Cyclins_Cell_Cycle_Regulation外文学习材料.pptVIP

P P P P CDK1 CDK1 CDK1 CDK1 Cyclin-A Ub Rb P P P P P P P P P P P P P Rb P P P P P ATR P P E2F DP1 DP1 E2F P Rb Rb CDC25A P Ub Ub Ubiquitination Ubiquitination Cyclin-H CDC25A E2F Rb Cyclin-B Cyclin-A CDC25A P Wee1 MYT1 p21 E2F Rb Wee1 PP2A Raf1 CDC25A p21 P Cyclin-A Wee1 p21 Wee1 TGFb p19(INK4D) MYT1 Cyclin-D/D1 Cyclin-E p18(INK4C) p16(INK4A) p15(INK4B) GSK3b p27(KIP1) Cell CycleProgression Nucleus S-Phase Genes[Cyclin-A, E,E2F, CDC2] ReplicativeScenescece ContactInhibition M G2 ReplicativeSenescence Growth FactorWithdrawal CIP/KIPFamily Off On G1 Cyclins and Cell Cycle Regulation DNA Damage CDK4/6 ATM p27(KIP1) CDK7 Cyclin-H CDK2 CDK2 Cyclin-A CDK2 CDK2 p27(KIP1) p27(KIP1)Degradation SCF HDACs p53 2009 ProteinL C * Review: Progress in the eukaryotic cell cycle is driven by oscillations in the activities of CDKs (Cyclin-Dependent Kinases). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits, Cyclins, as well as by fluctuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over two new nuclei in the process of mitosis. These two phases are separated by two so called “Gap” phases, G1 and G2, in which the cell prepares for the upcoming events of S and M, respectively (Ref.1). The different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle, accumulate and activate CDKs at the appropriate times during the cell cycle and then are degraded, causing kinase inactivation. Levels of some CKIs, which specifically inhibit certain Cyclin/CDK complexes, also rise and fall at specific times during the cell cycle (Ref.2). A breakdown in the regulation of this cycle leads to uncontrolled growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle also lead to tumor progressi