTUBULE ORGANIZING CENTERS CENTROSOME FUNCTIONS CENTROSOME DYSFUNCTION AND CANCER/DISEASE CENTROSOME STRUCTURE CENTROSOME DUPLICATION CENTROSOME MATURATION CENTROSOME SEPARATION LICENSING OF CENTROSOME DUPLICATION POST-MITOSIS RETURN TO G1 THE UBIQUITIN-PROTEASOME PATHWAY IN CELL CYCLE CONTROL THE UBIQUITIN-PROTEASOME PATHWAY PROTEIN-UBIQUITIN LIGASES IN THE CELL CYCLE CORE MACHINERY APC/C PROTEIN-UBIQUITIN LIGASES APC/C SUBSTRATES AND BIOLOGY APC/C AND MEIOSIS SCF PROTEIN-UBIQUITIN LIGASES SCF SUBSTRATES AND BIOLOGY REGULATION OF SCF ACTIVITY CHECKPOINT CONTROL ATYPICAL ROLES OF PROTEASOMES AND UBIQUITYLATION DEUBIQUITYLATING ENZYMES THE RETINOBLASTOMA GENE FAMILY IN CELL CYCLE REGULATION AND SUPPRESSION OF TUMORIGENESIS CANCER AND GENETIC ALTERATIONS THE PRB CELL CYCLE CONTROL PATHWAY: COMPONENTS AND THE CANCER CONNECTION REGULATION OF E2F RESPONSIVE GENES BY PRB THE RETINOBLASTOMA GENE FAMILY RB GENE FAMILY MEMBERS PRB FAMILY PROTEIN STRUCTURE SIMILAR AND DISTINCT FUNCTIONS OF THE PRB PROTEIN FAMILY PRB FAMILY MEDIATED REGULATION OF E2F BY CELLULAR LOCALIZATION REGULATION OF E2F MEDIATED GENE EXPRESSION THE PRB FAMILY AND THE CELLULAR RESPONSE TOWARDS GROWTH-INHIBITORY SIGNALS THE PRB AND P53 PATHWAY IN SENESCENCE AND TUMOR SURVEILLANCE REPLICATIVE SENESCENCE TUMOR SURVEILLANCE INTERCONNECTIVITY BETWEEN THE PRB AND P53 PATHWAY THE RB GENE FAMILY IN TUMOR SUPPRESSION IN MICE MECHANISTIC INSIGHTS IN THE TUMOR SUPPRESSIVE ROLE OF THE RB GENE FAMILY ROLE OF P107 AND P130 IN HUMAN CANCER THE RETINOBLASTOMA GENE FAMILY IN DIFFERENTIATION AND TUMORIGENESIS A LINK BETWEEN PAX, BHLH AND POCKET PROTEINS IN DIFFERENTIATION AND TUMORIGENESIS PAX AND BHLH PROTEINS IN RETINA AND PULMONARY EPITHELIUM DEVELOPMENT MODELING CELL CYCLE CONTROL AND CANCER WITH PRB TUMOR SUPPRESSOR INTRODUCTION AND BACKGROUND EPIDEMIOLOGY MODELING HUMAN CANCER IN THE MOUSE THE UNIVERSALITY OF THE CELL CYCLE THE PRB TUMOR SUPPRESSOR PATHWAY THE DISCOVERY OF PRB UPSTREAM REGULATORS OF PRB PHENOTYPE OF MICE LACKING PRB FAMILY MEMBERS PRB REGULATES GROWTH AND DIFFERENTIATION THE E2F/DP TRANSCRIPTION FACTOR FAMILY E2F TARGET GENES AND REPRESSION MICE DE?CIENT IN E2F FAMILY MEMBERS CYCLIN-DEPENDENT KINASES AND THEIR INHIBITORS DEREGULATION OF CYCLINS, CDKS AND CKIS IN HUMAN TUMORS MICE DE?CIENT IN CYCLINS, CDKS AND CKIS LINKS BETWEEN THE PRB AND P53 TUMOR SUPPRESSOR PATHWAY MURINE MODELS OF RETINOBLASTOMA REVISING CELL CYCLE MODELS SENESCENCE AND CELL CYCLE CONTROL SENESCENCE ROLE OF THE P53 PATHWAY IN SENESCENCE ROLE OF THE RB PATHWAY IN SENESCENCE THE ROLE OF THE INK4A/ARF LOCUS IN SENESCENCE MOUSE CELLS VS HUMAN CELLS: ROLES OF REACTIVE OXYGEN SPECIES AND TELOMERE ATTRITION MOUSE MODELS OF CELL CYCLE REGULATORS: NEW PARADIGMS