This laboratory is focused on the mechanisms of steroid hormone action. These studies grew from the cloning of a cDNA encoding the AR and the use of this and related tools to analyze genetic defects that caused various forms of resistance to the action of one class of steroid hormones, androgens.
In these syndromes, 46,XY genotypic males with defects within the X-linked androgen receptor (AR) gene manifest a range of abnormalities in sexual phenotype, ranging from men with mild defects in virilization to individuals who are phenotypically female. The definition of the genetic defects in these individuals, coupled with biochemical and physical studies of the normal and mutant AR proteins, has provided important insight into the mechanism of androgen action and more specifically into the function of the AR.
Despite these insights, a number of important questions remain:
1. A substantial number of individuals manifest abnormalities of virilization compatible with an abnormality of androgen action that cannot be accounted by defects of know genes (e.g. the AR, 5alpha- reductase). These are represented by fibroblasts in our fibroblast repository of more than 1000 samples established from normal subjects and patients with characterized and uncharacterized defects of androgen action.
2. Functionally, the amino terminus of the AR is a critical element of AR function. The role of this structure in mediating the normal function of the AR has not been defined.
3. Steroid hormone responsive genes demonstrate a wide range in the level and kinetics of regulation by androgen. Existing models of androgen action do not account for these variations.
4. Selected biological scenarios suggest that alterations of androgen signaling may be abnormally active (i.e. responsive to very low androgen concentrations or active in the absence of ligand). These include the virilization of the spotted female hyena and advanced human prostate cancer.
Ongoing projects are designed to expand our understanding of the mechanisms of androgen receptor function and to relate these findings to biological states in which androgen receptor function is defective or overactive.
1. We have purified a series of proteins that co-purify with the AR isolated from cells that natively express the human AR. We have demonstrated the presence of these proteins at the sites within and adjacent to the promoters of androgen regulated genes. Silencing of the expression of the proteins in this collection that we have examined has a profound effect on the capacity of the AR to regulate model responsive genes.
2. We have isolated a series of proteins that interact with the amino terminus of the human AR. We are currently focused on determining the relevance of these proteins to the function of the AR in cells and in tissues.
RECENT PUBLICATIONS
McPhaul MJ, "Mutations That Alter Androgen Receptor Function: Androgen Insensitivity and Related Disorders" DeGroot LJ, Jameson JL(eds.) Endocrinology, 5th edition, Elsevier, Philadelphia, PA, Volume 3, Chapter 169,, 3139-3157., 2006
Lanzino M, De Amicis F, McPhaul MJ, Marsico S, Panno ML, Ando S, "Endogenous coactivator ARA70 interacts with ER alpha and modulates the functional ER alpha/AR interplay in MCF-7 cells." J Biol Chem,, 280:20421-20430, 2005
McPhaul MJ, "Defects of Androgen Action" Principles of Molecular Medicine, 2nd edition, Humana Press, Totowa, NJ., Chapter 44:466-472., 2006
Kohler B, Delezoide A-L, Boizet-Bonhoure B, McPhaul MJ, Sultan C, Lumbroso S, "WT1 and the androgen receptor: Coexpression in the genital tract of human male embryos and functional interaction in vitro" J Mol Endocriniol, 38:547?554, 2007
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