title: Supervillin-mediated suppression of p53 protein enhances cell survival.
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.
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: zhiyou.fang@umassmed.edu.
authors: Zhiyou
authors: Z
authors: Fang
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: elizabeth.luna@umassmed.edu.
authors: Elizabeth J
authors: EJ
authors: Luna
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003001:Cloning, Molecular; D003599:Cytoskeleton / Q000378:metabolism; D004249:DNA Damage; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005822:Genetic Vectors; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D020033:Protein Isoforms; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: D008565:Membrane Proteins; D008840:Microfilament Proteins; D020033:Protein Isoforms; C109413:SVIL protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D051416:Focal Adhesion Protein-Tyrosine Kinases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
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