20151108-细胞死亡及周期阻滞基本信号通路详解.ppt

● Senescence： Senescence can be triggered when telomeres—the ends of linear chromosomes—cannot fulfil their normal protective functions. Telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres Senescent human fibroblasts display molecular markers characteristic of cells bearing DNA DSBs: Senescent markers nuclear foci of phosphorylated histone H2AX their co-localization with DNA repair factors DNA damage checkpoint factors activation of the DNA damage checkpoint kinases CHK1 /CHK2 (S phase) Chromatin immunoprecipitation (ChIP) and whole-genome scanning approaches show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. （Fagagna Fd’AD, et al. Nature 2003; 426:194-198; Ventura A et al. Nature 2007; 445:661-665） DNA损伤的后果——细胞衰老 53BP1, MDC1 and NBS1 Determination of senescence Comparing PKH2 fluorescence profiles of the wild-type, p21-/- and p53-/- HCT116 cell lines six days after exposure to doxorubin (adriamycin, an anti-cancer chemotherapy drug and is classified as an anthracycline antiobiotic. Doxorubicin is used to treat many cancers ). The inhibition or knockout of p53 or p21 decreased but did not abolish drug- or radiation-induced senescence, indicating partial requirement for p53 and p21 in treatment-induced senescence. (Drug Resistance Update, 4:303, 2001） DNA损伤的后果——细胞衰老(及检测方法)(举例) (Tina Rich, et al, Nature 2000, 407:777-783) 3. CELL-CYCLE CHECKPOINT PATHWAYS 细胞周期检验点信号途径 ● G1-phase Checkpoint Pathway *ATM-CHK2-CDC25A-CDK2 axis forms a rapid response system; * ATR-CHK1-CDC25A-CDK2; CDC25A-CDK4; *ATM-CHK2/ATR-CHK1-p53-p21 pathway (Oncogene, 22:5834, 2003) G1-期检验点基本信号途径 ● S-phase Checkpoint Pathw