Mark Roberson, PhD
Department of Biomedical Sciences
Professor of Physiology
Director of Undergraduate Physiology
Department of Biomedical Sciences
Cornell University College of Veterinary Medicine
Veterinary Research Tower T5010B, Box 18
Ithaca, NY 14853
Regulation of pituitary-specific gene expression by gonadotropin-releasing hormone.
Gonadotropin releasing hormone (GnRH) is absolutely required for normal production of gonadotropins and subsequent gonadal function in mammals. Therapeutics for the positive and negative regulation of fertility have focused on manipulation of the GnRH system. My research in this area examines the intracellular signal transduction cascades induced by GnRH and the mechanisms of gene activation that results from these signaling cascades. Our cell signaling studies emphasize regulation and combinatorial effects of the mitogen-activated protein kinase pathways and the interrelationships between MAPK pathways and mobilization of calcium on target gene activation. The gene targets of these pathways include the glycoprotein hormone a subunit (a component of chorionic gonadotropin, luteinizing- and follicle-stimulating hormones), the GnRH receptor gene, the proto-oncogenes c-fos and c-jun and a newly described MAPK phosphatase, MKP-2. Our long-term goal is the identification of the complement of genes induced by GnRH receptor occupancy and the cellular mechanisms involved in the regulation of GnRH hormone action on pituitary-specific gene expression. Any one of these GnRH-dependent genes represents a potential target for fertility regulation in mammals.
Regulation of placental trophoblast cell function by combinatorial signaling.
Expression of the glycoprotein hormone a subunit gene is restricted to pituitary gonadotropes and placental trophoblast cells. Trophoblast production of chorionic gonadotropin (CG; consisting of the a subunit and separate bsubunits) is required for the maintenance of early pregnancy in non-human primates and women. Distinct elements within the a subunit promoter are required for placental-specific expression and includes dual cAMP responsive elements (CRE) that serve a twofold function; elements necessary to mediate activation by the protein kinase A (PKA) pathway and the epidermal growth factor (EGF) pathway. The combined action of the PKA and EGF pathways results in a remarkable synergistic activation of the a subunit gene in choriocarcinoma cells. The synergistic activation of the a subunit gene absolutely requires activation of MAPK pathways by EGF; however, MAPK activation alone is not sufficient to regulate the a subunit promoter. Our studies reveal that a unique CRE binding complex, consisting of CRE binding protein (CREB), c-jun and c-fos (AP-1), a histone deacetylase and CREB binding protein, is responsible for transcriptional regulation by PKA and EGF. Interestingly, an additional element within the a subunit promoter also serves to support synergistic regulation mediated at the dual CREs. Immediately downstream of the dual CREs lies the junctional regulatory element (JRE). Our most recent investigations reveal the JRE to be a binding site for the Distal-less class homeobox factor, Dlx 3. Dlx 3 is absolutely required for the developmental determination of the placenta in the mouse. Dlx 3 also appears to support both basal and agonist-induced a subunit gene expression in placental trophoblasts. The long-term goals of our studies in this area are to determine the role of multiple signaling pathways in the regulation of transcription of the a subunit gene via multiple cis elements and their cognate binding factors. Additionally, we are actively investigating the role and requirement for Dlx 3 in the early determination and development of the mouse and primate placentas.
- Postdoctoral Fellow, Oregon Health Sciences University and the University of Iowa (1990-1995)
- PhD, University of Nebraska, 1990
- MS, Montana State University, 1984
- BS, California Polytechnic State University, 1981
Awards and Honors
- American Association for the Advancement of Science
- The Endocrine Society
- Society for the Study of Reproduction