The liver is the initial target of orally administered sex steroids. Most of the effects of sex hormones on the liver are mediated through changes in the expression of specific genes. The major objective of this proposal is to explore cellular and molecular aspects of the androgenic regulation of alpha2u globulin gene expression in the liver, especially in the context of changing hormone responsiveness during maturation and aging. In the normal male rat, hepatic synthesis of alpha(2u) globulin and its mRNA begins at the onset of puberty (about 40 days) and ceases at senescence (about 800 days). Such age-dependent regulation of alpha(2u) globulin gene expression correlates with the temporal changes in hepatic androgen sensitivity that are associated with the appearance/disappearance of a 31 kDa cytoplasmic androgen binding (GAB) protein. A disjunction of hepatic androgen sensitivity and alpha(2u) globulin is observed in a mutant strain of rat (NIH Black rat). In this strain, alpha(2u) globulin is not induced by the androgen, despite the appearance of normal hepatic androgen sensitivity during puberty. We plan to utilize the NB rat model to obtain relevant mechanistic information concerning the androgenic regulation of this protein. Other areas of hormonal regulation of alpha(2u) globulin synthesis which will be explored include (I) examination of interaction between the cis- and trans-acting regulatory factors that are involved in the hormone- and age-dependent expression of the alpha(2u) globulin gene family. (II) establishment of the structure-function relationship of the cytoplasmic androgen-binding protein through molecular cloning and sequencing of both the cDNA and the purified protein, and (III) development of an in vitro model for studying the role of tissue architechture and cell-to-cell communication in the initiation and maintenance of hormone action. Results of these studies are expected to provide a deeper insight into the cellular and molecular aspects of steroid hormone action in the liver with important implications in the management of endocrine disorders associated with androgen action.
Showing the most recent 10 out of 39 publications
