The goal of this project is to explore the overlapping regulatory programs that control both the reproductive process and aging. This goal will be pursued by following the paradigm of the age-dependent regulation of the rat androgen receptor (rAR) gene in the liver. The hepatic expression of the rAR gene declines more than 70-fold from young-adult (3-month old) to senescent (24-month old) rats. During the previous funding period, we have characterized the rAR gene promoter and identified a number of regulatory elements that can potentially contribute to its age-dependent regulation. These include: 1) A novel positively acting trans-activator called the age-dependent factor (ADF) whose hepatic level declines by 5-to 7-fold during old age; 2) The nuclear factor kappa B (NF-kappa B), a negative regulator of the rAR gene, that undergoes a marked age-dependent increase in the liver; 3) A novel single-strand pyrimidine binding factor (ssPyrBF) which shows about a two-fold increase in the liver of old rats and can potentially interfere with the binding of Sp1 at the homopurine/homopyrimidine region of the rAR promoter; and 4) A negative composite regulatory element involving a DNA-bending protein (designated as androgen receptor repressor factor, ARRF) and the nuclear factor-1 (NF-1) which shows age- dependent alterations in the expression of its component isoforms.
The specific aims of this renewal application include: 1) Purification and characterization of ADF and ssPyrBF; 2) Cloning and characterization of the ADF and ssPyrBF cDNAs; 3) Elucidation of the mechanistic basis of NF-1 and ARRF interaction in the down-regulation of the rAR gene; and 4) Examination of the potential role of the CCAAT/enhancer binding protein (C/EBP) in the regulation of the rAR gene and investigation of its functional interaction with NF-kappa B through heterodimerization. Because of the important influence of these transcription factors in the age-dependent regulation of the rAR gene and the well-documented role of C/EBP-NF-kappa B system in the overall management of oxidative stress and inflammation, results of these studies are expected to provide new insights into the molecular basis of the androgen receptor gene regulation in the context of aging.
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