Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing

Jianlong Sun, Ashley L. Blair, Sarah E. Aiyar, Rong Li

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Transcriptional activity of nuclear receptors (NRs) is influenced by a large number of coregulators that exert their actions predominantly at the transcription initiation step. Unlike most well-characterized NR coregulators, cofactor of BRCA1 (COBRA1), a subunit of the negative elongation factor (NELF), binds to estrogen receptor α (ERα) and modulates estrogen-dependent transcription by impeding the movement of RNA polymerase II (RNAPII) during the transcription elongation stage. Here we show that, in addition to ERα, COBRA1 also displays various degrees of affinity for several other NRs. In particular, COBRA1 binds strongly to androgen receptor (AR) via its ligand-binding domain (LBD). Small hairpin RNA (shRNA)-mediated reduction of endogenous COBRA1 enhances androgen-mediated transcription. The effect of COBRA1 knockdown can be rescued by a silent mutant COBRA1 that is refractory to the shRNA action. Using a reporter assay for alternative splicing, we also provide evidence for a role of COBRA1 in influencing the exon skipping/inclusion of nascent transcripts produced from an androgen-dependent promoter. These findings suggest that COBRA1 may coordinate multiple steps in ligand-dependent gene expression, which in turn ensures both the quantity and quality of hormone-stimulated gene products.

Original languageEnglish (US)
Pages (from-to)131-139
Number of pages9
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume107
Issue number3-5
DOIs
StatePublished - Nov 2007

Fingerprint

Alternative Splicing
Transcription
Cytoplasmic and Nuclear Receptors
Androgens
Estrogen Receptors
Small Interfering RNA
Ligands
RNA Polymerase II
Androgen Receptors
Exons
Estrogens
Gene expression
Hormones
Refractory materials
Gene Expression
Elongation
Assays
Genes

Keywords

  • Alternative splicing
  • Androgen receptor
  • COBRA1
  • NELF
  • Transcriptional repression

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing. / Sun, Jianlong; Blair, Ashley L.; Aiyar, Sarah E.; Li, Rong.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 107, No. 3-5, 11.2007, p. 131-139.

Research output: Contribution to journalArticle

Sun, Jianlong ; Blair, Ashley L. ; Aiyar, Sarah E. ; Li, Rong. / Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing. In: Journal of Steroid Biochemistry and Molecular Biology. 2007 ; Vol. 107, No. 3-5. pp. 131-139.
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