A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor α gene expression

A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor α gene expression

^*Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138; ^‡The Center for Blood Research and Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115; and ^§Dana–Farber Cancer Institute and Harvard Medical School, Boston, MA 02115

Communicated by Tom Maniatis, Harvard University, Cambridge, MA (received for review December 14, 1999)

Abstract

The cAMP response element binding protein (CREB)-binding protein (CBP)/p300 family of coactivator proteins regulates gene transcription through the integration of multiple signal transduction pathways. Here, we show that induction of tumor necrosis factor α (TNF-α) gene expression in T cells stimulated by engagement of the T cell receptor (TCR) or by virus infection requires CBP/p300. Strikingly, in mice lacking one copy of the CBP gene, TNF-α gene induction by TCR activation is inhibited, whereas virus induction of the TNF-α gene is not affected. Consistent with these findings, the transcriptional activity of CBP is strongly potentiated by TCR activation but not by virus infection of T cells. Thus, CBP gene dosage and transcriptional activity are critical in TCR-dependent TNF-α gene expression, demonstrating a stimulus-specific requirement for CBP in the regulation of a specific gene.

Footnotes

↵ † J.V.F., B.M.N.B., and A.V.T. contributed equally to this work.
↵ ¶ Present address: Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710.
↵ ‖ To whom reprint requests should be addressed. E-mail: goldfeld{at}cbr.med.harvard.edu.
Abbreviations:

CBP,

cAMP response element binding protein (CREB)-binding protein;

TNF,

tumor necrosis factor;

TCR,

T cell receptor;

NFAT,

nuclear factor of activated T cells;

CAT,

chloramphenicol acetyltransferase