Alternate cyclin D1 mRNA splicing modulates p27KIP1 binding and cell migration.
Cyclin D1 is an important cell cycle regulator, but in cancer its overexpression also increases cellular migration mediated by p27 KIP1 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 p27 KIP1 and inhibited RhoA-induced ROCK kinase activity, promoting cellular migration, cyclin D1b failed to stabilize p27 KIP1 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.
Li
Zhiping
Z
Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Wang
Chenguang
C
Jiao
Xuanmao
X
Katiyar
Sanjay
S
Casimiro
Mathew C
MC
Prendergast
George C
GC
Powell
Michael J
MJ
Pestell
Richard G
RG
D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D019938:Cyclin D1 / Q000737:chemistry / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism; D011110:Polymorphism, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D012333:RNA, Messenger; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012313:RNA; D020742:rhoA GTP-Binding Protein