This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wei, W.
Right arrow Articles by Sedivy, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wei, W.
Right arrow Articles by Sedivy, J. M.

 Previous Article  |  Next Article 

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.


This article has been cited by other articles:

  • Gao, D., Inuzuka, H., Korenjak, M., Tseng, A., Wu, T., Wan, L., Kirschner, M., Dyson, N., Wei, W. (2009). Cdh1 Regulates Cell Cycle through Modulating the Claspin/Chk1 and the Rb/E2F1 Pathways. Mol. Biol. Cell 20: 3305-3316 [Abstract] [Full Text]  
  • Peters, G. (2008). Tumor Suppression for ARFicionados: The Relative Contributions of p16INK4a and p14ARF in Melanoma. JNCI J Natl Cancer Inst 100: 757-759 [Full Text]  
  • Kwok, W. K., Ling, M.-T., Yuen, H. F., Wong, Y.-C., Wang, X. (2007). Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells. Carcinogenesis 28: 2467-2475 [Abstract] [Full Text]  
  • Ha, L., Ichikawa, T., Anver, M., Dickins, R., Lowe, S., Sharpless, N. E., Krimpenfort, P., DePinho, R. A., Bennett, D. C., Sviderskaya, E. V., Merlino, G. (2007). ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc. Natl. Acad. Sci. USA 104: 10968-10973 [Abstract] [Full Text]  
  • Bracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Monch, K., Minucci, S., Porse, B. T., Marine, J.-C., Hansen, K. H., Helin, K. (2007). The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 21: 525-530 [Abstract] [Full Text]  
  • Hemann, M. T., Narita, M. (2007). Oncogenes and senescence: breaking down in the fast lane. Genes Dev. 21: 1-5 [Full Text]  
  • Mallette, F. A., Gaumont-Leclerc, M.-F., Ferbeyre, G. (2007). The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 21: 43-48 [Abstract] [Full Text]  
  • Casavant, N. C., Luo, M. H., Rosenke, K., Winegardner, T., Zurawska, A., Fortunato, E. A. (2006). Potential Role for p53 in the Permissive Life Cycle of Human Cytomegalovirus.. J. Virol. 80: 8390-8401 [Abstract] [Full Text]  
  • Kim, S.-H., Rowe, J., Fujii, H., Jones, R., Schmierer, B., Kong, B.-W., Kuchler, K., Foster, D., Ish-Horowicz, D., Peters, G. (2006). Upregulation of chicken p15INK4b at senescence and in the developing brain. J. Cell Sci. 119: 2435-2443 [Abstract] [Full Text]  
  • Kortum, R. L., Johnson, H. J., Costanzo, D. L., Volle, D. J., Razidlo, G. L., Fusello, A. M., Shaw, A. S., Lewis, R. E. (2006). The Molecular Scaffold Kinase Suppressor of Ras 1 Is a Modifier of RasV12-Induced and Replicative Senescence.. Mol. Cell. Biol. 26: 2202-2214 [Abstract] [Full Text]  
  • Boiko, A. D., Porteous, S., Razorenova, O. V., Krivokrysenko, V. I., Williams, B. R., Gudkov, A. V. (2006). A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev. 20: 236-252 [Abstract] [Full Text]  
  • Matheu, A., Klatt, P., Serrano, M. (2005). Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors. J. Biol. Chem. 280: 42433-42441 [Abstract] [Full Text]  
  • Zhang, H., Cohen, S. N. (2004). Smurf2 up-regulation activates telomere-dependent senescence. Genes Dev. 18: 3028-3040 [Abstract] [Full Text]  
  • Charrier-Savournin, F. B., Chateau, M.-T., Gire, V., Sedivy, J., Piette, J., Dulic, V. (2004). p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress. Mol. Biol. Cell 15: 3965-3976 [Abstract] [Full Text]  
  • Satyanarayana, A., Greenberg, R. A., Schaetzlein, S., Buer, J., Masutomi, K., Hahn, W. C., Zimmermann, S., Martens, U., Manns, M. P., Rudolph, K. L. (2004). Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling. Mol. Cell. Biol. 24: 5459-5474 [Abstract] [Full Text]  
  • Martin-Ruiz, C., Saretzki, G., Petrie, J., Ladhoff, J., Jeyapalan, J., Wei, W., Sedivy, J., von Zglinicki, T. (2004). Stochastic Variation in Telomere Shortening Rate Causes Heterogeneity of Human Fibroblast Replicative Life Span. J. Biol. Chem. 279: 17826-17833 [Abstract] [Full Text]  
  • Benanti, J. A., Galloway, D. A. (2004). Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence. Mol. Cell. Biol. 24: 2842-2852 [Abstract] [Full Text]  
  • Shamanin, V. A., Androphy, E. J. (2004). Immortalization of Human Mammary Epithelial Cells Is Associated with Inactivation of the p14ARF-p53 Pathway. Mol. Cell. Biol. 24: 2144-2152 [Abstract] [Full Text]  
  • Melk, A. (2003). Senescence of renal cells: molecular basis and clinical implications. Nephrol Dial Transplant 18: 2474-2478 [Full Text]  
