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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 p14ARF in Replicative and Induced Senescence of Human Fibroblasts

Wenyi Wei, Ruth M. Hemmer,dagger 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 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.


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

dagger Present address: Department of Biology, Roger Williams University, Bristol, RI 02809.


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.



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