Cyclin D1 and pancreatic carcinoma: a proliferative agonist and chemotherapeutic antagonist.
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Animals↗
Biomedical subjects
Sharon Benzeno
Publications and source records attributed to Sharon Benzeno.
A novel WISp39 protein links Hsp90 and p21 stability to the G2/M checkpoint.
Transcriptional regulation of the p21(Cip1) cyclin-dependent kinase inhibitor is a well-established mechanism by which the cell orchestrates a proper spatial and temporal cell cycle progression. Now, in the January 2005 issue of Molecular Cell (2005; Vol 17, 237-49), a study by Jascur et al identifies a novel multi-protein complex that is critical in contributing to a p53-dependent G2 cell cycle checkpoint. The authors demonstrate the significance of stabilizing the p21 protein in the context of this complex.
Cell Cycle Proteins↗
C-terminal sequences direct cyclin D1-CRM1 binding.
GSK-3beta-dependent phosphorylation of cyclin D1 at a conserved C-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export. Herein, we have identified a short stretch of residues adjacent to Thr-286 that mediates CRM1 association and thus cyclin D1 nuclear export. We found that disruption of this hydrophobic patch, stretching from amino acids 290 to 295 within cyclin D1, results in constitutively nuclear cyclin D1-CDK4 complexes with an increased propensity to potentiate transformation of murine fibroblasts. Our data support a model wherein deregulation of cyclin D1 nuclear export might contribute to human neoplastic growth.
Active Transport, Cell Nucleus↗
Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1.
Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate and colon cancers, as well as in astrocytic gliomas. Here, we establish that KLF6 mediates growth inhibition through an interaction with cyclin D1, leading to reduced phosphorylation of the retinoblastoma protein (Rb) at Ser(795). Furthermore, introduction of KLF6 disrupts cyclin D1-cyclin-dependent kinase (cdk) 4 complexes and forces the redistribution of p21(Cip/Kip) onto cdk2, which promotes G(1) cell cycle arrest. Our data suggest that KLF6 converges with the Rb pathway to inhibit cyclin D1/cdk4 activity, resulting in growth suppression.
CDC2-CDC28 Kinases↗
Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.
BACKGROUND & AIMS: Kruppel-like factor 6 (KLF6) is a ubiquitous zinc finger tumor suppressor that is often mutated in prostate cancer. Our aims were to establish the frequency of KLF6 inactivation in sporadic and inflammatory bowel disease (IBD)-associated colorectal cancers (CRC); to correlate these abnormalities with mutation and/or loss of TP53, APC, and K-RAS; and to characterize the behavior of mutant KLF6 in colon-derived cell lines. METHODS: We analyzed DNA isolated from 50 microdissected CRC cases, including 35 sporadic and 15 IBD-associated tumors. Microsatellite analysis and direct sequencing were used to establish the incidence of microsatellite instability, KLF6 and TP53 allelic imbalance, and KLF6, K-RAS, TP53, and APC mutation. Loss of growth suppressive function of the CRC-derived KLF6 mutants was characterized by in vitro thymidine incorporation assays and Western blotting. RESULTS: KLF6 was inactivated by loss and/or mutation in most sporadic and IBD-related CRCs. The KLF6 locus was deleted in at least 55% of tumors, and mutations were identified in 44%. Rates of KLF6 loss and mutation were similar to those of TP53 and K-RAS in the same samples. KLF6 mutations were present in tumors with either microsatellite or chromosomal instability and were more common, particularly in the IBD-related cancers, in the presence of wild-type APC. Unlike wild-type KLF6, cancer-derived KLF6 mutants neither suppressed growth nor induced p21 following transfection into cultured cells. CONCLUSIONS: Deregulation of KLF6 by a combination of allelic imbalance and mutation may play a role in the development of CRC.
Cells, Cultured↗