Associate
Professor of Oncology
B.A., 1985, Genetics, University of California-Berkeley
Ph.D., 1991, Physiology, University of California-Berkeley
Office: 710A McArdle Laboratory
Telephone: Office - (608) 265-9319; Lab - (608) 265-9318
Email: alarid@oncology.wisc.edu
Research Interests: Molecular mechanisms of steroid hormone action
Research Description: The focus of our research is on understanding the molecular mechanisms governing the activity of estrogen receptor (ER), a member of the nuclear receptor transcription factor family that is critical in normal reproduction and is implicated in the pathogenesis of breast cancer.
ER is an intracellular receptor that when activated by estrogen and other estrogen-like compounds, binds directly to DNA and activates or represses gene transcription. It serves as an important model for the understanding of basic mechanisms of transcription, as well as the regulatory pathways that control the cellular responses to steroid hormones.
Currently, we are pursuing projects that address the role of post-translational regulation in the control of ERa protein activity, with emphasis on proteasome-mediated proteolysis. Experiments are aimed at better defining the signals that target ER for destruction and understanding how protein stability affects ERa transcriptional function.
In trying to elucidate the link between protein stability and transactivation, our research has identified novel regulatory and activation mechanisms for ERa and is placed into an emerging model of a “transcriptional clock” (Figure 1) that explores the dynamics and specificity of macromolecular complexes governing gene expression.
Figure 1: Model of a "Transcriptional Clock"
Selected publications
Valley, C. C., Solodin, N. M., Powers, G. L., Ellison, S. J., and Alarid, E. T. Temporal Variation in Estrogen Receptor-a Protein Turnover in the Presence of Estrogen. J. Mol. Endocrinol., 40: 23-34, 2008.
Abstract | Full Text | PDF
Fowler, A. M., and Alarid, E. T. Amping Up Estrogen Receptors in Breast Cancer. Breast Cancer Res., 9:305, 2007.
Abstract
Jiang, X., Ellison, S. J., Alarid, E. T., and Shapiro, D. J. Interplay between the Levels of Estrogen and Estrogen Receptor Controls the Level of the Granzyme Inhibitor, Proteinase Inhibitor 9 and Susceptibility to Immune Surveillance by Natural Killer Cells. Oncogene, 26: 4106-4114, 2007.
Abstract | Full Text | PDF
Weinberg, A. L., Carter, D., Ahonen, M., Alarid, E. T., Murdoch, F. E., and Fritsch, M. K. The DNA Binding Domain of Estrogen Receptor a Is Required for High-Affinity Nuclear Interaction Induced by Estradiol. Biochemistry, 46: 8933-8942, 2007.
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Alarid, E. T. Lives and Times of Nuclear Receptors. Mol. Endocrinol., 20: 1972-1981, 2006.
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Fowler, A. M., Solodin, N. M., Valley, C. C., and Alarid, E. T. Altered Target Gene Regulation Controlled by Estrogen Receptor-a Concentration. Mol. Endocrinol., 20: 291-301, 2006.
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Valley, C. C., Métivier, R., Solodin, N. M., Fowler, A. M., Mashek, M. T., Hill, L., and Alarid, E. T. Differential Regulation of Estrogen-Inducible Proteolysis and Transcription by the Estrogen Receptor a N Terminus. Mol. Cell. Biol., 25: 5417-5428, 2005.
Abstract | Full Text | PDF
Fowler, A. M., and Alarid, E. T. Nuclear Receptor and Transcriptional Complex Cycles. Science STKE, (262), tr11, 2004.
Abstract
Fowler, A. M., and Alarid, E. T. Dynamic Control of Nuclear Receptor Transcription. Science STKE, (256), pe51, 2004.
Abstract | View Animation (caution: 7.5 MB)
Fowler, A. M., Solodin, N., Preisler-Mashek, M. T., Zhang, P., Lee, A. V., and Alarid, E. T. Increases in Estrogen Receptor-a Concentration in Breast Cancer Cells Promote Serine 118/104/106-independent AF-1 Transactivation and Growth in the Absence of Estrogen. FASEB J., 18: 81-93, 2004.
Abstract | Full Text | PDF
Alarid, E. T., Preisler-Mashek, M. T., and Solodin, N. M. Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor-a Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary. Endocrinology, 144: 3469-3476, 2003.
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Preisler-Mashek, M. T., Solodin, N., Stark, B. L., Tyriver, M. K., and Alarid, E. T. Ligand-Specific Regulation of Proteasome-Mediated Proteolysis of Estrogen Receptor-a. Am. J. Physiol. Endocrinol. Metab., 282: E891-E898, 2002.
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Alarid, E. T., Bakopoulos, N., and Solodin, N. Proteasome-Mediated Proteolysis of Estrogen Receptor: A Novel Component in Autologous Down-Regulation. Mol. Endocrinol., 13: 1522-1534, 1999.
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Yusta, B., Alarid, E. T., Gordon, D. F., Ridgway, E. C., and Mellon, P. L. The Thyrotropin b-Subunit Gene Is Repressed by Thyroid Hormone in a Novel Thyrotrope Cell Line, Mouse TaT1 Cells. Endocrinology, 139: 4476-4482, 1998.
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Alarid, E. T., Windle, J. J., Whyte, D. B., and Mellon, P.L. Immortalization of Pituitary Cells at Discrete Stages of Development by Directed Oncogenesis in Transgenic Mice. Development, 122: 3319-3329, 1996.
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Alarid, E. T., and Mellon, P. L. Down-Regulation of the Gonadotropin-Releasing Hormone Receptor Messenger Ribonucleic Acid by Activation of Adenylyl Cyclase in aT3-1 Pituitary Gonadotrope Cells. Endocrinology, 136: 1361-1366, 1995.
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