TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Ali I. Kuraishy, Samuel W. French, Mara Sherman, Marco Herling, Dan Jones, Randolph Wall, Michael A. Teitell

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1 in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/p300 genes concurrently repress TCL1 to initiate its silencing.

Original languageEnglish (US)
Pages (from-to)10175-10180
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number24
DOIs
StatePublished - Jun 12 2007

Keywords

  • Gene regulation
  • Lymphomagenesis
  • Signal transduction

ASJC Scopus subject areas

  • General

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