title: Replicative senescence, aging and growth-regulatory transcription factors.
abstract: Normal somatic cells invariably enter a state of permanent growth arrest and altered function after a finite number of divisions. This phenomenon is termed cellular or replicative senescence. Replicative senescence is thought to be a tumor-suppressive mechanism, and a contributing factor in aging. Three features distinguish senescent from presenescent cells: an irreversible block to cell proliferation, increased resistance to apoptotic death, and changes in differentiated functions. Senescence entails an altered pattern of gene expression, much of which is due to altered transcription. At least three growth regulatory transcriptional modulators are repressed in senescent cells: the c-fos component of the AP1 transcription factor, the Id1 and Id2 helix-loop-helix (HLH) proteins that negatively regulate basic HLH transcription factors, and the E2F-1 component of the E2F transcription factor. Failure to express any one of these modulators is very likely sufficient to arrest cell proliferation. Loss of these modulators may also explain many of the functional changes shown by senescent cells. In the case of c-fos repression, the resulting decline in AP-1 activity may be exacerbated by an altered ratio of AP-1 components to a protein known as QM or Jif. QM interacts with the c-jun component of AP-1 and suppresses AP-1 activity. We cloned QM from a senescent fibroblast cDNA library, and found that it was neither cell cycle- nor senescence-regulated. However, QM suppressed the growth of murine and human fibroblasts when overexpressed. Thus, an altered balance between positive factors (e.g., AP-1 components) and negative factors (e.g., QM) may lead to the growth arrest, as well as the changes in differentiated gene expression, that are a hallmark of senescent cells.
authors.affiliation: Department of Cancer Biology, Berkeley National Laboratory, University of California 94720, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Dimri
authors.forename: A
authors.initials: A
authors.lastname: Testori
authors.forename: M
authors.initials: M
authors.lastname: Acosta
authors.forename: J
authors.initials: J
authors.lastname: Campisi
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002468:Cell Physiological Phenomena; D002477:Cells / Q000166:cytology / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D012097:Repressor Proteins; D056465:Retinoblastoma-Binding Protein 1; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins; D018808:Transcription Factor AP-1 / Q000378:metabolism; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C000630686:RPL10 protein, human; D012097:Repressor Proteins; D056465:Retinoblastoma-Binding Protein 1; D012269:Ribosomal Proteins; D018808:Transcription Factor AP-1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D004247:DNA