Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene.
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.
Olshavsky
Nicholas A
NA
Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio, USA.
Comstock
Clay E S
CE
Schiewer
Matthew J
MJ
Augello
Michael A
MA
Hyslop
Terry
T
Sette
Claudio
C
Zhang
Jinsong
J
Parysek
Linda M
LM
Knudsen
Karen E
KE
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic / Q000235:genetics*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors
D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D019938:Cyclin D1; D000068103:Serine-Arginine Splicing Factors
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