Modulation of alternative pre-mRNA splicing in vivo by pinin

Loss of Pnn expression results in mouse early embryonic lethality and cellular apoptosis through SRSF1-mediated alternative expression of Bcl-xS and ICA**

“…5A), thus may hint that SRSF1 functions as a mediator of regulation of apoptosis via alternative generation of pro-apoptotic genes. The fact that SRSF1 splicing is regulated by Pnn expression level also points to the important role of Pnn in modulating mRNA alternative splicing, which has been demonstrated previously by in vivo reporter gene splicing assay (Wang et al, 2002;Chiu and Ouyang, 2006), but whether the effect of Pnn on splicing of SRSF1 transcripts is direct or mediated by some other factors remains to be studied. The reduced expression of SRSF1 in Pnndepleted MCF-7 cells, together with the resistance to apoptosis and reversal of alternative splicing events through overexpression of SRSF1 (Fig.…”

“…Furthermore, by means of embryonic stem cells and breast carcinoma cells, we observed Pnn-deficiency-related cellular and biochemical changes and found that loss of Pnn expression not only perturbed distribution patterns and expression level of speckleassociated proteins but also resulted in apoptosis in both cell types. Based on the known role of Pnn in the regulation of mRNA alternative splicing (Wang et al, 2002;Chiu and Ouyang, 2006), we analyzed the alteration of isoform expression of several apoptosis-related genes and revealed that mRNA splicing was actively driven toward the pro-apoptotic isoforms of Bim, Bcl-x, and ICAD in Pnn-depleted MCF-7 cells. Pnn depletion also reduced functional SRSF1 messages through alternative splicing.…”

“…Despite the apparent absence of SR proteins in nuclear speckles, unlike SRSF1 and SRSF2, U1A, a component of snRNPs, displayed a diffuse staining pattern throughout the nucleoplasm in cells lacking Pnn expression , indicating that Pnn absence specifically compromises SR protein family expression rather than other components of the splicing machinery. Loss of Pnn promotes pre-apoptotic Bcl-xS alternative expression and alters SRSF1 splicing patterns Pnn has been identified in pre-mRNA splicing functional complexes in several genome-wide proteomic analyses (Chen et al, 2007) and also demonstrated to be a splicing regulator (Wang et al, 2002). Since numerous apoptotic factors are modulated via alternative splicing (Schwerk and SchulzeOsthoff, 2005), it is conceivable that cellular apoptosis triggered by Pnn depletion may be through differential isoform expression of certain apoptotic factors.…”

“…Pnn is multi-functional within the nucleus. Its roles include regulation of alternative splicing, mRNA export, and transcriptional activity regulation (Wang et al, 2002;Li et al, 2003;Alpatov et al, 2004). Yeast two-hybrid assay and co-immunoprecipitation experiments demonstrated that Pnn interacts with several splicing-related SR family proteins, including SRp75, SRm300, SRp130, SRcyclophilin and RNPS1 and binds preferentially to splicedmRNA (Li et al, 2003;Lin et al, 2004;Zimowska et al, 2003).…”

Protein composition of human mRNPs spliced in vitro and differential requirements for mRNP protein recruitment

“…For example, SRm160, RNPS1, and Pinin have been shown to act as splicing coactivators or alternative splicing factors (Mayeda et al 1999;Wang et al 2002). UAP56, Aly/REF, and NXF1/TAP are documented mRNA export factors, where UAP56 is thought to recruit Aly/REF to the mRNA which in turn recruits NXF1/ TAP, a factor directly interacting with proteins of the nuclear pore complex (Luo et al 2001).…”