Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.
نویسندگان
چکیده
PURPOSE Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. EXPERIMENTAL DESIGN First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. RESULTS Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. CONCLUSIONS These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.
منابع مشابه
Human Cancer Biology Cyclin D1 Splice Variants: Polymorphism, Risk, and Isoform-Specific Regulation in Prostate Cancer
Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, releva...
متن کاملIdentification 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 unsolv...
متن کاملSpecificity of cyclin D1 for androgen receptor regulation.
Androgen receptor (AR) activity is required for prostate growth, differentiation, and secretion. Deregulation of AR activity results in inappropriate mitogenic signaling and is thought to contribute both to the initiation and progression of prostate cancers. Cyclin D1 functions as a strong AR corepressor by directly interacting with and inhibiting receptor activity. However, the extent to which...
متن کاملAlternate cyclin D1 mRNA splicing modulates P27<sup>KlP1</sup> binding and cell migration
Cyclin D1 is an important cell cycle regulator but in cancer its overexpression also increases cellular migration mediated by p27 stabilization and RhoA inhibition. Recently, a common polymorphism at the exon 4-intron 4 boundary of the human cyclin D1 gene within a splice donor region was associated with an altered risk of developing cancer. Altered RNA splicing caused by this polymorphism give...
متن کاملAssociation between rs2735839 and Serum Prostate-specific Antigen Level Regarding Risk of Prostate Cancer in Iranian Population
Background and Objective: Prostate cancer is among the five common cancers in males. It is second cancer in terms of the age-standardized rate (ASR) (ASR=16.6) in Iran. The rs2735839 G/A, an intergenic polymorphism is located on chromosome 19q13.33 at 600 base pairs of the KLK3 gene untranslatable region. This gene which codes prostate-specific antigen (PSA) is used in the screening and diagnos...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Clinical cancer research : an official journal of the American Association for Cancer Research
دوره 15 17 شماره
صفحات -
تاریخ انتشار 2009