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PMID: 12842909 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Werner syndrome protein limits MYC-induced cellular senescence.

Genes & development ·Vol. 17 ·No. 13 ·2003-07-01 ·Pages 1569-74

Grandori C, Wu KJ, Fernandez P, Ngouenet C, Grim J, Clurman BE, Moser MJ, Oshima J, Russell DW, Swisshelm K, Frank S, Amati B, Dalla-Favera R, Monnat RJ

Abstract

The MYC oncoprotein is a transcription factor that coordinates cell growth and division. MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli. Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene, WRN, which encodes a conserved RecQ helicase. Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence. The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed by hTERT expression. We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence.

MeSH Terms
Cell Division Cell Transformation, Neoplastic Cells, Cultured Cellular Senescence DNA Helicases/genetics,physiology DNA-Binding Proteins Exodeoxyribonucleases Gene Expression Regulation Genes, myc Humans Models, Biological Promoter Regions, Genetic Proto-Oncogene Proteins c-myc/genetics,physiology RNA Interference RNA, Messenger/genetics,metabolism RecQ Helicases Telomerase/genetics,metabolism Transcription, Genetic Tumor Cells, Cultured Up-Regulation Werner Syndrome/genetics Werner Syndrome Helicase
Chemicals
DNA-Binding Proteins Proto-Oncogene Proteins c-myc RNA, Messenger Telomerase Exodeoxyribonucleases DNA Helicases RecQ Helicases WRN protein, human Werner Syndrome Helicase
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Grandori Carla
Basic Sciences, Human Biology and Clinical Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [email protected]
Wu Kou-Juey
Fernandez Paula
Ngouenet Celine
Grim Jonathan
Clurman Bruce E
Moser Michael J
Oshima Junko
Russell David W
Swisshelm Karen
Frank Scott
Amati Bruno
Dalla-Favera Riccardo
Monnat Raymond J
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1100303
Email
[email protected]
Published
2003-07-01
Pages
1569-74
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC196129
Subset
IM
Grants
NCI NIH HHS · R01 CA020525 · United States
NCI NIH HHS · R37 CA020525 · United States
NCI NIH HHS · CA20525 · United States
NCI NIH HHS · CA7515 · United States
External Links
PubMed source DOI: 10.1101/gad.1100303 PMC Full Text View journal details
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