Speeding through cell cycle roadblocks: Nuclear cyclin D1-dependent kinase and neoplastic transformation
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BioMed Central
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Speeding through cell cycle roadblocks: Nuclear cyclin D1-dependent kinase and neoplastic transformation Laura L Pontano and J Alan Diehl* Address: The Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA Email: Laura L Pontano - [email protected]; J Alan Diehl* - [email protected] * Corresponding author
Published: 2 September 2008 Cell Division 2008, 3:12
doi:10.1186/1747-1028-3-12
Received: 14 August 2008 Accepted: 2 September 2008
This article is available from: http://www.celldiv.com/content/3/1/12 © 2008 Pontano and Diehl; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Mitogenic induction of cyclin D1, the allosteric regulator of CDK4/6, is a key regulatory event contributing to G1 phase progression. Following the G1/S transition, cyclin D1 activation is antagonized by GSK3β-dependent threonine-286 (Thr-286) phosphorylation, triggering nuclear export and subsequent cytoplasmic degradation mediated by the SCFFbx4-αBcrystallin E3 ubiquitin ligase. Although cyclin D1 overexpression occurs in numerous malignancies, overexpression of cyclin D1 alone is insufficient to drive transformation. In contrast, cyclin D1 mutants refractory to phosphorylation-dependent nuclear export and degradation are acutely transforming. This raises the question of whether overexpression of cyclin D1 is a significant contributor to tumorigenesis or an effect of neoplastic transformation. Significantly, recent work strongly supports a model wherein nuclear accumulation of cyclin D1-dependent kinase during S-phase is a critical event with regard to transformation. The identification of mutations within SCFFbx4-αBcrystallin ligase in primary tumors provides mechanistic insight into cyclin D1 accumulation in human cancer. Furthermore, analysis of mouse models expressing cyclin D1 mutants refractory to degradation indicate that nuclear cyclin D1/CDK4 kinase triggers DNA re-replication and genomic instability. Collectively, these new findings provide a mechanism whereby aberrations in post-translational regulation of cyclin D1 establish a cellular environment conducive to mutations that favor neoplastic growth.
Introduction Mitogenic signalling induces transcription and translation of the D-type cyclins, the allosteric regulators of CDK4/6, during G1 phase coupling growth stimuli to cell cycle progression [1]. Active cyclin D1/CDK4 complexes translocate to the nucleus and phosphorylate the retinoblastoma protein (Rb) and related pocket proteins, thereby triggering E2F-dependent transcription of genes required for Sphase entry [2-6]. The timely expression and accumulation of cyclin D1 is ensured through several mechanisms. Initially, cyclin D1 express
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