Differential expression of androgen receptor (AR) mRNA in rat liver during maturation and aging directly correlates with androgen responsiveness of the young-adult male liver, and androgen insensitivity during prepuberty and senescence. A 31 kDa androgen-repressible liver protein, designated as SMP-2, is expressed at relatively high abundance during the periods of hepatic androgen insensitivity compared to its very low level of expression in the androgen-responsive adult male. Nuclear run off studies show that age-dependent reactivation and androgen-mediated repression of SMP-2 are primarily regulated through altered rates of gene transcription. The proposed studies have been designed to examine the following: 1) Identification of putative transcription transactivators whose differential expression/activity during maturation and aging results in the differential temporal regulation of the androgen receptor (AR) gene in the liver. 2) Dissection of the DNA sequences of the androgen receptor gene which play critical roles in hepatic expression of the receptor. 3) Delineation of the cis elements responsible for androgenic repression of the SMP-2 gene. 4) The possible role of additional cis elements, distinct from androgen response elements, which may participate in the age-dependent regulation of the SMP-2 gene. 5) The role of androgen receptor and other non-receptor transcription regulatory proteins in the age-dependent regulation of SMP-2 gene expression. The DNA response elements of interest will be identified through gene transfer into cells containing androgen receptor. Additional cis elements responding to changes in maturation and aging will be detected via DNA transfection into cultured hepatocytes from young and old rats. Putative transcription transactivators regulating differential temporal expression of the AR gene in the liver, as well as some that are possibly involved in SMP-2 gene regulation during aging, will be identified using complementary analyses of specific protein-DNA binding and in vitro transcription. The DNA binding studies will utilize Southwestern blotting, mobility shift and DNase 1 footprinting analyses. Transcription competence of liver nuclear extracts from young and old rats will be compared in their ability to support SMP-2 promoter-directed in vitro transcription of appropriate templates. The results of these studies are expected to provide important new insights into gene regulation during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG003527-11
Application #
3114775
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1988-02-01
Project End
1996-04-30
Budget Start
1993-05-05
Budget End
1994-04-30
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Song, C S; Jung, M H; Kim, S C et al. (1998) Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. J Biol Chem 273:21856-66
Chatterjee, B; Song, C S; Jung, M H et al. (1996) Targeted overexpression of androgen receptor with a liver-specific promoter in transgenic mice. Proc Natl Acad Sci U S A 93:728-33
Chatterjee, B; Song, C S; Kim, J M et al. (1994) Androgen and estrogen sulfotransferases of the rat liver: physiological function, molecular cloning, and in vitro expression. Chem Biol Interact 92:273-9
Song, C S; Her, S; Slomczynska, M et al. (1993) A distal activation domain is critical in the regulation of the rat androgen receptor gene promoter. Biochem J 294 ( Pt 3):779-84
Demyan, W F; Song, C S; Kim, D S et al. (1992) Estrogen sulfotransferase of the rat liver: complementary DNA cloning and age- and sex-specific regulation of messenger RNA. Mol Endocrinol 6:589-97
Mancini, M A; Song, C S; Rao, T R et al. (1992) Spatio-temporal expression of estrogen sulfotransferase within the hepatic lobule of male rats: implication of in situ estrogen inactivation in androgen action. Endocrinology 131:1541-6
Song, C S; Rao, T R; Demyan, W F et al. (1991) Androgen receptor messenger ribonucleic acid (mRNA) in the rat liver: changes in mRNA levels during maturation, aging, and calorie restriction. Endocrinology 128:349-56
Mancini, M A; Chatterjee, B; Roy, A K (1991) Age-dependent reversal of the lobular distribution of androgen-inducible alpha 2u globulin and androgen-repressible SMP-2 in rat liver. J Histochem Cytochem 39:401-5
Song, C S; Kim, J M; Roy, A K et al. (1990) Structure and regulation of the senescence marker protein 2 gene promoter. Biochemistry 29:542-51
Chatterjee, B; Mancini, M A; Roy, A K (1990) The senescence marker protein (SMP-2) of the rat liver: purification, immunochemical characterization and age-dependent regulation. Biochim Biophys Acta 1034:162-9

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