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

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
Pages (from-to)91-99
Number of pages9
JournalNature Medicine
Volume18
Issue number1
DOIs
Publication statusPublished - Jan 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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