Dr. Marion B. Sewer: Gene Regulation and Hormone Metabolism

Research Summary: Steroid Hormone Metabolism

Dr. Sewer's research focuses on elucidating the molecular mechanisms that regulate the transcription of cytochrome P450 enzymes that are metabolize cholesterol into steroid hormones. Precise control of gene transcription is integral in maintaining optimal the circulating concentrations of cortisol, estradiol, and androgens. Aberrant steroid hormone production is associated with multiple disease states, including cancer, polycystic ovary syndrome, Cushing’s disease, and congenital adrenal hyperplasia. Dr. Sewer's group utilizes various molecular, biochemical, and analytical approaches to investigate the factors that control steroid hormone biosynthesis. Recent work from the Sewer lab has identified that distinct sphingolipid and phospholipid species are endogenous ligands for the nuclear receptor steroidogenic factor 1. These studies have revealed a novel role for nuclear phospholipid and sphingolipid metabolism in the control of gene transcription.
Ongoing efforts are targeted at employing mass spectrometric approaches to define the nuclear metabolome and to determine how cell signaling changes the nuclear concentrations of bioactive lipids.
Dr. Sewer’s group is also interested in determining how signaling-dependent posttranslational modifications of nuclear proteins and cytochrome P450 enzymes modulate lipid metabolism. Studies are also aimed at examining how the cytoskeleton and signaling pathways control substrate exchange between mitochondria and the endoplasmic reticulum during adrenocorticosteroid biosynthesis.

Academic Achievements

Education: B.S. in Biochemistry (1993) Spelman College; Ph.D. in Pharmacology (1998) Emory University.

Awards and Honors: Howard Hughes Medical Institute Predoctoral Fellowship (1993); UNCF-Merck Postdoctoral Fellowship (1999); Georgia Cancer Coalition Distinguished Scientist (2002); NSF Career Development Award (2004).

Teaching

• Pharmacy: Contemporary Topics in Pharmacology (SPPS 218A/B).

Key Contributions to Pharmaceutical Sciences

• Identified endogenous ligands for steroidogenic factor 1, a member of the nuclear receptor superfamily.
• Established a role for nuclear production of bioactive sphingolipids and phospholipids in gene transcription.
• Defined the mechanism by which cell signaling controls inter-organelle substrate delivery during adrenocortiosteroid biosynthesis.
• Elucidated how post-translational modification of multiple nuclear proteins regulate steroidogenic P450 gene transcription.

Selected Recent Publications

Urs et al. (2006). Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology. 147:5249-58.

Li et al. (2007). cAMP-Stimulated Interaction Between Steroidogenic Factor-1 and Diacylglycerol Kinase-θ Facilitates Induction of CYP17. Molecular and Cellular Biology. 27:6669-6685.

Dammer et al. (2008). Phosphorylation of CtBP1 by PKA Modulates Induction of CYP17 by Stimulating Partnering of CtBP1 and 2. Journal of Biological Chemistry. 283:6925-6934.

Lucki et al. (2009). The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells. Biochimie Biophysica Acta – Molecular Biology of Lipids. 1791:706-713.

Potential Collaborative Programs with the Pharmaceutical Industry

• Over 15 years of experience in characterizing the regulation of cytochrome P450 genes (xenobiotic and endogenous substrates).
• Broad array of molecular, genetic, biochemical, and analytical approaches to identify endogenous ligands and screen novel synthetic ligands for orphan nuclear receptors