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 journalArticle

127 Citations (Scopus)

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

Fingerprint

Tumors
Ubiquitination
Cells
Apoptosis
Breast Neoplasms
Thioridazine
Sertraline
Degradation
Neoplasms
Neoplastic Stem Cells
translationally-controlled 1 tumor protein
Neoplasm Genes
Transcription
Transgenic Mice
Screening
Genes
Switches
Pharmacology
Feedback

ASJC Scopus subject areas

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

Cite this

Reciprocal repression between P53 and TCTP. / 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.

In: Nature Medicine, Vol. 18, No. 1, 01.2012, p. 91-99.

Research output: Contribution to journalArticle

Amson, R, Pece, S, Lespagnol, A, Vyas, R, Mazzarol, G, Tosoni, D, Colaluca, I, Viale, G, Rodrigues-Ferreira, S, Wynendaele, J, Chaloin, O, Hoebeke, J, Marine, JC, Di Fiore, PP & Telerman, A 2012, 'Reciprocal repression between P53 and TCTP', Nature Medicine, vol. 18, no. 1, pp. 91-99. https://doi.org/10.1038/nm.2546
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. / Reciprocal repression between P53 and TCTP. In: Nature Medicine. 2012 ; Vol. 18, No. 1. pp. 91-99.
@article{f6fd6320d97849cbbf5fabb3e3e6ab91,
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.",
author = "Robert Amson and Salvatore Pece and Alexandra Lespagnol and Rajesh Vyas and Giovanni Mazzarol and Daniela Tosoni and Ivan Colaluca and Giuseppe Viale and Sylvie Rodrigues-Ferreira and Jessika Wynendaele and Olivier Chaloin and Johan Hoebeke and Marine, {Jean Christophe} and {Di Fiore}, {Pier Paolo} and Adam Telerman",
year = "2012",
month = "1",
doi = "10.1038/nm.2546",
language = "English",
volume = "18",
pages = "91--99",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Reciprocal repression between P53 and TCTP

AU - Amson, Robert

AU - Pece, Salvatore

AU - Lespagnol, Alexandra

AU - Vyas, Rajesh

AU - Mazzarol, Giovanni

AU - Tosoni, Daniela

AU - Colaluca, Ivan

AU - Viale, Giuseppe

AU - Rodrigues-Ferreira, Sylvie

AU - Wynendaele, Jessika

AU - Chaloin, Olivier

AU - Hoebeke, Johan

AU - Marine, Jean Christophe

AU - Di Fiore, Pier Paolo

AU - Telerman, Adam

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84855535930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855535930&partnerID=8YFLogxK

U2 - 10.1038/nm.2546

DO - 10.1038/nm.2546

M3 - Article

VL - 18

SP - 91

EP - 99

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 1

ER -