TY - JOUR
T1 - An Alternatively Spliced Cyclin D1 Isoform, Cyclin D1b, Is a Nuclear Oncogene
AU - Lu, Fengmin
AU - Gladden, Andrew B.
AU - Diehl, J. Alan
PY - 2003/11/1
Y1 - 2003/11/1
N2 - Glycogen synthase kinase-3β-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.
AB - Glycogen synthase kinase-3β-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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M3 - Article
C2 - 14612495
AN - SCOPUS:0242526150
SN - 0008-5472
VL - 63
SP - 7056
EP - 7061
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -