Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.

Abstract	Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.
Authors	Priya Aggarwal, Laura Pontano Vaites, Jong Kyong Kim, Hestia Mellert, Buddha Gurung, Hiroshi Nakagawa, Meenhard Herlyn, Xianxin Hua, Anil K Rustgi, Steven B McMahon, J Alan Diehl
Journal	Cancer cell (Cancer Cell) Vol. 18 Issue 4 Pg. 329-40 (Oct 19 2010) ISSN: 1878-3686 [Electronic] United States
PMID	20951943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2010 Elsevier Inc. All rights reserved.
Chemical References	Adaptor Proteins, Signal Transducing CDT1 protein, human Cell Cycle Proteins Cullin Proteins F-Box Proteins Fbx4 protein, mouse Histones MEP50 protein, human Cyclin D1 Protein Methyltransferases Cyclin-Dependent Kinase 4
Topics	Adaptor Proteins, Signal Transducing (metabolism) Animals Cell Cycle Proteins (metabolism) Cell Line, Tumor Cell Nucleus (enzymology) Cell Proliferation Cell Survival Cell Transformation, Neoplastic (genetics, pathology) Cullin Proteins (genetics, metabolism) Cyclin D1 (metabolism) Cyclin-Dependent Kinase 4 (metabolism) DNA Methylation DNA Replication Enzyme Activation F-Box Proteins (metabolism) Gene Expression Regulation, Neoplastic Histones (metabolism) Humans Lymphoma (enzymology, genetics, pathology) Mice Neoplasms (enzymology, genetics, pathology) Phosphorylation Promoter Regions, Genetic (genetics) Protein Binding Protein Methyltransferases (metabolism) Protein Stability

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