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, N., Comstock, C., Schiewer, M., Augello, M., Hyslop, T., Sette, C., et al. (2010). Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. CANCER RESEARCH, 70(10), 3975-3984 [10.1158/0008-5472.CAN-09-3468].

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

SETTE, CLAUDIO;
2010-05-15

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/16
English
Con Impact Factor ISI
Immunoprecipitation; Male; Alleles; Gene Expression Regulation, Neoplastic; Oligonucleotide Array Sequence Analysis; Gene Expression Profiling; Immunoenzyme Techniques; Prostate; Blotting, Western; Alternative Splicing; Humans; Polymorphism, Genetic; Cell Line, Tumor; Nuclear Proteins; Disease Progression; Protein Isoforms; Prostatic Neoplasms; RNA, Messenger; Tumor Markers, Biological; Reverse Transcriptase Polymerase Chain Reaction; Neoplasms, Hormone-Dependent; Cyclin D1
Olshavsky, N., Comstock, C., Schiewer, M., Augello, M., Hyslop, T., Sette, C., et al. (2010). Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. CANCER RESEARCH, 70(10), 3975-3984 [10.1158/0008-5472.CAN-09-3468].
Olshavsky, N; Comstock, C; Schiewer, M; Augello, M; Hyslop, T; Sette, C; Zhang, J; Parysek, L; Knudsen, K
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/39425
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