Differential recruitment of nuclear receptor coactivators may determine alternative RNA splice site choice in target genes

Abstract

The biological consequences of steroid hormone-mediated transcriptional activation of target genes might be difficult to predict because alternative splicing of a single neosynthesized precursor RNA can result in production of different protein isoforms with opposite biological activities. Therefore, an important question to address is the manner in which steroid hormones affect the splicing of their target gene transcripts. In this report, we demonstrate that individual steroid hormones had different and opposite effects on alternative splicing decisions, stimulating the production of different spliced variants produced from genes driven by steroid hormone-dependent promoters. Steroid hormone transcriptional effects are mediated by steroid hormone receptor coregulators that also modify alternative splicing decisions. Our data suggest that activated steroid hormone receptors recruit coregulators to the target promoter that participate in both the production and the splicing of the target gene transcripts. Because different coregulators activating transcription can have opposite effects on alternative splicing decisions, we conclude that the precise nature of the transcriptional coregulators recruited by activated steroid receptors, depending on the promoter and cellular contexts, may play a major role in regulating the nature of the spliced variants produced from certain target genes in response to steroid hormones. G ene expression regulation is a multistep process, including the synthesis of the pre-mRNA or transcription; the 5Ј and 3Ј end maturation of the transcript or capping and polyadenylation, respectively; the removal of the introns from the premRNA; and the export to the cytosol of the mRNA and its translation (1). Steroid hormones play a major role in the control of cellular fate and cellular homeostasis by modulating the expression of genes, the products of which are involved in cellular programs such as apoptosis, proliferation, differentiation, and in cellular metabolism (2, 3). Most of the studies of steroid hormone action focus on transcriptional effects that are mediated by the binding of steroid hormone receptors to hormone response elements localized in target gene promoters (4). Nevertheless, the biological consequences resulting from the modulation of the transcriptional activity of genes cannot be precisely predicted because of alternative splicing. Approximately 60% of human pre-mRNAs undergo an alternative splicing process that results in the synthesis from one gene of different mRNAs encoding different proteins having different biological actions (5). For instance, the products of many genes involved in apoptosis are alternatively spliced and this splicingcan result in the synthesis of isoforms that antagonize each other by having pro-vs. antiapoptosis effects (6). Therefore, the alternative splicing process can change considerably the biological consequences resulting from the transcriptional modulation of steroid hormone target genes and an important question to address is the mechanis...

Regulation of vascular endothelial growth factor in prostate cancer

“…Consistent with this, animal studies have indicated a role for androgens and estrogen in prostate vascularization (Daehlin et al 1985). In this context, it is interesting to note that nuclear receptor-coregulator complexes can regulate splicing events (Auboeuf et al 2002(Auboeuf et al , 2004. Thus, a role for the aberrant recruitment of nuclear receptor complexes to the VEGF promoter in the induction of pro-angiogenic VEGF splicing during carcinogenesis cannot be excluded (Fig.…”

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.…”

Switch ofHLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis

“…In this regard, steroid hormones have been previously described as controlling alternative premessenger-RNA splicing. 45,46 For instance, the alternatively spliced isoforms of the CD44 gene are regulated in breast tumor cells in which each isoform may play a particular role in time and space. 47 We may hypothesize that such specific factor(s) affecting HLA-G splicing may be upregulated according to the physiopathological context and related microenvironment.…”