Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

Abstract

Imbalanced splicing of premessenger RNA is typical of tumorous malignancies, and the regulatory mechanisms involved in several tumorigenesis-associated splicing events are identified. Elevated expression of serine-arginine protein kinase 1 (SRPK1) may participate in the pathway responsible for the dysregulation of splicing events in malignant tumor cells. In this study, we observed a correlation between the cytoplasmic accumulation of RNA-binding motif protein 4 (RBM4) and up-regulated SRPK1 in breast cancer cells. The production of the IR-B and MCL-1 S transcripts was induced separately by the overexpression of RBM4 and SRPK1 gene silencing. Overexpressed RBM4 simultaneously bound to the CU-rich elements within the MCL-1 exon2 and the downstream intron, which subsequently facilitated the exclusion of the regulated exon. Breast cancer cells are deprived of apoptotic resistance through the RBM4-mediated up-regulation of the IR-B and MCL-1 S transcripts. These findings suggest that the splicing events regulated by the SRPK1-RMB4 network may contribute to tumorigenesis through altered sensitivity to apoptotic signals in breast cancer cells.

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

“…It is consistent that the nuclear nonphosphorylatable S309A, but not the cytoplasmic phosphomimetic S309D mutant, possesses activity similar to that of WT RBM4 of modulating alternative splicing events in differentiating cells. 22,26 However, SRPK1-mediated hyperphosphorylation of RBM4 and other SR proteins may be another molecular mechanism that modulates tissue-or stage-specific splicing events. Nevertheless, the detailed mechanism involved in BA-specific splicing events is worthy of further investigation through distinct approaches.…”

“…Figure 2C also shows that the nonphosphorylatable S309A mutant, but not the phosphomimetic S309D or RNA recognition motif mutant (mRRM), exerted a similar effect as did WT RBM4 on upregulating MEF2Cg-transcripts as demonstrated in other splicing events. 26 In addition, the influence of other splicing factors, including hnRNP A1 and ASF/SF1, on the splicing of MEF2C pre-mRNA was evaluated. As shown in Figure 2D, overexpression of FLAG-tagged splicing factors but not RBM4 had no obvious effect on inducing the level of MEF2Cg-transcripts.…”

“…25 However, the simultaneous binding of RBM4 to CU-elements within the regulated exon and upstream or downstream intron results in its exclusion. 21,26 A CU-rich element is present in MEF2C exon 10 adjacent to the alternative 3 0 splice site (Fig. 3A, underlined characters), which may participate in RBM4-mediated skipping of the g region.…”

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

“…Although it is generally thought that the SR proteins promote alternative splicing whereas hnRNPs inhibit it, there is accumulating evidence that both SR proteins and hnRNPs work through a combinatorial effect of positive and negative regulation to control alternative splicing. Additional RNA binding proteins such as SAM68, 50,51 members of the RBM family, [52][53][54] and HuR, [55][56][57] will not be discussed here.…”

The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas

“…SRPK1, a highly conserved protein in eukaryotic organisms, is comprised of a PKC superfamily kinase domain and a spacer region that divides the kinase domain by half [6,7]. Some reports demonstrate the key role of SRPK1 in phosphorylation of specific amino acids of proteins rich in serinearginine repeats that is called as RS domain proteins [8]. RS domain proteins are involved in precursor mRNA translation, processing and splicing, chromatin reconstruction, cell cycle progression, and remodeling of cellular structures [9].…”