Nuclear Cyclin D1: An Oncogenic Driver in Human Cancer
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Nuclear Cyclin D1: An Oncogenic Driver in Human Cancer
JONG KYONG KIM AND J. ALAN DIEHL*
Kim su-hyun2010020727
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Introduction
• Cyclin D1 is frequently overexpressed in cancers.• its overexpression can be attributed to many fact
ors including increased transcription, translation, and protein stability.
• This review provides a brief overview of cyclin D1 regulation in human cancers and their impact on neoplastic transformation.
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Cell cycle regulator ; Cyclin -CDK
• The cyclin-cdks are master regulators of cell proliferation.
• These serine/theronine kinase are the motors that both start and stop the cell cycle in respose to proliferative or antiproliferative signals.
• Among which the main players in animal cells include cyclins, CDKs(cyclin-depandent kinase, positive regulator) and CDK inhibitors(negative regulators such as p21cip1 and p27kip1).
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Cell-cycle regulation. WormBook. 2005
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Cyclin D
• Cyclin Ds are key regulators during the G1 phase.
• There are three types of cyclin Ds, D1, D2 and D3 in mammalian cells.
• Associated cyclin-dependent kinases CDK4 and CDK6
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Yew et al., 2001
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D-Cyclins : Mediators of Mitogenic Signals to Core Cell Cycle Machinery
• Mitogen-dependent cyclin D1 regulation is more advanced than that for cyclin D2 and D3.
• Cyclin D1 expression and accumulation are induced by growth factors and occur at multiple levels including increased transcription, translation, and protein stability.
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Cook et al. Genome Biology 2001 2:research0012.1
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• Various types of cancer, including mantle cell lymphoma (MCL), non-small cell lung cancer, and carcinomas of breast, head and neck, esophagus.
• Cyclin D1 overexpression in human tumors is driven by multiple mechanisms comprising genomic alterations, posttranscriptional regulation, and post-translational protein stabilization.
D-Cyclin Overexpression in Human Cancer
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• Genomic alterations: chromosomal translocations, gene amplification, and polymorphisms
• Post-transcriptional mechanisms: a target of microRNA action
• Post-translational mechanisms: perturbed nuclear export and proteolysis
D-Cyclin Overexpression in Human Cancer
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Fig. 1. Cyclin D1 regulation in normal versus cancer cells.
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Aberrant Nuclear Accumulation of the Cyclin D1/CDK4 Kinase and Neoplastic Transformation• Overexpression of cyclin D has been shown
to contract the G1 phase, decrease cell size, and reduce the dependency of the cell on mitogens in animal models and cell lines.
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Genomic Instability in Tumors Harboring a Nuclear Cyclin D1/CDK4 Kinase
• Cyclin D1/CDK4 kinase is likely to participate more directly in the neoplastic process.
• Nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complex stabilizes Cdt1, As a result, stabilized Cdt1 continually primes DNA re-replication during S phase and induces genomic instability characterized by aneuploidy.
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Fig. 1. Cyclin D1 regulation in normal versus cancer cells.
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Targeting Cyclin D/CDK Activity as aTherapeutic Modality• Recent studies have reported that GSK-3b
regulates proteosomal degradation of cyclin D1 protein and overexpression of cyclin D1 results from loss of GSK-3b activity.
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Summary
• Individual cyclin-dependent kinases that are activated during distinct cell cycle phases.
• Cyclin D1 overexpression in human tumors is driven by multiple mechanisms.
• The contributions of cyclin D1 in human neoplasms.