PROJECT
Genetic Mechanisms of Androgen Action

Steroid hormones are carried through the blood to all parts of the body, yet they exert their effects through the activation of specific genes in certain target tissues. The tissues that respond to the steroid have a protein called a receptor, which has a high affinity for the particular steroid. Steroid receptors are members of a larger family of proteins called nuclear receptors that includes receptors for vitamin D, retinoids, and thyroid hormone, as well as a number with no known ligand (called orphan receptors).

When a steroid molecule becomes bound to its receptor, it interacts in the nucleus with specific regulatory regions adjacent to genes called promoters and activates them. Some genes are activated only in a particular type of cell, not in all cells that have the receptor. The Kap (kidney androgen-regulated protein) gene provides a useful experimental model of both cell-specific and androgen-regulated gene expression. The Kap promoter targets gene expression to specific cells in the kidney and epididymis in transgenic mice. Deletion analysis of the Kap promoter in transgenic mice has shown that L1 repeat sequences are indispensable for gene function in vivo. Investigators also used a cultured cell line that has been shown to support Kap gene expression to analyze the regulatory region of the Kap gene. The goals of this research have been to achieve a better understanding of the molecular mechanisms of androgen action, to identify the determinants of cell specificity, and to enable the androgen-regulated expression of any gene in the targeted cell types in transgenic animals.

Current research funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health involves generating mice that express Cre recombinase in specific cells under the control of a Kap promoter/enhancer. Breeding mice that have this site-specific recombinase with mice that contain a gene flanked by lox binding sites that are recognized by Cre recombinase will result in the cell-specific inactivation of that gene. This strategy of gene inactivation avoids the systemic effects of genetic mutations or traditional knock-out models in which loss of gene activity causes abnormalities in early development or embryonic lethality. For instance, androgen receptor mutations disrupt male sexual development resulting in the loss of secondary sexual characteristics in adults. The cell-specific gene inactivation approach would allow examination of androgen receptor function in specific cells in adult animals that has not been possible up to now.

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Population Council researchers

James F. Catterall, Dianne Hardy

Donor

US National Institutes of Health

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