Molecular Basis of Cell and Developmental Biology
Alternate Cyclin D1 mRNA Splicing Modulates p27KIP1 Binding and Cell Migration*

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Cyclin D1 is an important cell cycle regulator, but in cancer its overexpression also increases cellular migration mediated by p27KIP1 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 gives rise to a variant cyclin D1 isoform termed cyclin D1b, which has the same N terminus as the canonical cyclin D1a isoform but a distinct C terminus. In this study we show that these different isoforms have unique properties with regard to the cellular migration function of cyclin D1. Although they displayed little difference in transcriptional co-repression assays on idealized reporter genes, microarray cDNA expression analysis revealed differential regulation of genes, including those that influence cellular migration. Additionally, whereas cyclin D1a stabilized p27KIP1 and inhibited RhoA-induced ROCK kinase activity, promoting cellular migration, cyclin D1b failed to stabilize p27KIP1 or inhibit ROCK kinase activity and had no effect on migration. Our findings argue that alternate splicing is an important determinant of the function of cyclin D1 in cellular migration.

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This work was supported by National Institutes of Health Grants R01CA70896, R01CA75503, R01CA86072 (to R. G. P.) and the Susan Komen Breast Cancer Foundation Grant BCTR0504227 (to C. W.). This project is funded in part from the Dr. Ralph and Marian C. Falk Medical Research Trust (to R. G. P.) and grants from Pennsylvania Department of Health (to R. G. P. and C. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and data 3.