Regulation of two E2F-related genes in presenescent and senescent human fibroblasts.
Several mammalian genes expressed in late G1 are positively regulated by E2F, a heterodimeric transcription factor. Genes encoding two E2F proteins, E2F-1 and DP-1, were regulated differently during the cell cycle and replicative senescence of normal human fibroblasts. In presenescent cells, E2F-1 mRNA was cell-cycle regulated, appearing a few hours before S phase. By contrast, DP-1 mRNA was constitutively expressed, independent of position in the cell cycle. After a finite number of divisions, normal cells enter a state of irreversible growth arrest termed senescence. Many genes remain mitogen-inducible in senescent cells; there are, however, exceptions, including several late G1 genes potentially regulated by E2F. Senescent cells expressed DP-1 at the presenescent level, but did not express E2F-1 mRNA. Senescent cells were also markedly deficient in E2F binding activity associated with the dihydrofolate reductase promoter. E2F-1 and DP-1 expression vectors only weakly induced DNA synthesis in quiescent or senescent human cells and immortal murine NIH3T3 cells, although the E2F-1 vector stimulated DNA synthesis in immortal murine A31 cells, and transactivated E2F-responsive promoters in NIH3T3 cells. The results suggest that senescent cells may fail to express late G1 genes due to repression of E2F-1, leading to a deficiency of E2F activity. Furthermore, although E2F-1 stimulates DNA synthesis in some cells, other cells, including normal human fibroblasts, require additional factors.
Dimri
G P
GP
Department of Cell and Molecular Biology, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
Hara
E
E
Campisi
J
J
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D000957:Antigens, Viral, Tumor; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D012333:RNA, Messenger; D056465:Retinoblastoma-Binding Protein 1; D016329:Sp1 Transcription Factor; C493735:TFDP1 protein, human; C493736:Tfdp1 protein, mouse; D050680:Transcription Factor DP1; D014157:Transcription Factors