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Professor of Human Genetics Research Scientist for Reproductive Sciences Program |
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| 4706 Med Sci II 1241 E. Catherine St. SPC 5618 Ann Arbor, MI 48109 -5618 |
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We study gene regulation as exerted by steroid hormone receptors, focusing on three areas: basic mechanisms of transcription, development of hormone-dependent cancers, and sex-dependent gene modulation. Steroid receptors are ligand-activated transcription factors and link extracellular cues for development, reproduction, and homeostasis directly to gene expression. Despite their diverse functions, several receptors act via common DNA elements and interact with common transcriptional coactivators, leading to a paradox in how precise gene control is attained. Our lab addresses this problem for the androgen receptor (AR) in vitro, in chromatin and in mice.
The androgen receptor plays a central role in prostate cancer. These tumors depend on androgen for their initial growth, and AR remains active even after tumors progress to an androgen-independent lethal state. We converted the endogenous mouse AR gene to the human sequence ("humanized") to better model human disease, and introduced several alleles varying in a region correlated with differential cancer risk in man. These alleles confer differences in cancer initiation, progression, and response to hormone treatment in mice. Mechanisms and alternative pathways underlying these differences in mice will ultimately be informative for prognosis in man and will aid development of novel therapies targeting the human AR.
We also study sex-specific gene expression in non-reproductive tissues, which is a far broader phenomenon than previously thought and may underlie sex differences in disease occurrence. In the mouse mutant, regulator of sex-limitation, we identified a set of genes that influence sexual dimorphism of the liver. Rsl1 and Rsl2 encode KRAB zinc finger repressors whose targets function in reproduction, xenobiotic and lipid metabolism, and immunity. Rsl in mice may prove informative to sex differences in drug metabolism and liver pathology in man. Further, as the first members of the huge KRAB zinc finger family to have biological functions identified, Rsl may reveal the role of these rapidly diverging proteins in vertebrate evolution.
2007-9 Member, Board of Scientific Counselors of the NIH National Toxicology Program
2007 Crosby Award, NSF ADVANCE at the University of Michigan
2006-9 Chair, UICC Review Panel for ACS Fellowships
2005- Advisor, NIEHS Center for Rodent Genetics
1999 Member, American Cancer Society Council
1996 Career Development Award, Michigan Agenda for Women
1995-97, 2000-01 Chair, Molecular Biology Review Panels for DOD Breast Cancer Awards
1995-96 Chair, Developmental Biology Advisory Committee, American Cancer Society
1978 Kallman Award
1982 Columbia University, Post-doc (Jane Coffin Childs Postdoc Fellowship)
1978 Stanford University, Ph.D. (National Science Foundation Grad Fellowship)
1973 Yale University, B.S.
Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, LaPensee E, Dhanasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA, Pienta KJ, Robins DM: Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Research 2009; 69:4434-4442.
Krebs CJ, Khan S, MacDonald JW, Sorenson M, Robins DM: (2009) The regulator of sex-limitation (Rsl) KRAB zinc finger proteins modulate sex-dependent and -independent liver metabolism. Physiological Genomics 38;16-28.
O'Mahony OA, Steinkamp MP, Albertelli MA, Brogley M, Rehman H, Robins DM: (2008) Profiling human androgen receptor mutations reveals treatment effects in a mouse model of prostate cancer. Molecular Cancer Research 6: 1691-1701.
Albertelli MA, O'Mahony OA, Brogley M, Tosoian J, Steinkamp M, Daigneault S, Wojno K, Robins DM: (2008) Glutamine tract length of human androgen receptors affects both androgen-dependent and -independent prostate cancer in mice. Human Molecular Genetics 17: 98-110.
Robins DM, Albertelli MA, O'Mahony OA: (2008) Androgen receptor variants and prostate cancer in humanized AR mice. Journal of Steroid Biochemistry and Molecular Biology 108: 230-6.
Lieberman AP, Robins DM: (2008) The androgen receptor's CAG/glutamine tract in mouse models of neurological disease and cancer. Journal of Alzheimer's Disease 14: 247-55.
Yu Z, Dadgar N, Albertelli MA, Gruis K, Jordan C, Robins DM, Lieberman AP: (2006) Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. Journal of Clinical Investigation 116: 2663-72.
Albertelli MA, Scheller A, Brogley M, Robins DM: (2006) Replacing the mouse androgen receptor with human alleles demonstrates glutamine tract length dependent effects on physiology and tumorigenesis in mice. Molecular Endocrinology, 20:1248-1260.
Yu Z, Dadgar N, Albertelli M, Scheller A, Albin R, Robins DM, Lieberman AP: (2006) Abnormalities of germ cell maturation and Sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein. American Journal of Pathology, 168:195-204.
Robins DM: (2005) Androgen receptor and molecular mechanisms of male-specific gene expression. In: Molecular Mechanisms Influencing Aggressive Behaviour, Novartis Foundation Symp. 268: 42-52.
Krebs CJ, Larkins LK, Khan SM, Robins DM: (2005) Expansion and diversification of KRAB zinc-finger genes within a cluster including Regulator of sex-limitation 1 and 2. Genomics 85: 752-761
Robins DM: (2004) Multiple Mechanisms of Male-specific Gene Expression: Lessons from the Mouse Sex-limited Protein Gene, Slp. In Progress in Nucleic Acids Research and Molecular Biology, vol. 78:1-36.
Krebs CJ, Larkins LK, Price R, Tullis KM, Miller RD, Robins DM: (2003) Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression. GenesDev. 17: 2664-2674.
Gonzalez MI, Robins DM: (2001) OCT-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of the coactivator SRC-1. J. Biol. Chem. 276: 6420-8.
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