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Raging Hormones

By Roger L. Miesfeld, Ph.D.

Steroid hormones are small organic molecules that control a vast array of biochemical and physiological processes. Steroids are derived from cholesterol and contain four carbon rings that give them a fat soluble property. There are two major types of steroid hormones in humans; the reproductive hormones progesterone, estradiol and testosterone, and the metabolic hormones, glucocorticoid and aldosterone. Reproductive hormones are synthesized in gonadal tissue, whereas metabolic hormones are produced by the adrenal gland. Steroids were some of the first pharmaceutical agents produced by organic chemists to specifically treat human diseases. The pharmacological glucocorticoids hydrocortisone, triamcinolone acetonide and dexamethasone are potent anti-inflammatory agents used to treat asthma and arthritis, as well as acute lymphoblastic leukemia. Testosterone and estradiol are used for hormone replacement therapy, and progesterone is one of the active ingredients in birth control pills. With so many physiological effects and biomedical applications, steroid hormones have intrigued biochemists, pharmacologists and endocrinologists since the early 1900s.

How do steroids mediate their effects at the molecular level? We now know that steroid hormones can enter cells by diffusing across the cell membrane and binding to specific cellular receptor proteins that function as gene regulators. Steroid hormones therefore act as on/off switches that control which genes are induced or repressed in a given cell type. Steroid receptor protein complexes bind DNA sequences with high affinity and are an important class of proteins called transcription factors. In fact, the steroid receptor gene family was found to be related to the largest class of transcription factors in the recently sequenced human genome, and steroid receptor-like proteins are found in plants, fruit flies and worms. Since the mechanism of action of steroid hormones is at the level of gene expression, it is important to identify critical target genes as a way to understand cellular responses in normal and diseased tissues.

As a professor of biochemistry and molecular biophysics, I have always been fascinated by steroid hormones, perhaps because of growing up in a household where steroid hormones were often the topic of conversation. Not only was it the early 1970s in Southern California, where raging hormones were a part of popular culture, but my father was a physician, who, as an obstetrician and gynecologist in San Diego, participated in some of the early clinical studies of birth control pills. Needless to say, when given the opportunity to investigate steroid hormone action as a postdoctoral fellow in Dr. Keith Yamamoto's lab at UC San Francisco in 1983, I jumped at the chance. My contribution to the field was the isolation and characterization of the glucocorticoid receptor gene, one of the first steroid receptors to be cloned and characterized by molecular genetics. I joined the faculty at the U of A in 1987 as an assistant professor in Biochemistry, with labs in the Arizona Cancer Center. Over the last 14 years our research group has used a combination of molecular genetics and biochemical approaches to investigate glucocorticoid-induction of cell death in the immune system and androgen control of prostate cell growth and differentiation.

Programmed cell death, also called apoptosis, is an important developmental process that has been implicated in negative T cell selection. Leukemias and lymphomas have long been treated with glucocorticoids and it has been proposed that glucocorticoid therapy induces the apoptotic cell death pathway in thymocytes. Glucocorticoids are also used to treat asthma and it is thought that one of their anti-inflammatory actions in the airways is induction of apoptosis in eosinophils, a type of blood cell found in inflamed tissues. Our lab has used several molecular genetic approaches to identify glucocorticoid-regulated genes in murine thymocytes and in human eosinophils, most recently by employing DNA microarray technology. Sanjay Chauhan, a postdoc in the lab, and Suzy Kunz, a senior research specialist, have used this powerful high throughput method to simultaneously monitor the expression of thousands of genes using DNA microchips produced by the Microarray Core Facility in the Arizona Cancer Center. A number of potentially important glucocorticoid target genes are currently being studied in the lab, with the main focus being to understand how the encoded gene products may contribute to glucocorticoid-induced apoptosis in thymocytes and eosinophils. University of Arizona collaborators in these projects include John Bloom, associate professor of medicine and pharmacology, and Fernando Martinez, professor of medicine and Director of the Respiratory Sciences Center. A former graduate student in the Miesfeld lab, Frank Flomerfelt, who is now a staff scientist in the Laboratory of Cellular and Molecular Immunology at the NIH, is also collaborating with the lab by providing gene expression data from a wide variety of mouse tissues and immune cell subtypes.

The second major project in the our lab involves studying the effects of androgens on prostate cell proliferation and differentiation. The prostate is male-specific androgen-dependent gland that can become hyperplastic in older men causing urinary dysfunction. The prostate gland is also is prone to carcinogenesis with prostate cancer being the second leading cancer type in American males. The American Cancer Society estimates that nearly 200,000 new cases of prostate cancer will be diagnosed in 2001. Based on what is known about the role of androgens in prostate development, androgen-ablation therapy is often used to treat prostate disease as a means to inhibit cell growth. Our lab has studied androgen action in prostate cells for the past 10 years and has recently begun a collaboration with Anne Cress, professor of radiation oncology, and Ray Nagle, professor of pathology, to characterize a new model of in vitro prostate cell differentiation developed in the lab by Debra Gordon, a former postdoctoral fellow, and David Whitacre, a BMCB graduate student. The CA25 cell line model was derived from an immortalized rat prostate basal epithelial cell and has the unusual property of undergoing terminal differentiation, rather than proliferation, in the presence of dihydrotestosterone. CA25 is being used to investigate androgen control of normal prostate cell functions, with the goal of discovering how prostate cells escape terminal differentiation to become highly proliferative, and ultimately, androgen-insensitive which is a hallmark of advanced prostate disease.