  • Milyavsky, M., Shats, I., Erez, N., Tang, X., Senderovich, S., Meerson, A., Tabach, Y., Goldfinger, N., Ginsberg, D., Harris, C. C., Rotter, V. (2003). Prolonged Culture of Telomerase-Immortalized Human Fibroblasts Leads to a Premalignant Phenotype. Cancer Res. 63: 7147-7157 [Abstract] [Full Text]  
  • Bulavin, D. V., Kovalsky, O., Hollander, M. C., Fornace, A. J. Jr. (2003). Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a. Mol. Cell. Biol. 23: 3859-3871 [Abstract] [Full Text]  
  • Sviderskaya, E. V., Gray-Schopfer, V. C., Hill, S. P., Smit, N. P., Evans-Whipp, T. J., Bond, J., Hill, L., Bataille, V., Peters, G., Kipling, D., Wynford-Thomas, D., Bennett, D. C. (2003). p16/Cyclin-Dependent Kinase Inhibitor 2A Deficiency in Human Melanocyte Senescence, Apoptosis, and Immortalization: Possible Implications for Melanoma Progression. JNCI J Natl Cancer Inst 95: 723-732 [Abstract] [Full Text]  
  • Wei, W., Jobling, W. A., Chen, W., Hahn, W. C., Sedivy, J. M. (2003). Abolition of Cyclin-Dependent Kinase Inhibitor p16Ink4a and p21Cip1/Waf1 Functions Permits Ras-Induced Anchorage-Independent Growth in Telomerase-Immortalized Human Fibroblasts. Mol. Cell. Biol. 23: 2859-2870 [Abstract] [Full Text]  
  • O'Connell, B. C., Cheung, A. F., Simkevich, C. P., Tam, W., Ren, X., Mateyak, M. K., Sedivy, J. M. (2003). A Large Scale Genetic Analysis of c-Myc-regulated Gene Expression Patterns. J. Biol. Chem. 278: 12563-12573 [Abstract] [Full Text]  
  • Berardi, P., Meyyappan, M., Riabowol, K. T. (2003). A Novel Transcriptional Inhibitory Element Differentially Regulates the Cyclin D1 Gene in Senescent Cells. J. Biol. Chem. 278: 7510-7519 [Abstract] [Full Text]  
  • Gorbunova, V., Seluanov, A., Pereira-Smith, O. M. (2003). Evidence That High Telomerase Activity May Induce a Senescent-like Growth Arrest in Human Fibroblasts. J. Biol. Chem. 278: 7692-7698 [Abstract] [Full Text]  
  • Kim, S.-H., Mitchell, M., Fujii, H., Llanos, S., Peters, G. (2003). Absence of p16INK4a and truncation of ARF tumor suppressors in chickens. Proc. Natl. Acad. Sci. USA 100: 211-216 [Abstract] [Full Text]  
  • Deshpande, S. S., Qi, B., Park, Y. C., Irani, K. (2003). Constitutive Activation of rac1 Results in Mitochondrial Oxidative Stress and Induces Premature Endothelial Cell Senescence. Arterioscler. Thromb. Vasc. Bio. 23: e1-6 [Abstract] [Full Text]  
  • Huot, T. J., Rowe, J., Harland, M., Drayton, S., Brookes, S., Gooptu, C., Purkis, P., Fried, M., Bataille, V., Hara, E., Newton-Bishop, J., Peters, G. (2002). Biallelic Mutations in p16INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts. Mol. Cell. Biol. 22: 8135-8143 [Abstract] [Full Text]  
  • Benanti, J. A., Williams, D. K., Robinson, K. L., Ozer, H. L., Galloway, D. A. (2002). Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1. Mol. Cell. Biol. 22: 7385-7397 [Abstract] [Full Text]  
  • Gorbunova, V., Seluanov, A., Pereira-Smith, O. M. (2002). Expression of Human Telomerase (hTERT) Does Not Prevent Stress-induced Senescence in Normal Human Fibroblasts but Protects the Cells from Stress-induced Apoptosis and Necrosis. J. Biol. Chem. 277: 38540-38549 [Abstract] [Full Text]  
  • Wadhwa, R., Sugihara, T., Hasan, Md. K., Taira, K., Reddel, R. R., Kaul, S. C. (2002). A Major Functional Difference between the Mouse and Human ARF Tumor Suppressor Proteins. J. Biol. Chem. 277: 36665-36670 [Abstract] [Full Text]  
  • Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricala, C., O'Toole, K. M. (2002). A Two-Stage, p16INK4A- and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status. Mol. Cell. Biol. 22: 5157-5172 [Abstract] [Full Text]  
  • Marcotte, R., Wang, E. (2002). Replicative Senescence Revisited. Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57: B257-269 [Abstract] [Full Text]  
  • Han, Z., Wei, W., Dunaway, S., Darnowski, J. W., Calabresi, P., Sedivy, J., Hendrickson, E. A., Balan, K. V., Pantazis, P., Wyche, J. H. (2002). Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin. J. Biol. Chem. 277: 17154-17160 [Abstract] [Full Text]  
  • Sheen, J.-H., Dickson, R. B. (2002). Overexpression of c-Myc Alters G1/S Arrest following Ionizing Radiation. Mol. Cell. Biol. 22: 1819-1833 [Abstract] [Full Text]  
  • Mergny, J.-L., Riou, J.-F., Mailliet, P., Teulade-Fichou, M.-P., Gilson, E. (2002). Natural and pharmacological regulation of telomerase. Nucleic Acids Res 30: 839-865 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»