Wang Chuangui, Chen Jiandong
Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida 33612, USA.
J Biol Chem. 2003 Jan 17;278(3):2066-71. doi: 10.1074/jbc.M206697200. Epub 2002 Nov 8.
The p53 tumor suppressor is stabilized and activated by diverse stress signals. In this study, we investigated the mechanism of p53 activation by heat shock. We found that heat shock inhibited p53 ubiquitination and caused accumulation of p53 at the post-transcriptional level. Heat shock induced phosphorylation of p53 at serine 15 in an ATM kinase-dependent fashion, which may contribute partially to heat-induced p53 accumulation. However, p53 accumulation also occurred after heat shock in ATM-deficient cells. Heat shock induced conformational change of wild type p53 and binding to hsp90. Inhibition of hsp90-p53 interaction by geldanamycin prevented p53 accumulation partially in ATM-wild type cells and completely in ATM-deficient cells. Therefore, phosphorylation and interaction with hsp90 both contribute to stabilization of p53 after heat shock.
p53肿瘤抑制蛋白可被多种应激信号稳定并激活。在本研究中，我们探究了热休克激活p53的机制。我们发现热休克抑制p53泛素化，并在转录后水平导致p53积累。热休克以ATM激酶依赖的方式诱导p53丝氨酸15位点磷酸化，这可能部分促成热诱导的p53积累。然而，在ATM缺陷细胞中热休克后也会发生p53积累。热休克诱导野生型p53构象改变并与hsp90结合。格尔德霉素抑制hsp90-p53相互作用可部分阻止ATM野生型细胞中p53积累，并完全阻止ATM缺陷细胞中p53积累。因此，磷酸化以及与hsp90的相互作用均有助于热休克后p53的稳定。
