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

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

Published In Cancer Res, (2010 May 15)

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.

PubMed ID: 20460515

MeSH Terms: Alleles; Alternative Splicing/genetics*; Biomarkers, Tumor/genetics; Blotting, Western; Cell Line, Tumor; Cyclin D1/genetics*; Cyclin D1/metabolism; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic*; Humans; Immunoenzyme Techniques; Immunoprecipitation; Male; Neoplasms, Hormone-Dependent/genetics*; Neoplasms, Hormone-Dependent/metabolism; Neoplasms, Hormone-Dependent/pathology; Nuclear Proteins/physiology*; Oligonucleotide Array Sequence Analysis; Polymorphism, Genetic/genetics*; Prostate/metabolism; Prostate/pathology; Prostatic Neoplasms/genetics*; Prostatic Neoplasms/metabolism; Prostatic Neoplasms/pathology; Protein Isoforms; RNA, Messenger/genetics; RNA, Messenger/metabolism; RNA-Binding Proteins; Reverse Transcriptase Polymerase Chain Reaction; Serine-Arginine Splicing Factors