Role of p14(ARF) in replicative and induced senescence of human fibroblasts.
Following a proliferative phase of variable duration, most normal somatic cells enter a growth arrest state known as replicative senescence. In addition to telomere shortening, a variety of environmental insults and signaling imbalances can elicit phenotypes closely resembling senescence. We used p53(-/-) and p21(-/-) human fibroblast cell strains constructed by gene targeting to investigate the involvement of the Arf-Mdm2-p53-p21 pathway in natural as well as premature senescence states. We propose that in cell types that upregulate p21 during replicative exhaustion, such as normal human fibroblasts, p53, p21, and Rb act sequentially and constitute the major pathway for establishing growth arrest and that the telomere-initiated signal enters this pathway at the level of p53. Our results also revealed a number of significant differences between human and rodent fibroblasts in the regulation of senescence pathways.
Wei
W
W
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.
Hemmer
R M
RM
Sedivy
J M
JM
D000375:Aging; D015152:Blotting, Northern; D001973:Bromodeoxyuridine / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism*; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008954:Models, Biological; D011506:Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation
D011506:Proteins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D012260:Ribonucleases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D001973:Bromodeoxyuridine