Reciprocal repression between P53 and TCTP

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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