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

doi:10.1073/pnas.0704170104

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

Departments of *Human Genetics,
^†Pathology and Laboratory Medicine, and
^¶Microbiology, Immunology, and Molecular Genetics,
^‡Molecular Biology Institute, and
^‖Institute for Stem Cell Biology and Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; and
^§Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030

Communicated by Owen N. Witte, University of California, Los Angeles, CA, May 4, 2007 (received for review April 4, 2007)

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.

Footnotes

**To whom correspondence should be addressed at:
Department of Pathology and Laboratory Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095.
E-mail: mteitell{at}ucla.edu
Author contributions: A.I.K., M.S., R.W., and M.A.T. designed research; A.I.K., S.W.F., M.S., and M.H. performed research; A.I.K., S.W.F., M.S., M.H., D.J., R.W., and M.A.T. analyzed data; and A.I.K., R.W., and M.A.T. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0704170104/DC1.
Abbreviations:

GC,

germinal center;

dbcAMP,

dibutyryl cAMP;

mCREB,

mutant CREB;

AICAR,

5-aminoimidazole-4-carboxamide riboside.