Role of p14ARF in Replicative and Induced Senescence of Human Fibroblasts

doi:10.1128/MCB.21.20.6748-6757.2001

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Molecular and Cellular Biology, October 2001, p. 6748-6757, Vol. 21, No. 20
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.20.6748-6757.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role of p14^ARF in Replicative and Induced Senescence of Human Fibroblasts

Wenyi Wei, Ruth M. Hemmer, and John M. Sedivy^*

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912

Received 29 May 2001/Returned for modification 9 July 2001/Accepted 9 July 2001

Following a proliferative phase of variable duration, most normal somatic cells enter a growth arrest state known as replicativesenescence. In addition to telomere shortening, a variety of environmentalinsults and signaling imbalances can elicit phenotypes closelyresembling senescence. We used p53^/ and p21^/ human fibroblast cell strains constructed by gene targeting toinvestigate the involvement of the Arf-Mdm2-p53-p21 pathway innatural as well as premature senescence states. We propose thatin cell types that upregulate p21 during replicative exhaustion,such as normal human fibroblasts, p53, p21, and Rb act sequentiallyand constitute the major pathway for establishing growth arrestand that the telomere-initiated signal enters this pathway atthe level of p53. Our results also revealed a number of significantdifferences between human and rodent fibroblasts in the regulationof senescencepathways.

^* Corresponding author. Mailing address: Department of Molecular Biology, Cell Biology, and Biochemistry, Box G-J223, BrownUniversity, Providence, RI 02912. Phone: (401) 863-9654. Fax:(401) 863-9653. E-mail: john_sedivy{at}brown.edu.

Present address: Department of Biology, Roger Williams University, Bristol, RI02809.

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