John C. Chrivia, Ph.D.
Pharmacological and Physiological Science
Ph.D., University of Washington, 1987
Baylor College of Medicine
CREB-binding protein (CBP) functions as a coactivator for many transcription factors and is able to respond to extracellular signals to specifically regulate gene expression. Mutations within CBP have been found in patients with mental retardation and growth defects (Rubinstein-Taybi syndrome) and have been demonstrated in patients with acute myelogenous leukemia. Several viruses which cause diseases in humans (HTLV-1, HIV-1, CMV, HBV and adenovirus) use CBP to regulate gene expression. Regulation of transcription by CBP occurs in part through its ability to function as a histone acetylase transferase (HAT) and in part through contact with other molecules which themselves function as HATs or which function as general transcription factors such TBP.
Recent work indicates CBP contacts a specific subset of proteins to activate transcription at different promoters. We have identified a novel protein termed SRCAP, (SNF2-Related-CBP-Activator Protein) which binds to a region within CBP shown to be important for CBP to function as a coactivator for CREB. Structurally SRCAP is related to the SNF-2 family of proteins which are involved in various aspects of transcriptional regulation including chromatin remodelling. We have found that SRCAP regulates the ability of CREB and CBP to activate transcription and that SRCAP regulates transcription of several promoters (PEPCK, somstostatin and enkephalin ). In others studies we have also found that SRCAP functions as a coactivator for tglucocorticoid receptor-mediated transcription.
We have also found that SRCAP similar to CBP, is targeted by several viral proteins. These include: the HCV NS5A protein, which in conjunction with SRCAP represses transcription of the p21 gene; the adenovirus protein, DBP, which blocks CBP-SRCAP interaction and inhibits transcription mediated by SRCAP; and the adenovirus protein, E1a which binds CBP and blocks binding of CBP to SRCAP.
Our current studies include both in vitro and in vivo approaches aimed at elucidating the mechanism(s) by which SRCAP regulates transcription.
Madeline M. Wong, Linda K. Cox and John C. Chrivia. (2007). The chromatin remodeling protein, SRCAP is critical for deposition of the histone variant H2A.Z at promoters.. Journal of Biological Chemistry July 8 in Press.
Ruhl DD, Jin J, Cai Y, Swanson S, Florens L, Washburn MP, Conaway RC, Conaway JW, Chrivia JC. (2006). Purification of a human SRCAP complex that remodels chromatin by incorporating the histone variant H2A.Z into nucleosomes. Biochemistry. 2006 May 2;45(17):5671-7.
Human SRCAP and Drosophila domino are homologs that function in the Notch signaling pathway (2005). Eissenberg, J., Wong, M. and Chrivia, J.C. Molecular and Cellular Biology 25, 6559-6569.
Monroy, M.A., Schott, N., Cox, L., Chen, J.D., Ruh, M.F. and Chrivia, J.C. (2003) SNF2-Related CBP Activator protein (SRCAP) Functions as a Coactivator of Steroid Receptor-Mediated Transcription through Synergistic Interactions with CARM-1 and GRIP-1. Molecular Endocrinology 17, 2519-2528.
Xu, X, Tarakanova V., Chrivia, J.C. and Yaciuk, P. (2003). Adenovirus DNA binding protein inhibits SRCAP activated CBP and CREB-mediated transcription. Virology 313, 615-21.
Gusterson, R., Brar, B, Faulkes, D., Giordano, A., Chrivia, J. and Latchman, D. (2002). The transcriptional co-activators CBP and p300 are activated via Phenylephrine through the p42/p44 MAPK cascade. Journal of Biological Chemistry 277:2517-2524.
Monroy, M.A., Ruhl, D.D., Xu, X., Granner, D.K., Yaciuk, P and Chrivia, J.C. (2001) Regulation of CREB-mediated transcription by the SNF2/SWI-related protein, SRCAP. Journal of Biological Chemistry 276, 40721-40726.
Xu, X., Chackalaparampil, I., Monroy, M.A., Cannella, M., Pesek. B., Chrivia, J. and Yaciuk, P. (2001). Adenovirus DNA binding Protein interacts with the SNF2-Related CBP Activator Protein (SrCAP) and Inhibits SrCAP-mediated transcription. Journal of Virology, 75, 10033-10040.
Ghosh, A., Majumdar, M., Steele, R., Chrivia, J., Yaciuk, P., Ray, R. and Ray, R. (2000) Hepatitis C virus NS5A protein modulates transcription through a novel cellular factor SRCAP. Journal of Biological Chemistry 275, 7184-7188.
Johnston, H., Kneer, J., Chacklalparampil, I., Yaciuk, P. and Chrivia , J. (1999) Identification of a novel SNF2/SWI2 family member, SRCAP, which interacts with CREB Binding Protein. Journal of Biological Chemistry 274, 16370-16376.
Hu Shu-Ching, Chrivia, J., and Ghosh, A. Regulation of CBP-Mediated Transcription by neuronal calcium signaling. (1999) Neuron 22, 1-22.
Liu, Y-Z, Chrivia J. C. and Latchman, D. (1998). NGF upregulates the transcriptional activity of CBP through activation of the p42/P44 MAPK cascade. Journal of Biological Chemistry 273, 32400- 32407.
Swope, D.L., Mueller, C.L. and Chrivia J.C. CREB binding protein activates transcription through multiple domains.(1996) Journal of Biological Chemistry 271, 28138-28145.
Kwok, R.P.S., Lundblad, J.R., Roberts, S., Green, M.R., Chrivia, J.C. and Goodman, R.H. Nuclear protein CBP serves as a coactivator for the transcription factor CREB. (1994) Nature. 370: 223-226.
Chrivia, J.C., Kwok, R.P.S., Lamb, N., Hagiwara, M., Montminy, M.R. and Goodman R.H. Phosphorylated CREB binds specifically to the nuclear protein CBP.(1993) Nature 365:855-859.