Chaperone-dependent stabilization and degradation of p53 mutants.

Komentováno: 29. 5. 2013

p53 missense mutant proteins commonly show increased stability compared to wild-type p53, which is thought to depend largely on the inability of mutant p53 to induce the ubiquitin ligase MDM2. However, recent work using mouse models has shown that the accumulation of mutant p53 occurs only in tumour cells, indicating that stabilization requires additional factors. To clarify the stabilization of p53 mutants in tumours, we analysed factors that affect their folding and degradation. Although all missense mutants that we studied are more stable than wild-type p53, the levels correlate with individual structural characteristics, which may be reflected in different gain-of-function properties. In the absence of Hsp90 activity, the less stable unfolded p53 mutants preferentially associate in a complex with Hsp70 and CHIP (carboxy terminus of Hsp70-interacting protein), and we show that CHIP is responsible for ubiquitination and degradation of these mutants. The demonstration of a complex interplay between Hsp90, Hsp70 and CHIP that regulate the stability of different p53 mutant proteins improves our understanding of the pro-tumorigenic effects of increased Hsp90 activity during multi-stage carcinogenesis. Understanding the roles of Hsp90, Hsp70 and CHIP in cancers may also provide an important avenue through which to target p53 to enhance treatment of human cancers. 

Oncogene. 2008 May 29;27(24):3371-83

Mgr. Roman Hrstka, Ph.D.: V případě, že je protein p53 mutovaný, dochází k jeho hromadění v buňce pravděpodobně z důvodu, že mutovaný protein p53 není schopen indukovat zvýšenou expresi MDM2 a dále z důvodu zvýšené stability mutovaného p53. Bylo prokázáno, že na stabilitě mutovaného p53 se podílejí chaperony, především HSP90, HSP70 a další. Dále se podařilo prokázat, že degradace mutovaného p53 se účastní protein CHIP, avšak jeho aktivita je ovlivněna typem mutace, respektive konformací mutovaného proteinu p53.

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