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Science 8 August 1997:
Vol. 277. no. 5327, pp. 831 - 834
DOI: 10.1126/science.277.5327.831
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Reports

Bypass of Senescence After Disruption of p21CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts

Jeremy P. Brown, * Wenyi Wei, John M. Sedivy dagger

Most somatic cells die after a finite number of cell divisions, a phenomenon described as senescence. The p21CIP1/WAF1 gene encodes an inhibitor of cyclin-dependent kinases. Inactivation of p21 by two sequential rounds of targeted homologous recombination was sufficient to bypass senescence in normal diploid human fibroblasts. At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered. These results establish the feasibility of using gene targeting for genetic studies of normal human cells.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
*   Present address: Department of Pathology, New York University Medical Center, New York, NY 10016, USA.

dagger    To whom correspondence should be addressed. E-mail: John_Sedivy{at}Brown.edu

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M. A. Dickson, W. C. Hahn, Y. Ino, V. Ronfard, J. Y. Wu, R. A. Weinberg, D. N. Louis, F. P. Li, and J. G. Rheinwald (2000)
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   Abstract »    Full Text »    PDF »
Distinct Role of cAMP and cGMP in the Cell Cycle Control of Vascular Smooth Muscle Cells : cGMP Delays Cell Cycle Transition Through Suppression of Cyclin D1 and Cyclin-Dependent Kinase 4 Activation.
S. Fukumoto, H. Koyama, M. Hosoi, K. Yamakawa, S. Tanaka, H. Morii, and Y. Nishizawa (1999)
Circ. Res. 85, 985-991
   Abstract »    Full Text »    PDF »
c-Jun Transactivates the Promoter of the Human p21WAF1/Cip1 Gene by Acting as a Superactivator of the Ubiquitous Transcription Factor Sp1.
D. Kardassis, P. Papakosta, K. Pardali, and A. Moustakas (1999)
J. Biol. Chem. 274, 29572-29581
   Abstract »    Full Text »    PDF »
Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest.
H. Fan and P. A. Khavari (1999)
J. Cell Biol. 147, 71-76
   Abstract »    Full Text »    PDF »
Microinjection of Anti-p21 Antibodies Induces Senescent Hs68 Human Fibroblasts to Synthesize DNA but not To Divide.
Y. Ma, S. A. Prigent, T. L. Born, C. R. Monell, J. R. Feramisco, and B. L. Bertolaet (1999)
Cancer Res. 59, 5341-5348
   Abstract »    Full Text »    PDF »
High-Fidelity Correction of Mutations at Multiple Chromosomal Positions by Adeno-Associated Virus Vectors.
N. Inoue, R. K. Hirata, and D. W. Russell (1999)
J. Virol. 73, 7376-7380
   Abstract »    Full Text »    PDF »
Apoptosis in Proliferating, Senescent, and Immortalized Keratinocytes.
V. Chaturvedi, J.-Z. Qin, M. F. Denning, D. Choubey, M. O. Diaz, and B. J. Nickoloff (1999)
J. Biol. Chem. 274, 23358-23367
   Abstract »    Full Text »    PDF »
Control of Replicative Life Span in Human Cells: Barriers to Clonal Expansion Intermediate Between M1 Senescence and M2 Crisis.
J. A. Bond, M. F. Haughton, J. M. Rowson, P. J. Smith, V. Gire, D. Wynford-Thomas, and F. S. Wyllie (1999)
Mol. Cell. Biol. 19, 3103-3114
   Abstract »    Full Text »    PDF »
Expression of Catalytically Active Telomerase Does Not Prevent Premature Senescence Caused by Overexpression of Oncogenic Ha-Ras in Normal Human Fibroblasts.
S. Wei, W. Wei, and J. M. Sedivy (1999)
Cancer Res. 59, 1539-1543
   Abstract »    Full Text »    PDF »
Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening.
J. Zhu, H. Wang, J. M. Bishop, and E. H. Blackburn (1999)
PNAS 96, 3723-3728
   Abstract »    Full Text »    PDF »
Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species.
A. C. Lee, B. E. Fenster, H. Ito, K. Takeda, N. S. Bae, T. Hirai, Z.-X. Yu, V. J. Ferrans, B. H. Howard, and T. Finkel (1999)
J. Biol. Chem. 274, 7936-7940
   Abstract »    Full Text »    PDF »
Telomerase Activity Is Sufficient To Allow Transformed Cells To Escape from Crisis.
T. L. Halvorsen, G. Leibowitz, and F. Levine (1999)
Mol. Cell. Biol. 19, 1864-1870
   Abstract »    Full Text »    PDF »
Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts.
G. H. Stein, L. F. Drullinger, A. Soulard, and V. Dulic (1999)
Mol. Cell. Biol. 19, 2109-2117
   Abstract »    Full Text »    PDF »


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