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Yamamoto, Keith
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| Research Statement | | Signaling and Transcriptional Regulation by Intracellular Receptors
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 coherentresponses.
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. |
Publications | | Tee MK, Rogatsky I, Tzagarakis-Foster C, Cvoro A, An J, Christy RJ, Yamamoto KR, Leitman DC. Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors (alpha) and (beta). Mol. Biol. Cell. 2004; 15(3): 1262-1272.
Rogatsky I, Wang J-C, Kakefuda-Derynck M, Nonaka D, Haqq CM, Darimont BD, Garabedian MJ, Yamamoto KR. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA. 2003; 100(24): 13845-13850.
Rogatsky I, Luecke HF, Leitman DC, Yamamoto KR. Alternate surfaces of transcriptional co-regulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. Proc. Natl. Acad. Sci. USA. 2002; 99(26): 16701-16706.
Freeman BC, Yamamoto KR. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science. 2002 Jun 21; 296(5576):2232-5.
Rogatsky I, Zarember KA, Yamamoto KR. Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J. 2001 Nov 1; 20(21):6071-83.
Freeman BC, Yamamoto KR. Continuous recycling: a mechanism for modulatory signal transduction. Trends Biochem Sci. 2001 May; 26(5):285-90.
Sitcheran R, Emter R, Kralli A, Yamamoto KR. A genetic analysis of glucocorticoid receptor signaling. Identification and characterization of ligand-effect modulators in Saccharomyces cerevisiae. Genetics. 2000 Nov; 156(3):963-72.
Nissen RM, Yamamoto KR. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 2000 Sep 15; 14(18):2314-29.
van Tilborg MA, Lefstin JA, Kruiskamp M, Teuben J, Boelens R, Yamamoto KR, Kaptein R. Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA. J Mol Biol. 2000 Aug 25; 301(4):947-58.
Jamieson CA, Yamamoto KR. Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. Proc Natl Acad Sci U S A. 2000 Jun 20; 97(13):7319-24.
Freeman BC, Felts SJ, Toft DO, Yamamoto KR. The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies. Genes Dev. 2000 Feb 15; 14(4):422-34.
Diamond MI, Robinson MR, Yamamoto KR. Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. Proc Natl Acad Sci U S A. 2000 Jan 18; 97(2):657-61. |
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