研究生课 细胞周期调控与癌症 分子生物学课.ppt

* More than 36 amino acids of p53 are reported to be modified. The major sites of p53 phosphorylation (P), ubiquitination (Ub), and acetylation (Ac) are shown with the corresponding major modifying enzymes and signals. Furthermore, additional phosphorylation and acetylation sites, as well as major sites of methylation (Me), sumoylation (S), neddylation (N8), glycosylation (O-Glc), and ribosylation (ADP), are indicated. * Different proteins can bind to p53 to induce different cellular outcomes to p53 activity. Brn3A, Hzf, c-Abl, YB1, and p18/Hamlet selectively induce p53 activation of genes encoding cell cycle regulators such as p21 to facilitate cell cycle arrest. In contrast, ASPPs, the zebrafish p53 variant delta113p53, the p53 isoform p53β, Brn3b, NFκB/ p52, and Muc1 selectively activate the expression of apoptotic regulators such as PUMA, Bax, and Noxa to promote cell death. * * * * Anaphase promoting complex, or cyclosome, is an E3 ubiquitin ligase. Puts a small polypeptide, ubiquitin, on to a lysine residue cyclin b has a destruction box More Ubs added to make a poly Ub chain This is a signal which targets the protein for proteolysis mediated by the proteosome, a large structure with protease activity. The key question is how is the APC regulated such that cyclin b is not degraded prematurely (lecture 6) Control of p53 O n c o g e n i c i n s u l t s p 5 3 M D M 2 A R F E 2 U b cell cycle arrest or apoptosis p53 p 5 3 M D M 2 Ub p53 Ub Ub Ub Ub Ub DNA damage MDM2 P p 5 3 P p53 P p53 p53 p53 P P P A A A A Ub p53 p53 P A p53 Ub Ub Ub Ub p53 p53 target genes HAUSP Apoptosis MDM2 Phosphorylation ATM, Chk1, Chk2, etc PID/HDAC1 Other factors: COP1, YY1, Pirh2, gankyrin 26S Some corepressor: CTBP2, IFI61, mSin3a Oncogene ARF Sir 2α Acetylation CBP/P300, etc Bcl2/Bcl XL Ub p53 26S MDM2 Apoptosis Cell cycle arrest DNA repair Senescence E4 Cellular stress p53的调控网络 Rb and p53 tumor suppression pathways Rb G0/G1 S Normal cell CDK p53 MDM2 oncogenes ARF mitogen cycl