Alternative splicing of SYK regulates mitosis and cell survival

Abstract

Most human genes produce multiple mRNA isoforms through alternative splicing. However, the biological relevance of most splice variants remains unclear. In this study, we evaluated the functional impact of alternative splicing in cancer cells. We modulated the splicing pattern of 41 cancer-associated splicing events and scored the effects on cell growth, viability and apoptosis, identifying three isoforms essential for cell survival. Specifically, changing the splicing pattern of the spleen tyrosine kinase gene (SYK) impaired cell-cycle progression and anchorage-independent growth. Notably, exposure of cancer cells to epithelial growth factor modulated the SYK splicing pattern to promote the pro-survival isoform that is associated with cancer tissues in vivo. The data suggest that splicing of selected genes is specifically modified during tumor development to allow the expression of isoforms that promote cancer cell survival.

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

“…Interestingly, it has been recognized that these intergenic splicing events between heterologous genes may mark the breakpoint sites that are targeted by chromosomal translocations at the genomic level (42,44). Indeed, intra-and interchromosomal chimeric fusions arising from cis or trans splicing events with genes within intra-or interchromosomal loci have been described and implicated in the pathogenesis of other neoplasia (16,18,19,21,42,44). In the present study however, no evidence for breakpoints at the genomic level that account for the YPEL5/ PPP1CB and reciprocal chimera was identified.…”

“…Similarly, the glycolytic enzyme pyruvate kinase M is known to undergo alternative splicing to yield a protein product (PKM2) that regulates cancer metabolism (18). Alternative splicing of the tyrosine kinase SYK has been shown to promote oncogenesis in ovarian cancer cells (19). Indeed, chimeric transcripts that exert oncogenic effects have been described.…”

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

“…In certain malignancies of B-cell origin, it is tonic signaling from the BCR that is proposed to activate Syk to promote cell survival (4,7,8). Interestingly, the repertoire of cells in which Syk functions as a prosurvival factor extends to tumors of B-cell origin that have not yet rearranged immunoglobulin genes, hematological malignancies not of B-cell origin, and nonhematological cancers, such as retinoblastoma and certain carcinomas of the lung and pancreas (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Whether ITAM-bearing receptors other than the BCR are involved in sending tonic signals via Syk in these cell types is as yet unclear.…”

“…Retinoblastoma cells in which the expression of Syk is induced by changes in gene methylation also undergo apoptosis in response to reductions in the activity or level of the kinase (18). The survival of breast and ovarian cancer cells is promoted by the alternative splicing of SYK transcripts in response to epidermal growth factor, which enhances expression of the long form of the kinase (19). While the mechanisms by which Syk promotes cancer cell survival are incompletely understood, these observations have led to the exploration of Syk inhibitors as antitumor agents (e.g., see references 18 and 20 to 22).…”

Exon expression QTL (eeQTL) analysis highlights distant genomic variations associated with splicing regulation

“…For example, the spleen tyrosine kinase gene (SYK) has an effect on breast cancer when it undergoes aberrant alternative splicing [11]. Later its alternative splicing is found as a regulator of mitosis and cell survival, and has effects on multiple types of tumors [23][24][25][26][27]. Alternative splicing was found as a rare event when it was discovered in 1970s.…”