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[Cancer Research 63, 7056-7061, November 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

An Alternatively Spliced Cyclin D1 Isoform, Cyclin D1b, Is a Nuclear Oncogene1

Fengmin Lu, Andrew B. Gladden and J. Alan Diehl2

The Leonard and Madlyn Abramson Family Cancer Research Institute [F. L., A. B. G., J. A. D.], Cancer Biology [J. A. D.], and Cell and Developmental Biology [J. A. D.], University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104

Glycogen synthase kinase-3ß-dependent phosphorylation of cyclin D1 at a conserved COOH-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export at the G1-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.




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Copyright © 2003 by the American Association for Cancer Research.