Title

Supervillin-mediated Suppression of p53 Protein Enhances Cell Survival

UMMS Affiliation

Department of Cell and Developmental Biology

Date

3-15-2013

Document Type

Article

Subjects

Membrane Proteins; Microfilament Proteins; Tumor Suppressor Protein p53; Ubiquitin Thiolesterase

Abstract

Integrin-based adhesions promote cell survival as well as cell motility and invasion. We show here that the adhesion regulatory protein supervillin increases cell survival by decreasing levels of the tumor suppressor protein p53 and downstream target genes. RNAi-mediated knockdown of a new splice form of supervillin (isoform 4) or both isoforms 1 and 4 increases the amount of p53 and cell death, whereas p53 levels decrease after overexpression of either supervillin isoform. Cellular responses to DNA damage induced by etoposide or doxorubicin include down-regulation of endogenous supervillin coincident with increases in p53. In DNA-damaged supervillin knockdown cells, p53 knockdown or inhibition partially rescues the loss of cell metabolic activity, a measure of cell proliferation. Knockdown of the p53 deubiquitinating enzyme USP7/HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression. Conversely, supervillin overexpression decreases the association of USP7 and p53 and attenuates USP7-mediated p53 deubiquitination. USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin. Supervillin also is stabilized by derivatization with the ubiquitin-like protein SUMO1. These results show that supervillin regulates cell survival through control of p53 levels and suggest that supervillin and its interaction partners at sites of cell-substrate adhesion constitute a locus for cross-talk between survival signaling and cell motility pathways.

Rights and Permissions

Citation: J Biol Chem. 2013 Mar 15;288(11):7918-29. doi: 10.1074/jbc.M112.416842. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

23382381