Identification of ASF/SF2 as a Critical, Allele-Specific Effector of the Cyclin D1b Oncogene

Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio, USA.
Cancer Research (Impact Factor: 9.33). 05/2010; 70(10):3975-84. DOI: 10.1158/0008-5472.CAN-09-3468
Source: PubMed


The cyclin D1b oncogene arises from alternative splicing of the CCND1 transcript, and harbors markedly enhanced oncogenic functions not shared by full-length cyclin D1 (cyclin D1a). Recent studies showed that cyclin D1b is selectively induced in a subset of tissues as a function of tumorigenesis; however, the underlying mechanism(s) that control tumor-specific cyclin D1b induction remain unsolved. Here, we identify the RNA-binding protein ASF/SF2 as a critical, allele-specific, disease-relevant effector of cyclin D1b production. Initially, it was observed that SF2 associates with cyclin D1b mRNA (transcript-b) in minigene analyses and with endogenous transcript in prostate cancer (PCa) cells. SF2 association was altered by the CCND1 G/A870 polymorphism, which resides in the splice donor site controlling transcript-b production. This finding was significant, as the A870 allele promotes cyclin D1b in benign prostate tissue, but in primary PCa, cyclin D1b production is independent of A870 status. Data herein provide a basis for this disparity, as tumor-associated induction of SF2 predominantly results in binding to and accumulation of G870-derived transcript-b. Finally, the relevance of SF2 function was established, as SF2 strongly correlated with cyclin D1b (but not cyclin D1a) in human PCa. Together, these studies identify a novel mechanism by which cyclin D1b is induced in cancer, and reveal significant evidence of a factor that cooperates with a risk-associated polymorphism to alter cyclin D1 isoform production. Identification of SF2 as a disease-relevant effector of cyclin D1b provides a basis for future studies designed to suppress the oncogenic alternative splicing event.

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Available from: Michael A Augello, Dec 17, 2013
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    • "MYC also stimulates the expression of the SR protein SRSF1, which drives oncogenesis through alternative splicing of a network of transcripts encoding signaling molecules (e.g., RON and MKNK2) and transcription factors (e.g., BIN1; Das and Krainer, 2014). SRSF1 also elicits the production of variants, such as CASC4 with antiapoptotic function, as well as MDM2 and cyclin D1 variants with prooncogenic properties (Olshavsky et al., 2010; Anczuków et al., 2012 Anczuków et al., , 2015 Comiskey et al., 2015). Positive feedback likely occurs because the SRSF1-mediated splice variant BIN1-12a no longer binds to MYC and lacks tumor suppressor activity (Ge et al., 1999; Karni et al., 2007). "

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    • "The alternatively spliced transcripts of Bcl-2-like 1 (BCL2L1) and myeloid cell leukemia 1 (MCL-1) genes encode either the anti-apoptotic or pro-apoptotic isoforms that manipulate the therapeutic response of cancer cells (Moore et al. 2010; Gautrey and Tyson-Capper 2012). The inclusion of cyclin D intron 4 leads to the production of the cyclin D1b isoform which acts as an oncogene in prostate cancer cells (Burd et al. 2006; Olshavsky et al. 2010). An increase in the short S6K1 variant facilitates the transformation of breast epithelial cells, whereas the presence of the long S6K1 isoform mediates the opposite effect by inhibiting Ras-induced transformation and tumor growth (Ben-Hur et al. 2013). "
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    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-1S 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-1S 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.
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    • "In non-small lung cancer, SRSF1 was shown to act as oncogene in mTOR pathway dependent manner.85 In PCa, SRSF1 expression correlates with the CCND1b isoform expression.86 Taken together, it appears that SRSF1 is an interesting target for investigation. "
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