{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Guney I"],"funding":["NCRR NIH HHS","NIA NIH HHS","NIGMS NIH HHS"],"pagination":["3645-50"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC1450136"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["103(10)"],"pubmed_abstract":["Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a)."],"pmcid":["PMC1450136"],"funding_grant_id":["P20 RR015578","P20 RR15578","R01 GM41690","R01 GM041690","R01 AG16694","R01 AG016694"],"pubmed_authors":["Sedivy JM","Guney I","Wu S"],"additional_accession":[]},"is_claimable":false,"name":"Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).","description":"Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.","dates":{"release":"2006-01-01T00:00:00Z","publication":"2006 Mar","modification":"2026-04-29T19:50:01.216Z","creation":"2019-03-27T01:26:20Z"},"accession":"S-EPMC1450136","cross_references":{"pubmed":["16537449"],"doi":["10.1073/pnas.0600069103"]}}