Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts.
Normal cells in culture invariably undergo senescence, whereby they cease proliferation after a finite number of doublings. Irreversible changes in gene expression occurred in senescent human fetal lung fibroblasts: a non-cell cycle-regulated mRNA was partially repressed; an unusual polyadenylated histone mRNA was expressed; although serum induced c-H-ras, c-myc, and ornithine decarboxylase mRNA normally, ornithine decarboxylase activity was deficient; and serum did not induce mRNA for a replication-dependent histone and for the c-fos proto-oncogene. The loss of c-fos inducibility was the result of a specific, transcriptional block. The results suggest that senescent fibroblasts were unable to proliferate because of, at least in part, selective repression of c-fos; moreover, the multiple changes in gene expression support the view that cellular senescence is a process of terminal differentiation.
Seshadri
T
T
Department of Biochemistry, Boston University Medical School, MA 02118.
Campisi
J
J
D001769:Blood; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D009955:Ornithine Decarboxylase / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013489:Suppression, Genetic; D014158:Transcription, Genetic
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D009955:Ornithine Decarboxylase