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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Cell Division
-
Cell Transformation, Neoplastic
-
Cells, Cultured
-
Cellular Senescence*
-
DNA Helicases / genetics*
-
DNA Helicases / physiology*
-
DNA-Binding Proteins
-
Exodeoxyribonucleases
-
Gene Expression Regulation*
-
Genes, myc
-
Humans
-
Models, Biological
-
Promoter Regions, Genetic
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / physiology*
-
RNA Interference
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
RecQ Helicases
-
Telomerase / genetics
-
Telomerase / metabolism
-
Transcription, Genetic
-
Tumor Cells, Cultured
-
Up-Regulation
-
Werner Syndrome / genetics*
-
Werner Syndrome Helicase
Substances
-
DNA-Binding Proteins
-
Proto-Oncogene Proteins c-myc
-
RNA, Messenger
-
Telomerase
-
Exodeoxyribonucleases
-
DNA Helicases
-
RecQ Helicases
-
WRN protein, human
-
Werner Syndrome Helicase