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  • Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants.

Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants.

Communications biology (2021-12-10)
Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
ABSTRACT

Tumor suppressor p53, a critical regulator of cell fate, is frequently mutated in cancer. Mutation of p53 abolishes its tumor-suppressing functions or endows oncogenic functions. We recently found that p53 binds via its proline-rich domain to peptidase D (PEPD) and is activated when the binding is disrupted. The proline-rich domain in p53 is rarely mutated. Here, we show that oncogenic p53 mutants closely resemble p53 in PEPD binding but are transformed into tumor suppressors, rather than activated as oncoproteins, when their binding to PEPD is disrupted by PEPD knockdown. Once freed from PEPD, p53 mutants undergo multiple posttranslational modifications, especially lysine 373 acetylation, which cause them to refold and regain tumor suppressor activities that are typically displayed by p53. The reactivated p53 mutants strongly inhibit cancer cell growth in vitro and in vivo. Our study identifies a cellular mechanism for reactivation of the tumor suppressor functions of oncogenic p53 mutants.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Histone Acetyltransferase p300 Inhibitor, C646, Histone Acetyltransferase p300 Inhibitor, C646, CAS 328968-36-1, is a cell-permeable, reversible inhibitor of p300/CBP HAT (Ki = 400 nM). Competes with acetyl-CoA for the p300 Lys-CoA binding pocket.
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 3, DMSO solution
Sigma-Aldrich
Puromycin dihydrochloride from Streptomyces alboniger, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
Monoclonal Anti-PEPD antibody produced in mouse, clone 1D5-H3, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-acetyl-p53 (Lys320) Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse