CoAA, a Nuclear Receptor Coactivator Protein at the Interface of Transcriptional Coactivation and RNA Splicing

Abstract

We have shown that steroid hormones coordinately control gene transcriptional activity and splicing decisions in a promoter-dependent manner. Our hypothesis is that a subset of hormonally recruited coregulators involved in regulation of promoter transcriptional activity also directly participate in alternative RNA splicing decisions. To gain insight into the molecular mechanisms by which transcriptional coregulators could control splicing decisions, we focused our attention on a recently identified coactivator, CoAA. This heterogeneous nuclear ribonucleoprotein (hnRNP)-like protein interacts with the transcriptional coregulator TRBP, a protein recruited to target promoters through interactions with activated nuclear receptors. Using transcriptional and splicing reporter genes driven by different promoters, we observed that CoAA mediates transcriptional and splicing effects in a promoter-preferential manner. We compared the activity of CoAA to the activity of other hnRNP-related proteins that, like CoAA, contain two N-terminal RNA recognition motifs (RRMs) followed by a C-terminal auxiliary domain and either have or have not been implicated in transcriptional control. By swapping either CoAA RRMs or the CoAA auxiliary domain with the corresponding domains of the proteins selected, we showed that depending on the promoter, the RRMs and the auxiliary domain of CoAA are differentially engaged in transcription. This contributes to the promoter-preferential effects mediated by CoAA on RNA splicing during the course of steroid hormone action.Regulation of gene expression is a complex process occurring in several steps, including transcription, splicing, transcript 5Ј-and 3Ј-end modification (capping and polyadenylation, respectively), transcript export, and stability. It is now accepted that these different steps are "mechanistically" coupled: transcription is coupled to capping, splicing, and polyadenylation; and splicing is coupled to capping, polyadenylation, and export (9,30,32,40,44). An emerging view of the coupling among gene expression machines indicates that proteins involved in early steps in the pathway can influence subsequent downstream steps (9,30,32). Transcriptional coregulators recruited to target gene promoters by DNA-binding transcriptional factors, including nuclear receptors, could play a major role in this regard (2, 13, 35, 37). Among the more than 100 coregulators identified to date that participate directly in transcriptional regulation, a subset of these proteins are structurally or functionally related to proteins involved in pre-mRNA processing (2, 11, 13, 14, 37).Functional principles for the "mechanical" coordination between the different steps of the gene expression process are emerging (7,12,38). Most human primary transcripts contain several exons separated by introns that are removed during the splicing reaction. Due to the presence of multiple splice sites, the RNA-splicing process can lead to the production of multiple mature transcripts. Alternative splicing is more a rule than an e...

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.…”

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

“…In addition, transcriptional coregulators of the nuclear receptor family recruited at the promoter level not only enhances the transcriptional activity of this promoter, but also affects the nature of the splice variants produced. [28][29][30] Moreover, some transcription factors have been reported to bind to proteins of the spliceosome and/or display dual functions in splicing and transcription. [31][32] Taken together, these results indicate a function for proteins controlling transcription in splicing regulation.…”

“…The anti-E2F1 (C-20), anti-SC35 (H-55) and anti-Bcl-x L (H5) antibodies were purchased from Santa Cruz, the anti-Bcl-x S (Ab-1) from Oncogene Research, the anti-E2F1 (KH95) and anti-procaspase-3 from Pharmingen, the anti-FLIP (NF6) from Alexis, the anti-actin (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) from Sigma, the anti-SC35 (4F-11) from Euromedex and the anti-SRp20 (7B4) and anti-SF2/ASF from Zymed. Cleaved caspase-3 (Asp175) was from Cell Signaling.…”

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

“…Genetic deletion of TRBP in mice is embryonically lethal, with severe defects in embryonic development (Kuang et al, 2002;Antonson et al, 2003). CoAA has been shown to synergistically activate transcription with TRBP and participate in the regulation of alternative splicing decisions (Auboeuf et al, 2004(Auboeuf et al, , 2005. CoAA, also called PSP2, is a major component of nuclear paraspeckles and colocalizes with p54 nrb which regulates pre-mRNA splicing (Fox et al, 2002).…”