Transcriptional regulation of the TGF-beta1 promoter by androgen receptor

Biochem J. 2008 Dec 15;416(3):453-62. doi: 10.1042/BJ20080651.

Abstract

TGF (transforming growth factor)-beta1 is a multifunctional cytokine that influences homoeostatic processes of various tissues. TGF-beta1 expression is inhibited by androgens in the prostate gland, whereas its expression is enhanced by androgens in highly metastatic prostate cancer cells. Here, we examined regulation of human TGF-beta1 promoter activity by androgen in prostate cancer cells. The full-length (-3363 to +110) promoter showed a high level of activity in response to androgen in PC3mm2 cells expressing AR (androgen receptor). Further deletion analysis revealed three distal and three proximal AREs (androgen-response elements) in the promoter. Gel-shift and footprint assays show that these AREs physically interact with the DNA-binding domain of AR. Chromatin immunoprecipitation assays revealed the androgen-dependent recruitment of AR to the ARE-containing regions of the TGF-beta1 gene. More importantly, a negative ARE was detected in the TGF-beta1 promoter. Both positive and negative AREs are functional in the androgen-regulated transcription of the TGF-beta1 promoter. These findings imply that androgen signalling may positively or negatively regulate TGF-beta1 expression in response to various signals or under different environmental conditions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Gene Expression Regulation*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • Prostatic Neoplasms
  • Rats
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Response Elements
  • Sequence Alignment
  • Signal Transduction
  • Transcription, Genetic*
  • Transforming Growth Factor beta1 / genetics*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • AR protein, human
  • Receptors, Androgen
  • Transforming Growth Factor beta1