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Nat Med. 2011 Dec 11;18(1):91-9. doi: 10.1038/nm.2546.

Reciprocal repression between P53 and TCTP.

Author information

1
Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8113, Laboratoire de Biotechnologie et Pharmacologie génétique Appliquée, École Normale Supérieure, Cachan, France.

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.

PMID:
22157679
DOI:
10.1038/nm.2546
[Indexed for MEDLINE]

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