肿瘤学细胞周期重点分析.pptVIP

2001 Nobel Prize Interphase: – G1: gap – (G0: quiescent state during which cell cycle does not proceed) – S: replication of DNA and assembly of chromosomal proteins on daughter DNA molecules – G2: gap M phase: mitosis (nuclear division) cytokinesis (cytoplasmic division) 细胞增殖是生命的基本特征 初生婴儿1012个细胞，成人1014个，约200种类型。 成人体内每秒钟有数百万新细胞产生，以补偿衰老和死亡的细胞。 一个大肠杆菌若按20分钟分裂一次，并保持这一速度，则两天即可超过地球的重量。 Mechanisms involved in cell cycle control: Checkpoint regulation Differential cyclin gene expression Protein degradation (ubiquitin pathway) CDK activities regulated by – phosphorylation – binding of cyclins 1. MPF(M phase –promoting factor) , Cyclin ,CDK budding yeast Fission yeast Cdc 25 Wee1 mutant T. Hunt 1980s发现海胆的卵裂过程中两种蛋白质的含量随细胞周期振荡，命名为cyclin A和B，其mRNA能诱导蛙卵成熟。 2 CHECKPOINT 组成：感受器、信号传导通路、效应器。 主要检验点： G1/S检验点：DNA是否损伤？细胞外环境是否适宜？细胞体积是否足够大？在酵母中称start点，在哺乳动物中称R点(restriction point)。 S期检验点：DNA复制是否完成？ G2/M检验点：DNA是否损伤？细胞体积是否足够大？ 中-后期检验点：纺锤体组装检验点。 Four checkpoints 2.1 The G1 /S Checkpoint Environmental Growth factors- (from other cells), e g PDGF Density dependent inhibition Internal DNA damage G1 cyclin D(D1,D2,D3),E,A G1 CDK,CDK2,4,6 cyclin D+CDK4,6 cyclin E,A+CDK2 cyclin D(D1,D2,D3) is key factor for G1/S cyclin E is key factor for startup s-phase G1 phase cyclin degradation by Ubiquitin through PEST 2.2 S/G2/M DNA replication checkpoint If DNA did not complete replication, s-phase could not change into G2 This G2checkpoint senses unreplicated DNA, which generates a signal that leads to cell cycle arrest. CDC25 activity is low but Weel activity is high ◆ G2 checkpoint : ●G2 checkpoint prevents the initiation of mitosis until DNA replication is completed ● Only the inhibition of G2 progression relieved, allowing the cell to initiate mitosis and distribute the completely replicated chromosomes to daughter cells. 2.3 M-phase regulation MPF activate M phase checkpoint MPF the G2 Checkpoint MPF- pushes cell past G2 checkpoint So MPF gets us into mitosis, how do we get ou