An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene.
Glycogen synthase kinase-3beta-dependent phosphorylation of cyclin D1 at a conserved COOH-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export at the G(1)-S boundary. Mutations that perturb the phosphorylation of cyclin D1 at Thr-286 contribute to cell transformation, although to date, no such mutations have been found in human cancers. Cyclin D1 (CCND1) undergoes alternative splicing leading to the production of an mRNA predicted to encode a unique cyclin D1 isoform, cyclin D1b, which lacks Thr-286. We have cloned and expressed cyclin D1b, and find that it retains the ability to bind to and activate CDK4. Unlike canonical cyclin D1a, cyclin D1b remains nuclear through the cell cycle where its constitutive expression facilitates cellular transformation. Using antisera specific for cyclin D1b, the protein was detected in a high percentage of esophageal cancer-derived cell lines and in primary esophageal carcinomas. Therefore, alternative splicing leads to expression of a nuclear, oncogenic cyclin D1 isoform that is expressed in human cancer.
Lu
Fengmin
F
The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Gladden
Andrew B
AB
Diehl
J Alan
JA
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009857:Oncogenes / Q000502:physiology*; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases