TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation.
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.
Kuraishy
Ali I
AI
Department of Human Genetics, and Jonsson Comprehensive Cancer Center, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
French
Samuel W
SW
Sherman
Mara
M
Herling
Marco
M
Jones
Dan
D
Wall
Randolph
R
Teitell
Michael A
MA
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D010957:Plasmids; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
C493245:CRTC2 protein, human; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D014157:Transcription Factors