Our objective is to elucidate the molecular basis of steroid hormone regulation of gene expression. We are pursuing this in a model system that displays hormonal, developmental and tissue-specific regulation. The S locus of the murine major histocompatibility complex includes the genes for C4 (fourth component of complement) and S1p (sex-limited protein). S1p is regulated by androgens while its homologous neighbor gene, C4, is not under hormonal control. Regulatory mutations exist in both genes, affecting levels of expression as well as S1p's dependence on androgen. Thus characterization of the structure and expression of these genes should allow us to correlate differences in DNA sequence with differences in regulation.
The specific aims of this proposal are: 1) Characterization of cDNA clones for C4 and S1p from mice of two haplotypes. 2) Comparison of S locus genes from mice of several haplotypes. 3) In vivo analysis of hormonal regulation of S1p and tissue-specific regulation of C4. 4) Identification, by expression of transfected genes, of cis-acting DNA sequences involved in hormonal and tissue-specific regulation. 5) Correlation of specific chromatin configurations with patterns of gene expression, for a variety of C4 and S1p alleles. 6) Characterization of trans-acting regulatory factors that may be involved in committment events in gene expression. 7) Examination of androgen receptor protein-nucleic acid interactions, and study of regulation of expression of the receptors. Our long-term goal is to understand regulation of gene expression in general and steroid hormone action in particular. These studies will be enhanced by the genetics of the C4/S1p system in which a variety of alleles differing in regulation can be contrasted, at a molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM031546-04
Application #
3279623
Study Section
Molecular Biology Study Section (MBY)
Project Start
1983-01-01
Project End
1988-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Graduate Schools
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Ning, Y M; Robins, D M (1999) AML3/CBFalpha1 is required for androgen-specific activation of the enhancer of the mouse sex-limited protein (Slp) gene. J Biol Chem 274:30624-30
Scheller, A; Hughes, E; Golden, K L et al. (1998) Multiple receptor domains interact to permit, or restrict, androgen-specific gene activation. J Biol Chem 273:24216-22
Scarlett, C O; Scheller, A; Thompson, E et al. (1997) Involvement of an octamer-like sequence within a crucial region of the androgen-dependent Slp enhancer. DNA Cell Biol 16:45-57
Nelson, S A; Robins, D M (1997) Regulatory capacity of an androgen-specific enhancer of the mouse Slp gene in transgenic mice. Mol Cell Endocrinol 133:89-97
Nelson, S A; Robins, D M (1997) Two distinct mechanisms elicit androgen-dependent expression of the mouse sex-limited protein gene. Mol Endocrinol 11:460-9
Burgos-Trinidad, M; Youngblood, G L; Maroto, M R et al. (1997) Repression of cAMP-induced expression of the mouse P450 17 alpha-hydroxylase/C17-20 lyase gene (Cyp17) by androgens. Mol Endocrinol 11:87-96
Scarlett, C O; Robins, D M (1995) In vivo footprinting of an androgen-dependent enhancer reveals an accessory element integral to hormonal response. Mol Endocrinol 9:413-23
Adler, A J; Scheller, A; Robins, D M (1993) The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences. Mol Cell Biol 13:6326-35
Adler, A J; Danielsen, M; Robins, D M (1992) Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors. Proc Natl Acad Sci U S A 89:11660-3
Cox, B J; Robins, D M (1988) Tissue-specific variation in C4 and Slp gene regulation. Nucleic Acids Res 16:6857-70

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