Werner syndrome protein limits MYC-induced cellular senescence.
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.
Grandori
Carla
C
Basic Sciences, Human Biology and Clinical Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. cgrandor@fhcrc.org
Wu
Kou-Juey
KJ
Fernandez
Paula
P
Ngouenet
Celine
C
Grim
Jonathan
J
Clurman
Bruce E
BE
Moser
Michael J
MJ
Oshima
Junko
J
Russell
David W
DW
Swisshelm
Karen
K
Frank
Scott
S
Amati
Bruno
B
Dalla-Favera
Riccardo
R
Monnat
Raymond J
RJ
D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D004265:DNA Helicases / Q000235:genetics* / Q000502:physiology*; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D019098:Telomerase; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase