Supervillin-mediated suppression of p53 protein enhances cell survival.
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.
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GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y
USP7 p53 USP7 supervillin supervillin Supervillin ubiquitin SUMO1 supervillin supervillin N p53 supervillin tumor suppressor protein p53 supervillin (isoform 4) or both isoforms 1 and 4 p53 p53 supervillin supervillin p53 etoposide supervillin p53 p53 USP7 HAUSP supervillin p53 supervillin p53 Supervillin doxorubicin p53 Integrin supervillin supervillin adhesion regulatory protein USP7 p53