Transcriptional repression of the glycoprotein hormone alpha subunit gene by androgen may involve direct binding of androgen receptor to the proximal promoter

• Published in: The Journal of biological chemistry Vol. 268; no. 18; pp. 13556 - 13564
• Main Authors: CLAY, C. M, KERI, R. A, FINICLE, A. B, HECKERT, L. L, HAMERNIK, D. L, MARSCHKE, K. M, WILSON, E. M, FRENCH, F. S, NILSON, J. H
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 25-06-1993
• Subjects: Androgens - physiology; Animals; Base Sequence; Biological and medical sciences; Chloramphenicol O-Acetyltransferase - antagonists & inhibitors; Chloramphenicol O-Acetyltransferase - genetics; Chloramphenicol O-Acetyltransferase - metabolism; DNA - metabolism; Estrogens - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Glycoprotein Hormones, alpha Subunit - genetics; Humans; Male; Mice; Mice, Transgenic; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Orchiectomy; Promoter Regions, Genetic; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Regulatory Sequences, Nucleic Acid; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Human; Promoter; Transcription; Androgen; Molecular interaction; Inhibition; Glycoprotein hormone; LH; Hormonal receptor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(19)38685-5

Testicular androgens suppress the synthesis and secretion of the pituitary gonadotropins, in particular, luteinizing hormone.
This suppressive effect includes transcription of both the common alpha subunit gene and the unique beta subunit genes. Herein,
we demonstrate that 1500 base pairs (bp) of proximal 5'-flanking region derived from the human alpha subunit gene and a shorter
315-bp segment of the bovine alpha subunit gene confer negative regulation by androgen to the gene encoding bacterial chloramphenicol
acetyltransferase in transgenic mice. Cotransfection assays with human androgen receptor indicated that the 1500-bp promoter
region of the human alpha subunit gene also confers androgen regulation (transcriptional suppression) to reporter genes in
both pituitary and placental cell lines. This raises the possibility of a role for DNA binding in suppression of alpha subunit
transcription by activated androgen receptor. Consistent with this possibility, we have used a gel-mobility shift assay to
detect several high affinity binding sites for androgen receptor located in the proximal promoter of the human alpha subunit
gene. The strongest androgen receptor binding site is located at approximately -101 in the proximal 5'-flanking region. This
steroid receptor binding site overlaps another binding site that defines one of several contiguous cis-acting regulatory elements
required for basal transcriptional activity. Thus, binding of activated androgen receptor to this region may block the binding
of a requisite trans-acting factor and lead to an attenuation in transcription. We conclude that this interaction, which occurs
directly at the level of the pituitary, represents one of several physiological avenues through which androgens regulate gonadotropin
gene expression.