Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene

Nicholas A. Olshavsky, Clay E S Comstock, Matthew J. Schiewer, Michael A. Augello, Terry Hyslop, Claudio Sette, Jinsong Zhang, Linda M. Parysek, Karen E. Knudsen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3975-3984
Number of pages10
JournalCancer Research
Volume70
Issue number10
DOIs
Publication statusPublished - May 15 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Olshavsky, N. A., Comstock, C. E. S., Schiewer, M. J., Augello, M. A., Hyslop, T., Sette, C., Zhang, J., Parysek, L. M., & Knudsen, K. E. (2010). Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer Research, 70(10), 3975-3984. https://doi.org/10.1158/0008-5472.CAN-09-3468