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Signal
Transduction and Transcriptional Regulation 
We study the activity of the intracellular receptors (IRs), including
receptors for glucocorticoids (GR), androgens (AR) and thyroid hormone
(TR), in signal transduction and transcriptional control. These hormone-receptor
complexes bind to specific DNA sequences termed hormone response elements,
which enhance or repress linked promoters. Our goal is to understand the
molecular and cellular logic by which IRs integrate multiple signaling
inputs to produce specific, distinct and coherent responses.
We have defined IR domains for hormone and DNA binding, dimerization,
nuclear localization, phosphorylation, interaction with various cellular
factors and transcriptional regulation. IRs functions faithfully when
expressed in simpler organisms such as yeast and Drosophila, thus facilitating
genetic analyses of their actions and identification of other factors
involved in its activities. Studies of IRs in C. elegans permit analyses
of developmental and physiologic control by these factors in an experimentally
accessible metazoan. We are also pursuing 3D structure analyses of various
domains of the receptor, and we employ biochemical strategies with purified
components for mechanistic analyses. Thus, using genetic, structural,
molecular and biochemical approaches, we use IRs as "biological probes"
to define how a single regulatory protein can specify diverse patterns
of specific gene expression in different cellular contexts.
These reductionist strategies can increasingly be applied to studies of
complex physiological and pathological processes. For example, we are
pursuing: (a) a signaling "crosstalk" pathway in developing T-cells in
which activation of the T-cell receptor abrogates glucocorticoid-induced
apoptosis; (b) dramatic shifts in AR activity and ligand responses during
prostate cancer ontogeny and progression; (c) the consequences of glutamine
repeat expansion in AR, leading to motor neuron degeneration in spinal
and bulbar muscular atrophy.
Selected Publications:
Lefstin, J.A., Yamamoto, K.R. (1998) Allosteric effects of DNA on transcriptional
regulators. Nature, 392, 885-888.
Darimont, B.D., Wagner, R.L., Apriletti, J.W., Stallcup, M.R., Kushner,
P.J., Baxter, J.D., Fletterick, R.L., Yamamoto, K.R. (1998) Structure
and specificity of nuclear receptor-coactivator interactions. Genes Dev.
12, 3343-3356.
Yamamoto, K.R., Darimont, B.D., Wagner, R.L., Iniguez-Lluhi, J.A. (1998)
Building transcriptional regulatory complexes: Signals and surfaces. Cold
Spring Harb. Symp. Quant. Biol. 63, 587-598.
Diamond, M.I., Robinson, M.R., Yamamoto, K.R. (1999) Regulation of expanded
polyglutamine protein aggregation and nuclear localization by the glucocorticoid
receptor. Proc. Natl. Acad. Sci. USA 97, 657-661.
Freeman, B.C., Felts, S.J., Toft, D.O., Yamamoto, K.R. (2000) The p23
molecular chaperones act at a late step in intracellular receptor action
to differentially affect ligand efficacies. Genes Dev. 14, 422-434.
Sitcheran, R., Emter, R., Kralli, A., Yamamoto, K.R. (2000) A genetic
analysis of glucocorticoid receptor signaling: identification and characterization
of ligand-effect modulators in Saccharomyces cerevisiae. Genetics 156,
963-972.
Jamieson, C.A.M., Yamamoto, K.R. (2000) Crosstalk pathway for inhibition
of glucocorticoid-induced apoptosis by T-cell receptor signaling. Proc.
Natl. Acad. Sci. USA 97, 7319-7324.
Nissen, R.M., Yamamoto, K.R. (2000) The glucocorticoid receptor inhibits
NFkB by interfering with serine-2 phosphorylation of the RNA polymerase
II carboxyl-terminal domain. Genes Dev. 14, 2314-2329.
van Tilborg, M.A.A., Lefstin, J.A., Kruiskamp, M., Teuben, J-M., Boelens,
R., Yamamoto, K.R., Kaptein, R. (2000) Mutations in the glucocorticoid
receptor DNA-binding domain mimic an allosteric effect of DNA. J. Mol
Biol. 301, 947-958.
Contact Information:
Email: yamamoto@cmp.ucsf.edu
Phone: 415/ 476-3128
Address: Box 2280, Genentech Hall, Room S 572 D
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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