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PMID: 20951943 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 18 ·No. 4 ·2010-10-19 ·Pages 329-40

Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB, Diehl JA

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.

MeSH Terms
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
Chemicals
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
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Aggarwal Priya
Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, 19104, USA.
Vaites Laura Pontano
Kim Jong Kyong
Mellert Hestia
Gurung Buddha
Nakagawa Hiroshi
Herlyn Meenhard
Hua Xianxin
Rustgi Anil K
McMahon Steven B
Diehl J Alan
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2010.08.012
Published
2010-10-19
Pages
329-40
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2957477
Subset
IM
Grants
NCI NIH HHS · R01 CA093237 · United States
NCI NIH HHS · CA090465 · United States
NCI NIH HHS · P01-CA098101 · United States
NIDDK NIH HHS · R01 DK097555 · United States
NCI NIH HHS · R01 CA098172 · United States
NCI NIH HHS · P30 CA016520 · United States
NCI NIH HHS · R01 CA090465 · United States
NCI NIH HHS · CA098172 · United States
NCI NIH HHS · CA93237 · United States
NCI NIH HHS · P01 CA098101 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2010.08.012 PMC Full Text View journal details
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