HISTORY OF THE CELL CYCLE MODEL THE CONCEPT OF MAMMALIAN CELL CYCLE REGULATION LESSONS FROM YEAST HUMAN CDC2, CDK2 AND CYCLIN E G1 PHASE IN MAMMALIAN CULTURED CELLS MOUSE MODELS OF CELL CYCLE REGULATORS TARGETING OF INDIVIDUAL CELL CYCLE REGULATORS RESULTS IN EMBRYONIC LETHALITY STERILITY MOUSE MODELS WITH HEMATOPOIETIC DEFECTS MOUSE MODELS WITH PANCREATIC DEFECTS PLACENTAL DEFECTS AND ENDOREDUPLICATION TUMORIGENESIS IN MOUSE MODELS OF CELL CYCLE REGULATORS PITUITARY TUMORS SKIN CANCER AND MELANOMA BREAST CANCER OVARIAN TUMORS NEW FUNCTIONS FOR OLD PLAYERS CDC2 REGULATES S PHASE ENTRY P27 REGULATES THE RHO PATHWAY GENETIC INTERACTION AND FUNCTIONAL COMPLEMENTATION OF CELL CYCLE REGULATORS INTERACTIONS OF CYCLIN D1 AND P27 IN G1/S PHASE TRANSITION FUNCTIONAL COOPERATION BETWEEN CDK2, CDK4 AND P27 COMPENSATION BETWEEN THE D-TYPE CYCLINS INTERACTIONS BETWEEN CDK4 AND CDK6 IMPLICATIONS OF DATA FROM CELL CYCLE MOUSE MODELS TO HUMAN CANCER CDK2 IN HUMAN TUMORS AND IN TUMOR CELL LINES CONTROL OF CELL PROLIFERATION AND GROWTH BY MYC PROTEINS MECHANISMS OF MYC ACTION TARGETS CHECKPOINTS AND APOPTOSIS CELL CYCLE REGULATION IN MAMMALIAN GERM CELLS CELL CYCLE REGULATORY GENES REQUIRED FOR INITIATION AND MAINTENANCE OF MEIOSIS TRANSCRIPTIONAL AND TRANSLATIONAL FACTORS CELL SIGNALING CYTOPLASMIC AND APOPTOTIC FACTORS CELL CYCLE REGULATION DURING PROPHASE I FUTURE PERSPECTIVES G1 PHASE: COMPONENTS, CONUNDRUMS, CONTEXT ABSTRACT A EUKARYOTIC CELL MUST COORDINATE DNA SYNTHESIS AND CHROMOSOMAL SEGREGATION TO GENERATE A FAITHFUL REPLICA OF ITSELF THESE EVENTS ARE CON?NED TO DISCRETE PERIODS DESIG- NATED SYNTHESIS (S) AND MITOSIS (M), AND ARE SEPARATED BY TWO GAP PERIODS (G1 AND G2) A COMPLETE PROLIFERATIVE CYCLE ENTAILS SEQUENTIAL AND REGULATED PROGRESSION THROUGH G1, S, G2, AND M PHASES DURING G1, CELLS RECEIVE INFORMATION FROM THE EXTRACELLULAR ENVIRON- MENT AND DETERMINE WHETHER TO PROLIFERATE OR TO ADOPT AN ALTERNATE FATE WORK IN YEAST AND CULTURED MAMMALIAN CELLS HAS IMPLICATED CYCLIN DEPENDENT KINASES (CDKS) AND THEIR CYCLIN REGULATORY PARTNERS AS KEY COMPONENTS CONTROLLING G1 UNIQUE CYCLIN/CDK COM- PLEXES ARE TEMPORALLY EXPRESSED IN RESPONSE TO EXTRACELLULAR SIGNALING, WHEREUPON THEY PHOSPHORYLATE SPECI?C TARGETS TO PROMOTE ORDERED G1 PROGRESSION AND S PHASE ENTRY CY- CLINS AND CDKS ARE THOUGHT TO BE REQUIRED AND RATE-LIMITING FOR CELL PROLIFERATION BECAUSE MANIPULATING THEIR ACTIVITY IN YEAST AND CULTURED MAMMALIAN CELLS ALTERS G1 PROGRESSION HOWEVER, RECENT EVIDENCE SUGGESTS THAT THESE SAME COMPONENTS ARE NOT NECESSARILY RE- QUIRED IN DEVELOPING MOUSE EMBRYOS OR CELLS DERIVED FROM THEM THE IMPLICATIONS OF THESE INTRIGUING OBSERVATIONS FOR UNDERSTANDING G1 PROGRESSION AND ITS REGULATION ARE