Coordinate Regulation of Transcription and Splicing by Steroid Receptor Coregulators

Abstract

Recent observations indicating that promoter identity influences alternative RNA-processing decisions have created interest in the regulatory interactions between RNA polymerase II transcription and precursor messenger RNA (pre-mRNA) processing. We examined the impact of steroid receptor-mediated transcription on RNA processing with reporter genes subject to alternative splicing driven by steroid-sensitive promoters. Steroid hormones affected the processing of pre-mRNA synthesized from steroid-sensitive promoters, but not from steroid-unresponsive promoters, in a steroid receptor-dependent and receptor-selective manner. Several nuclear receptor coregulators showed differential splicing effects, suggesting that steroid hormone receptors may simultaneously control gene transcription activity and exon content of the product mRNA by recruiting coregulators involved in both processes.

BARX2 and estrogen receptor-α (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion

“…BARX2 binds strongly to the E1 and F promoters, whereas ESR1 primarily binds to the F promoter; this differential binding might influence promoter use and thus alternative splicing. ESR1 was shown to regulate splicing of a synthetic minigene driven by an estrogen-responsive promoter in cooperation with the transcriptional coregulators COAA and CAPER (Auboeuf et al, 2002(Auboeuf et al, , 2004(Auboeuf et al, , 2005. It will be interesting to determine whether these same co-regulators can interact with BARX2.…”

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

“…Both genes produce alternative splicing regulators, they utilize a positive feedback loop to enhance their own expression, and their own genes can be alternatively spliced with distinct functional consequences. In the case of CoAA, a dominant negative CoAM that counterregulates CoAA transcriptional activity is produced through alternative splicing of the CoAA gene (Auboeuf et al, 2002). Whether CoAA target genes contain any splicing regulators remains to be determined.…”

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

“…Recent studies have suggested that AIB3 may enhance transcription through interacting and/or recruiting multiple coactivator complexes, such as SRC-1/ cAMP response element-binding protein binding protein complex, activating signal cointegrator 2 complex and TR-associated protein or VDR-interacting protein complex, and thereby facilitating chromatin remodeling and general transcription factor assembly (9 -13, 18). Furthermore, AIB3 interacts with the coactivator activator (COAA), and COAA contains an RNA recognition domain and modulates RNA splicing patterns in a nuclear receptor-dependent manner (19,20). AIB3 also interacts with a DNA-dependent protein kinase and regulates its kinase activity.…”