A nuclear phosphoinositide kinase complex regulates p53

被引：72

作者：

Choi, Suyong ^{[1
]}

Chen, Mo ^{[1
]}

Cryns, Vincent L. ^{[2
]}

Anderson, Richard A. ^{[1
]}

机构：

[1] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53706 USA

[2] Univ Wisconsin, Dept Med, Carbone Canc Ctr, Sch Med & Publ Hlth, Madison, WI USA

来源：

NATURE CELL BIOLOGY | 2019年 / 21卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ALPHA-B-CRYSTALLIN; PLECKSTRIN HOMOLOGY DOMAINS; HEAT-SHOCK PROTEINS; MUTANT P53; CANCER; HSP90; MDM2; DNA; STABILIZATION; LOCALIZATION;

D O I：

10.1038/s41556-019-0297-2

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The tumour suppressor p53 (encoded by TP53) protects the genome against cellular stress and is frequently mutated in cancer. Mutant p53 acquires gain-of-function oncogenic activities that are dependent on its enhanced stability. However, the mechanisms by which nuclear p53 is stabilized are poorly understood. Here, we demonstrate that the stability of stress-induced wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase (PIPKI-alpha (also known as PIP5K1A)) and its product phosphatidylinositol 4,5-bisphosphate (Ptdlns(4,5)P-2). Nuclear PIPKI-alpha binds to p53 upon stress, resulting in the production and association of Ptdlns(4,5)P(2 )with p53. Ptdlns(4,5)P(2 )binding promotes the interaction between p53 and the small heat shock proteins HSP27 (also known as HSPB1) and alpha B-crystallin (also known as HSPB5), which stabilize nuclear p53. Moreover, inhibition of PIPKI-alpha or Ptdlns(4,5)P(2 )association results in p53 destabilization. Our results point to a previously unrecognized role of nuclear phosphoinositide signalling in regulating p53 stability and implicate this pathway as a promising therapeutic target in cancer.

引用

页码：462 / +

页数：16

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