Journal
NATURE MEDICINE
Volume 18, Issue 1, Pages 91-99Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2546
Keywords
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Funding
- Agence Nationale de la Recherche Programme Blanc [ANR-09-BLAN-0292-01]
- European Union
- Association Sclerose Tubereuse de Bourneville
- Associazione Italiana per la Ricerca sul Cancro
- Italian Ministries of Education University Research (MIUR)
- Italian Ministry of Health
- European Community
- European Research Council
- Ferrari Foundation
- Monzino Foundation and the Cassa Risparmio Provincie Lombarde (CARIPLO) Foundation
- Vollaro Foundation
- Agency for Innovation by Science and Technology (IWT)
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0292] Funding Source: Agence Nationale de la Recherche (ANR)
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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 TCTPtranscription. 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.
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