Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing.
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 alpha (ERalpha) 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 ERalpha, 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.
Sun
Jianlong
J
Department of Molecular Medicine, Institute of Biotechnology, 15355 Lambda Drive, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Blair
Ashley L
AL
Aiyar
Sarah E
SE
Li
Rong
R
D017398:Alternative Splicing; D000728:Androgens / Q000502:physiology*; D001483:Base Sequence; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
D000728:Androgens; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C118437:negative elongation factor; D012313:RNA