Debra F. Skafar, Ph.D.
Department of Physiology
Joint appointment, Barbara Ann Karmanos Cancer Institute
5203 Scott Hall
540 E. Canfield
Detroit, MI 48201
Debra F. Skafar, Ph.D., earned her doctorate in Molecular Biology at Vanderbilt University and went on to do postdoctoral research in the Biophysics department of the University of Rochester in New York. Dr. Skafar's research interests are in the fundamental molecular mechanisms of action of the steroid hormone, estrogen, as well as the protein through which it carries out its biological activity, the estrogen receptor.
Estrogen is critical in the physiological function of many normal tissues, including bone, the central nervous system, and reproductive tissues and organs, as well as in the development and progression of breast and other cancers. It acts by binding to two specific proteins, the estrogen receptors alpha and beta, which are members of the nuclear receptor superfamily of proteins. All the proteins in the superfamily share a common arrangement of domains, including a central DNA-binding domain and a more carboxy-terminal ligand-binding domain (Figure 1). The binding of a steroid hormone or other ligand to its specific receptor(s) causes the cell to alter the expression of certain genes. The mechanism by which a receptor translates the hormonal signal into altered gene expression is complex, and is not completely characterized. Binding of a hormone or other ligand alters the conformation (shape) of the protein, that leads to altered phosphorylation of the protein, increased dimerization, increased binding to specific DNA sequences (EREs), recruitment of coactivator proteins, and altered transcription (Figure 2).
In addition to the binding of hormones such as estradiol, the estrogen receptor is also a target for drugs used to treat and prevent breast cancer and osteoporosis, such as tamoxifen and raloxifene. The differences in signaling between the binding of hormone, other ligands, and therapeutic agents are not completely understood, although the work of structural biologists has shown that the conformation of the receptor is different when an agonist or an antagonist (tamoxifen) is bound (Figure 3).
Dr. Skafar's work is focused on understanding how the binding of hormone and drugs alters the conformation of the estrogen receptor, and how this in turn alters the receptor's binding to DNA, formation of receptor dimers, interaction with coregulatory proteins, and ability to alter transcription (for example, see Zhao et al, 2003). Her laboratory uses molecular biological and biochemical techniques to study the changes steroids of different biological activity induce in the conformation of the receptor, as well as the influence of the protein's structure on the ability to undergo these changes in conformation and alter biological activity. Her laboratory complements the experimental data with molecular modeling. Her laboratory has identified regions in the receptor that are critical in determining the conformation of the receptor when bound to specific ligands, and which are necessary for the activity of specific ligands. In addition to the fundamental knowledge of receptor structure and function gained, a better understanding of the mechanism through which the steroid hormones regulate cellular functions should lead to innovative therapies for reproductive disorders and breast cancer, as well as the development of new compounds with highly selective activity.
Dr. Skafar’s research has received funding from the National Science Foundation, from the Department of Defense Breast Cancer Research Program, and from the National Institutes of Health. She has served as a grant proposal reviewer for the California Breast Cancer Research Program, the National Institutes of Health, and the Department of Defense Breast Cancer Research Program. For three years, she also served as chair of a grant proposal review panel for the Department of Defense Breast Cancer Research Program. Most recently, she has been invited to speak about her laboratory’s work at the upcoming “International Symposium on Steroid Hormone Receptor Superfamily & Molecular Signaling”, to be held in Kerala, India, in November, 2004.
A list of Dr. Skafar's publications can be found at PubMed-Skafar
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