DISCUSSED INTRODUCTION “ALL THEORY IS GREY, LIFE’S GOLDEN TREE ALONE IS GREEN ” EVER SINCE THE CELL WAS DESIGNATED THE FUNDAMENTAL UNIT OF LIVING ORGANISMS, EFFORTS HAVE BEEN INCREASINGLY DEVOTED TO SOLVING THE MYSTERY OF ITS PROPAGA- TION PHYSICAL OBSERVATION IN DIVERSE SYSTEMS, FROM SIMPLE UNICELLULAR BACTERIA TO COMPLEX MULTICELLULAR ANIMALS, REVEALED THAT THIS PROCESS INVOLVES DUPLI- CATING CELLULAR CONTENTS FOLLOWED BY DIVISION INTO TWO IDENTICAL CELLS (NURSE 2000A) CELL CYCLE THEORY IS A GENERALIZED CONCEPTUAL FRAMEWORK FOR DESCRIBING HOW A EUKARYOTIC CELL COPIES ITSELF BY COORDINATING AN INCREASE IN MASS, CHROMO- SOME REPLICATION/SEGREGATION, AND DIVISION (MITCHISON 1971) OVER THE PAST 3 DECADES, THE MACHINERY CONTROLLING THESE PROCESSES HAS BEEN IDENTI?ED AND ORGANIZED INTO A DESCRIPTION OF CELL CYCLE PROGRESSION NOW THAT THE ?ELD HAS ITS NOBEL PRIZE, ONE MIGHT ASSUME THAT THE PICTURE IS LARGELY COMPLETE AND ONLY DETAILS REMAIN A BROADER PERSPECTIVE, HOWEVER, REMINDS US THAT THOSE WHO IGNORE THE HISTORY OF SCIENTI?C ADVANCEMENT ARE OFTEN DOOMED NOT TO RE- PEAT IT THAT THE CELL CYCLE ?ELD WILL BE NO EXCEPTION IS EVIDENCED BY SURPRISING NEW OBSERVATIONS HINTING THAT IT MIGHT BE TIME TO START A NEW CANVAS THIS CHAPTER WILL ?RST UNDERTAKE AN EXAMINATION OF HOW CELL CYCLE THEORY DEVELOPED, WHICH REVEALS THE RATIONALE FOR G1 PHASE AND ITS ROLE IN CELL DIVI- SION WE NEXT LAY OUT IN BROAD STROKES THE CURRENT UNDERSTANDING OF MOLECULAR EVENTS CONTROLLING G1 PROGRESSION IN MAMMALIAN CELLS PRINCIPLES AND GENER- ALIZATIONS UNDERLYING THIS MODEL WILL BE EXPLICITLY IDENTI?ED AND DISCUSSED, WITH PARTICULAR EMPHASIS ON HOW THEY ARE NOW BEING CALLED INTO QUESTION BY RECENT EXPERIMENTAL DATA ANALYZING CELL CYCLE REGULATORS IN MICE ULTIMATELY, WE HOPE TO ILLUSTRATE HOW ACCUMULATING EVIDENCE PROVIDES HINTS OF A RICHER AND MORE COMPLEX PICTURE OF G1 PHASE WAITING TO BE DISCOVERED DISCRETE EVENTS DURING DIVISION PHYSICAL OBSERVATION OF ANIMAL CELL DUPLICATION IDENTI?ED DISCRETE EVENTS DUR- ING THIS PROCESS, THE MOST DRAMATIC BEING CONDENSATION OF THREAD-LIKE STRUC- TURES SHORTLY BEFORE CELL DIVISION (FLEMMING 1965) WE NOW KNOW THIS PERIOD AS MITOSIS, WHEN THE CHROMOSOMES SEGREGATE AND ARE EQUALLY DISTRIBUTED TO THE MOTHER AND DAUGHTER CELL SUBSEQUENT WORK REVEALED CHROMOSOMES CON- TAIN THE HEREDITARY MATERIAL, ARE COMPOSED OF DNA, AND ARE DUPLICATED AT A DE?NED PERIOD OCCURRING BEFORE CELL DIVISION (NURSE 2000A) THESE INITIAL OBSERVATIONS SUGGESTED THAT CELL DUPLICATION IS DIVIDED INTO DISCRETE PERIODS OR PHASES, AN ORGANIZING PRINCIPLE DISTINGUISHING BACTERIA FROM EUKARYOTIC CELLS MOLECULAR MECHANISMS ARE THEREFORE REQUIRED TO COORDINATE THESE PROCESSES IN TIME AND SPACE CELL DEATH THE ROLE OF PARP