A Novel Splice Variant of the Nuclear Coactivator p120 Functions Strongly for Androgen Receptor: Characteristic Expression in Prostate Disease

摘要

We cloned a novel splicing variant for nuclear coactivator pl20(α), designated as pl20β and studied its function and expression in several human prostate diseases. Transfection assays demonstrated that pl20β functions as a strong coactivator for androgen receptor (AR), but weakly for other nuclear receptors. GST-pull down assay showed that a glutamine-rich region of the pl20 bound to the ligand-binding domain of AR. Interestingly, pl20β mRNAs were expressed predominantly in the normal prostate, androgen-responsive prostate cancers and an androgen-sensitive prostate cancer cell line, LNCaP, but weakly in recurrent cancers and the androgen-insensitive prostate cancer cell lines PC3 and DU145. Furthermore, knockdown of pl20α by siRNA abolished coactivator activity on thyroid hormone receptors (TR) and PPARy, but did not affect that of ARs in PC3 cells. In addition, competitive assay with other nuclear receptors demonstrated that TR and PPARγ did not inhibit pl20β-induced stimulation. These findings suggested that while pi20α was essential for ligand-dependent stimulation of TRs and PPARγ, pl20β acted as a coactivating protein predominantly for AR.