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

Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10175-80. doi: 10.1073/pnas.0704170104. Epub 2007 Jun 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Genetic Vectors
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Humans
  • Jurkat Cells
  • Models, Biological
  • Plasmids
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Retroviridae / genetics
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • CRTC2 protein, human
  • Proto-Oncogene Proteins
  • TCL1A protein, human
  • Transcription Factors