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L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

TitoloL-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2015
AutoriAyroldi, E., Petrillo Maria Grazia, Bastianelli A., Marchetti M.C., Ronchetti S., Nocentini G., Ricciotti L., Cannarile L., and Riccardi C.
RivistaCell Death and Differentiation
Volume22
Paginazione118 – 130
Type of ArticleArticle
ISSN13509047
Parole chiaveanimal, animal cell, animal experiment, animal model, Animals, antineoplastic agent, antiproliferative activity, apoptosis regulatory protein, Apoptosis Regulatory Proteins, article, BBC3 protein, cancer cell, cancer inhibition, carcinoma cell line, Cell Line, colorectal carcinoma, complex formation, controlled study, dexamethasone, Dsip1 protein, gene activation, genetics, glucocorticoid, HEK293 cell line, HEK293 Cells, human, human cell, Humans, Knockout, knockout mouse, leucine zipper protein, long glucocorticoid induced leucine zipper, male, MDM2 protein, metabolism, Mice, mouse, Mus, nonhuman, oncoprotein, priority journal, protein expression, protein MDM2, protein p53, protein stability, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, PUMA protein, TP53 protein, transcription factor, Transcription Factors, TSC22D3 protein, Tumor, tumor cell line, tumor suppressor protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, ubiquitination, unclassified drug, xenograft
Abstract

The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53 +/+ HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53 +/+ cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation © 2015 Macmillan Publishers Limited.

Note

Cited by: 23; All Open Access, Bronze Open Access, Green Open Access

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84926631512&doi=10.1038%2fcdd.2014.129&partnerID=40&md5=1c1974fa1aab9622106b3237997d0ff0
DOI10.1038/cdd.2014.129
Citation KeyAyroldi2015118
PubMed ID25168242