Keith L. Parker, M.D., Ph.D.

Professor of Internal Medicine and Pharmacology

Chief, Division of Endocrinology and Metabolism

Email:  KEITH.PARKER@email.swmed.edu

Phone: 214-648-3494

RESEARCH SUMMARY

The biosynthesis of steroid hormones requires the concerted action of a group of cytochrome P450 steroid hydroxylases that act sequentially to convert cholesterol to physiologically active steroids. The major focus of our laboratory is to define the molecular mechanisms that regulate these steroid hydroxylases. Through a concerted analysis of three mouse steroid hydroxylases, we identified and cloned steroidogenic factor (SF-1), a cell-specific nuclear receptor that regulates their coordinate expression. Targeted disruption of the gene encoding SF-1 established essential roles in adrenal and gonadal development, pituitary gonadotrope function, and formation of the ventromedial hypothalamic nucleus. These studies have established SF-1 as the first transcriptional regulator that acts at all three levels of the hypothalamic-pituitary-gonadal axis. Ongoing studies are directed at making tissue-specific knockouts of SF-1 and at identifying target genes that mediate its key roles in endocrine development and function.

A second focus of the laboratory is the steroidogenic acute regulatory protein (StAR). By mechanisms not fully understood, StAR mediates the transport of cholesterol into the mitochondria where steroidogenesis is initiated. We have produced mice lacking StAR, providing an experimental model system for the human disorder congenital lipoid adrenal hyperplasia. Using these mice, efforts are underway to explore the structure/function relationships of StAR and to elucidate the pathogenesis for this human disorder.

SELECTED PUBLICATIONS:

1. Luo, X., Ikeda, Y., and Parker, K.L. (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell, 77, 481-490.

2. Ingraham, H. A., Lala, D. S., Ikeda, Y., Luo, X., Shen, W.-H., Nachtigal, M. W., Abbud, R., Nilson, J. H., and Parker, K. L. (1994) The nuclear receptor SF-1 acts at multiple levels of the reproductive axis. Genes Dev., 8, 2302-2312.

3. Clark, B.J., Soo, S.-C., Caron, K.M., Ikeda, Y., Parker, K.L., and Stocco, D.M. (1995) Hormonal and developmental regulation of the steroidogenic acute regulatory (StAR) protein. Mol. Endocrinol. 9, 1346-1355.

4. Parker KL and Schimmer BP 1997 Steroidogenic factor 1: a key determinant of endocrine development and function. Endocrine Rev. 18, 361-377.

5. Caron KM, Soo S-C, Clark BJ, Stocco DM, Wetsel W, and Parker KL 1997 Targeted disruption of the mouse gene encoding the steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc. Natl. Acad. Sci. USA 94, 11540-11545.

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