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Dr. Marion B. Sewer
Gene Regulation and Hormone Metabolism
Marion B. Sewer, Ph.D.
Skaggs School of Pharmacy and Pharmaceutical Sciences
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.
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).
- Pharmacy: Contemporary Topics in Pharmacology (SPPS 218A/B)
- Principles of Pharmacology & Physiology (SPPS249)
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 (view more)
- Lucki NC et al. (2012) Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor. Mol Biol Cell 32:4419-4431
- Lucki NC et al. (2012) Resveratrol stimulates cortisol biosynthesis by activating SIRT- dependent deacetylation of P450scc. Endocrinology 153:3258-3268
- Cai K et al. (2013) Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes. Biochem 454:267-274
- Li D et al. (2013) cAMP-stimulated phosphorylation of diaphanous 1 regulates protein stability and interaction with binding partners in adrenocortical cells. Mol Biol Cell 24:848-857
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.