Proc Natl Acad Sci U S A 2007,
PMID: 17548807
Kuraishy, Ali I; French, Samuel W; Sherman, Mara; Herling, Marco; Jones, Dan; Wall, Randolph; Teitell, Michael A
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.
Diseases/Pathways annotated by Medline MESH: Cell Transformation, Neoplastic
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Text Mining Data
TCL1 → TORC2: "
Here we show that the CREB coactivator
TORC2 directly
regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment
"
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