Molecular mechanisms of androgen action.

J. Lindzey, M. V. Kumar, M. Grossman, C. Young, D. J. Tindall

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Androgens directly regulate a vast number of physiological events. These direct androgen effects are mediated by a nuclear receptor that exhibits four major functions or activities: steroid binding, DNA binding, transactivation, and nuclear localization. The SBD consists of a hydrophobic pocket of amino acids that exhibits high-affinity, androgen-specific binding. Based on studies of mutant AR, it appears that a number of different amino acids contribute to the steroid binding characteristics of the AR. The DNA binding domain confers sequence-specific binding to structures called androgen-responsive elements. The specificity of steroid binding and DNA binding provides a crucial basis for androgen-specific regulation of target genes. The nuclear localization signal shares homology with known nuclear localization signals and, coupled with the presence of androgens, is responsible for localizing the AR to the nucleus. The transactivation functions reside mostly in the NH2 terminus but the responsible domains are as yet poorly defined. Though the different domains can act as independent moieties, one domain can clearly alter the behavior of another domain. For instance, the SBD appears to inhibit the transactivating functions until steroid is bound and the amino terminus prevents DNA binding activity until steroid is bound. The relative ease of introducing mutations with polymerase chain reaction technology will facilitate further delineation of critical amino acids and domains responsible for the various activities of the AR. The recent cloning and characterization of AR promoters revealed that the AR genes are driven by a TATA-less promoter characteristics of housekeeping genes. Analysis of transcription rates, mRNA levels, and protein levels indicates that androgens and pkA and pkC pathways modulate expression of AR mRNA and protein. This indicates that the same signal pathways that interact to regulate androgen target genes also regulate the levels of AR in the target tissues. Surprisingly few androgen-regulated genes have been well characterized for the mechanisms by which androgen regulates the gene. The C(3), Slp, probasin, PSA, and hKLK2 genes have provided examples where androgens regulate transcription. Posttranscriptional regulation by androgens has been demonstrated for the SVP1, 2, 3, and 4 and AR genes. The mechanisms underlying posttranscriptional regulation are poorly defined but substantial progress has been made in defining the critical elements that mediate transcriptional effects of androgens. Transcriptional effects are mediated through binding of androgen-AR complexes to specific DNA sequences called AREs. Simple AREs such as those found in C(3) and kallikrein genes tend to be permissive in that GR and PR can also act through the same element.(ABSTRACT TRUNCATED AT 400 WORDS)

Original languageEnglish (US)
Pages (from-to)383-432
Number of pages50
JournalVitamins and Hormones
Volume49
StatePublished - 1994

Fingerprint

Androgens
Genes
Steroids
Nuclear Localization Signals
DNA
Transcription
Amino Acids
Transcriptional Activation
Messenger RNA
Kallikreins
Cloning
Polymerase chain reaction
DNA sequences
Essential Genes
Cytoplasmic and Nuclear Receptors
Organism Cloning
Signal Transduction
Proteins
Tissue
Technology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Endocrinology
  • Physiology

Cite this

Lindzey, J., Kumar, M. V., Grossman, M., Young, C., & Tindall, D. J. (1994). Molecular mechanisms of androgen action. Vitamins and Hormones, 49, 383-432.

Molecular mechanisms of androgen action. / Lindzey, J.; Kumar, M. V.; Grossman, M.; Young, C.; Tindall, D. J.

In: Vitamins and Hormones, Vol. 49, 1994, p. 383-432.

Research output: Contribution to journalArticle

Lindzey, J, Kumar, MV, Grossman, M, Young, C & Tindall, DJ 1994, 'Molecular mechanisms of androgen action.', Vitamins and Hormones, vol. 49, pp. 383-432.
Lindzey J, Kumar MV, Grossman M, Young C, Tindall DJ. Molecular mechanisms of androgen action. Vitamins and Hormones. 1994;49:383-432.
Lindzey, J. ; Kumar, M. V. ; Grossman, M. ; Young, C. ; Tindall, D. J. / Molecular mechanisms of androgen action. In: Vitamins and Hormones. 1994 ; Vol. 49. pp. 383-432.
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