title: Reciprocal repression between P53 and TCTP.
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.
authors.affiliation: Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8113, Laboratoire de Biotechnologie et Pharmacologie génétique Appliquée, École Normale Supérieure, Cachan, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Amson
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pece
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lespagnol
authors.forename: Rajesh
authors.initials: R
authors.lastname: Vyas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.forename: Daniela
authors.initials: D
authors.lastname: Tosoni
authors.forename: Ivan
authors.initials: I
authors.lastname: Colaluca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rodrigues-Ferreira
authors.forename: Jessika
authors.initials: J
authors.lastname: Wynendaele
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.forename: Johan
authors.initials: J
authors.lastname: Hoebeke
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Adam
authors.initials: A
authors.lastname: Telerman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C495901:TP53 protein, human; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2