Abstract

Androgenic hormones (testosterone and dihydrotestosterone) stimulate sexual differentiation and development as well as the maintenance of male reproductive function. Androgens exert a major influence on gene expression in target tissues, however, the mechanisms by which they stimulate nucleic acid and protein synthesis remain unknown. The objective of this research is to define mechanisms by which androgens control gene expression. This will be accomplished by studies on the regulation of genes coding for the 3 subunits of prostatein, the major secretory protein of the rat ventral prostate and the 20K protein, another major androgen dependent protein. The androgen receptor recognition sequence (ARRS) will be identified by binding of partially and highly purified androgen receptor preparations to short segments of genomic DNA. ARRS will be mapped across the genes and their flanking DNA. Structural features of the gene regions surrounding receptor binding sites will be identified by DNA sequencing. The relationship of putative promotors or enhancers to ARRS will be established by mapping the DNAse I hypersensitive sites within and adjacent to prostatein genes. It will determine whether androgen receptors have a role in gene attachment to nuclear matrix. The androgen regulated genes will be cloned in eukaryotic expression vectors and transferred to androgen responsive primary cultures of ventral prostate epithelial cells and well differentiated epithelial cell lines for studies on the regulation of gene expression. Deletion mutants will be constructed to identify promotor and possible enhancer elements in androgen regulated genes. The interaction among androgen receptors and other regulatory proteins will be investigated using subcloned ARRS and promotor sequences as probes for sequence-specific DNA binding proteins. It is expected that the information derived from these studies will provide new insight into androgen regulation of male reproductive function and will be revelent to the problems of infertility and fertility control.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD004466-21
Application #
3310290
Study Section
Reproductive Biology Study Section (REB)
Project Start
1977-08-01
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
21
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Liao, M; Ruddock, P S; Rizvi, A S et al. (2005) Cationic peptide of the male reproductive tract, HE2alpha, displays antimicrobial activity against Neisseria gonorrhoeae, Staphylococcus aureus and Enterococcus faecalis. J Antimicrob Chemother 56:957-61
Gregory, Christopher W; Whang, Young E; McCall, Wesley et al. (2005) Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 11:1704-12
Quigley, Charmian A; Tan, Jiann-an; He, Bin et al. (2004) Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction. Mech Ageing Dev 125:683-95
Gregory, Christopher W; Fei, Xiaoyin; Ponguta, Liliana A et al. (2004) Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem 279:7119-30
Tan, Jiann-An; Hall, Susan H; Hamil, Katherine G et al. (2002) Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators. J Biol Chem 277:16993-7001
Zhou, Zhong-xun; He, Bin; Hall, Susan H et al. (2002) Domain interactions between coregulator ARA(70) and the androgen receptor (AR). Mol Endocrinol 16:287-300
Gregory, C W; He, B; Johnson, R T et al. (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61:4315-9
Tan, J; Sharief, Y; Hamil, K G et al. (1997) Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 11:450-9
Avellar, M C; Gregory, C W; Power, S G et al. (1997) Androgen-dependent protein interactions within an intron 1 regulatory region of the 20-kDa protein gene. J Biol Chem 272:17623-31
Choong, C S; Quigley, C A; French, F S et al. (1996) A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation. J Clin Invest 98:1423-31

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