VOLLUM INSTITUTE
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Richard Goodman is director of the Vollum Institute. He also holds appointments as professor of Cell and Developmental Biology and Biochemistry and Molecular Biology. After receiving his B.S. degree in Chemistry at the Massachusetts Institute of Technology, he entered the Medical Scientist Training Program at the University of Pennsylvania. He received his M.D. and Ph.D. degrees in 1976. Goodman trained in clinical medicine at Tufts-New England Medical Center from 1976 to 1978 and was an endocrinology fellow at New England Medical Center and Massachusetts General Hospital. He was appointed as an assistant professor of Medicine at Harvard Medical School in 1982 and returned to Tufts-New England Medical Center in 1983, where he rose to the rank of professor of Medicine and chief of the Division of Molecular Medicine. He has been at the Vollum since 1990. Research InterestsThe major focus of the Goodman lab is to determine how extracellular and intracellular signals are integrated to control the onset and level of gene expression. The cAMP-regulated enhancer (CRE), initially identified in the Goodman lab, is now recognized to be a critical control element in many genes expressed in the nervous system and other tissues. The presence of this element in multiple gene promoters provides a mechanism that may allow the coordinate regulation of various patterns of gene expression. Transcriptional signals mediated by the CRE depend upon the transcription factor CREB, which is activated through a variety of signaling pathways including cAMP, calcium, and growth factors. Phosphorylation of a single site in the CREB activation domain leads to the recruitment of the CREB binding protein, CBP, which was also identified in the Goodman lab. CBP was the first example of a metazoan transcriptional coactivator and has been shown to participate in virtually all positively-regulated transcriptional pathways. Thus, one can imagine a hierarchy in which multiple phosphorylation-dependent signaling pathways activate CREB, and multiple transcription factors, activated by an even wider variety of signaling events, recruit CBP. Not surprisingly, perturbation of CBP function has profound effects on cell growth, differentiation, and development. CBP activates gene expression through at least two mechanisms—by directing the recruitment of basal transcription factors to the promoter and by reversing the repressive effects of chromatin. A current interest of the lab is to define the family of CREB target genes in different cell types and determine whether binding to these targets is regulated. To address these questions, the lab has developed an approach called Serial Analysis of Chromatin Occupancy (SACO) to identify transcription factor binding sites in vivo. They are using this approach to characterize the targets of several transcription factors involved in development and oncogenesis. The transcriptional corepressor CtBP (carboxyl-terminal binding protein, so named because it binds to the carboxyl-terminus of the adenoviral transforming protein E1A), has functions that exactly oppose those of CBP. Like CBP, CtBP interacts with a wide variety of transcription factors (in this case, transcriptional repressors) important for growth and development. The lab has determined that CtBP binding to various repressor proteins is regulated by changes in the nuclear NADH levels. This property allows CtBP to serve as a redox sensor for transcription and may provide a mechanism for gene transcription to respond to alterations in the energy level of the cell. The lab is currently trying to elucidate precisely how CtBP represses transcription. Selected PublicationsImpey, S., McCorkle, S.R., Cha-Molstad, H., Dwyer, J.M., Yochum, G.S., Boss, J.M., McWeeney, S., Dunn, J.J., Mandel, G., and Goodman, R.H. (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119:1041-1054. Cha-Molstad, H., Keller, D.M., Yochum, G.S., Impey, S., and Goodman, R.H. (2004) Cell-type-specific binding of the transcription factor CREB to the cAMP-response element. Proc. Natl. Acad. Sci. USA 101:13572-13577. Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S.M., and Goodman, R.H. (2003) Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115:177-186. Impey, S., Fong, A.L., Wang, Y., Cardinaux, J.-R., Fass, D.M., Obrietan, K., Wayman, G.A., Storm, D.R., Soderling, T.R., and Goodman, R.H. (2002) Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34:235-244. Zhang, Q., Piston, D.W., and Goodman, R.H. (2002) Regulation of co-repressor function by nuclear NADH. Science 295:1895-1897. Smolik, S.M. and Goodman, R.H. (2000) CBP/p300 in cell growth, transformation, and development. Genes and Development 14:1553-1577.
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