Control of the reversibility of cellular quiescence by the transcriptional repressor HES1.
The mechanisms by which quiescent cells, including adult stem cells, preserve their ability to resume proliferation after weeks or even years of cell cycle arrest are not known. We report that reversibility is not a passive property of nondividing cells, because enforced cell cycle arrest for a period as brief as 4 days initiates spontaneous, premature, and irreversible senescence. Increased expression of the gene encoding the basic helix-loop-helix protein HES1 was required for quiescence to be reversible, because HES1 prevented both premature senescence and inappropriate differentiation in quiescent fibroblasts. In some human tumors, the HES1 pathway was activated, which allowed these cells to evade differentiation and irreversible cell cycle arrest. We conclude that HES1 safeguards against irreversible cell cycle exit both during normal cellular quiescence and pathologically in the setting of tumorigenesis.
Sang
Liyun
L
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Coller
Hilary A
HA
Roberts
James M
JM
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D056970:Co-Repressor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D024510:Muscle Development; D017570:MyoD Protein / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014161:Transduction, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D017570:MyoD Protein; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C493957:Cdkn1a protein, mouse; C057363:MyoD1 myogenic differentiation protein; C499043:TLE1 protein, human; C078493:HES1 protein, human