Cellular senescence, epigenetic switches and c-Myc.
In response to hyperproliferative signaling elicited by transforming oncogenes some normal human cells can enter replicative senescence as a tumor defense mechanism. We recently found that human fibroblasts or endothelial cells with genetically-engineered reduction of proto-oncogene c-Myc expression switched with an increased frequency to a senescent state by a telomere-independent mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent kinase inhibitor p16(INK4a). The same regulatory circuit was triggered upon exposure to mild oxidative stress. These findings point to the existence of a mechanism for monitoring hypoproliferative signaling, whose function may be to limit the proliferation and accretion of physiologically compromised cells. This mechanism may be another example of antagonistic pleiotropy leading to organismal aging.
Guney
Isil
I
Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics, Brown University, Providence, Rhode Island, USA.
Sedivy
John M
JM
D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D006801:Humans; D063146:Polycomb-Group Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction
C000715470:MAS1 protein, human; C489427:MYC protein, human; D063146:Polycomb-Group Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins