Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Nat Cell Biol. 2016 Nov;18(11):1233-1243. doi: 10.1038/ncb3427. Epub 2016 Oct 24.

DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway.

Author information

1
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
2
Department of Chemistry, Abeda Inamdar Senior College, Pune, Maharashtra 411001, India.
3
Department of Pharmacology, Toxicology and Therapeutics, Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
4
High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas 66047, USA.

Abstract

Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway-DNAJA1 axis, and highlights the significance of p53 status in impacting statins' efficacy on cancer therapy.

PMID:
27775703
PMCID:
PMC5340314
DOI:
10.1038/ncb3427
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center