Reciprocal repression between P53 and TCTP

Robert Amson, Salvatore Pece, Alexandra Lespagnol, Rajesh Vyas, Giovanni Mazzarol, Daniela Tosoni, Ivan Colaluca, Giuseppe Viale, Sylvie Rodrigues-Ferreira, Jessika Wynendaele, Olivier Chaloin, Johan Hoebeke, Jean Christophe Marine, Pier Paolo Di Fiore, Adam Telerman

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

Abstract

Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.

Original languageEnglish (US)
Pages (from-to)91-99
Number of pages9
JournalNature Medicine
Volume18
Issue number1
DOIs
StatePublished - Jan 2012

Bibliographical note

Funding Information:
A.T. and R.A. dedicate this work to G. Schnek for his sustained care. We thank C. Auclair for constant support; D. Galvagno for technical assistance; G. D’Ario and S. Confalonieri for statistical analyses; and B. Vogelstein (Johns Hopkins University), M. Oren (Weizmann Institute of Science) and B. Wasilyk and C. Wasilyk (IGBMC Illkirch) for HCT116, H1299 Trp53-null, temperature-sensitive P53 Val138 mutant cells, and P53 protein and plasmids, respectively. This work was supported by grants from the Agence Nationale de la Recherche Programme Blanc (ANR-09-BLAN-0292-01), the European Union Network of Excellence CONTICANET and the Association Sclérose Tubéreuse de Bourneville to A.T. and R.A., the Associazione Italiana per la Ricerca sul Cancro and the Italian Ministries of Education University Research (MIUR) and the Italian Ministry of Health to S.P. and P.P.D.F., the European Community (FP6 and FP7), the European Research Council, the Ferrari Foundation, the Monzino Foundation and the Cassa Risparmio Provincie Lombarde (CARIPLO) Foundation to P.P.D.F. and the G. Vollaro Foundation to S.P. J.W. received support from Agency for Innovation by Science and Technology (IWT).

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

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