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 Xu, Y.
Right arrow Articles by Baltimore, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xu, Y.
Right arrow Articles by Baltimore, D.

 Previous Article  |  Next Article 

Mol Cell Biol, July 1998, p. 4385-4390, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atmminus /minus Mice

Yang Xu,1 * Eva Marie Yang,1 James Brugarolas,2 Tyler Jacks,2 and David Baltimore3

Department of Biology, University of California, San Diego, La Jolla, California 92093-03221; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 021392; and California Institute of Technology, Pasadena, California 911253

Received 10 March 1998/Accepted 13 April 1998

Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm-/- p53-/- mice develop lymphomas earlier than Atm-/- or p53-/- mice, indicating that mutations in these two genes lead to synergy in tumorigenesis. The cell cycle G1/S checkpoint is abolished in Atm-/- p53-/- mouse embryonic fibroblasts (MEFs) following gamma -irradiation, suggesting that the partial G1 cell cycle arrest in Atm-/- cells following gamma -irradiation is due to the residual p53 response in these cells. In addition, the Atm-/- p21-/- MEFs are more severely defective in their cell cycle G1 arrest following gamma -irradiation than Atm-/- and p21-/- MEFs. The Atm-/- MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm-/- p21-/- MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm-/- p53-/- MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm-/- cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm-/- MEFs is lower than that in Atm+/+ MEFs, suggesting that the higher level of constitutive p21 protein in Atm-/- MEFs is likely due to increased stability of the p21 protein.

* Corresponding author. Mailing address: Department of Biology, University of California, San Diego, Bonner Hall 3430, 9500 Gilman Dr., La Jolla, CA 92093-0322. Phone: (619) 822-1084. Fax: (619) 534-0053. E-mail: yangxu{at}ucsd.edu.

Mol Cell Biol, July 1998, p. 4385-4390, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Halberg, R. B., Chen, X., Amos-Landgraf, J. M., White, A., Rasmussen, K., Clipson, L., Pasch, C., Sullivan, R., Pitot, H. C., Dove, W. F. (2008). The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background. Genetics 180: 601-609 [Abstract] [Full Text]  
  • Reimann, M., Loddenkemper, C., Rudolph, C., Schildhauer, I., Teichmann, B., Stein, H., Schlegelberger, B., Dorken, B., Schmitt, C. A. (2007). The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo. Blood 110: 2996-3004 [Abstract] [Full Text]  
  • Dar, I., Biton, S., Shiloh, Y., Barzilai, A. (2006). Analysis of the ataxia telangiectasia mutated-mediated DNA damage response in murine cerebellar neurons.. J. Neurosci. 26: 7767-7774 [Abstract] [Full Text]  
  • Lu, S., Shen, K. C., Wang, Y., Brooks, S.C., Wang, Y. A. (2005). Impaired hepatocyte survival and liver regeneration in Atm-deficient mice. Hum Mol Genet 14: 3019-3025 [Abstract] [Full Text]  
  • Shen, K. C., Heng, H., Wang, Y., Lu, S., Liu, G., Deng, C.-X., Brooks, S.C., Wang, Y. A. (2005). ATM and p21 Cooperate to Suppress Aneuploidy and Subsequent Tumor Development. Cancer Res. 65: 8747-8753 [Abstract] [Full Text]  
  • Winrow, C. J., Pankratz, D. G., Vibat, C. R. T., Bowen, T.J., Callahan, M. A., Warren, A. J., Hilbush, B. S., Wynshaw-Boris, A., Hasel, K. W., Weaver, Z., Lockhart, D. J., Barlow, C. (2005). Aberrant recombination involving the granzyme locus occurs in Atm-/- T-cell lymphomas. Hum Mol Genet 14: 2671-2684 [Abstract] [Full Text]  
  • Kang, J., Ferguson, D., Song, H., Bassing, C., Eckersdorff, M., Alt, F. W., Xu, Y. (2005). Functional Interaction of H2AX, NBS1, and p53 in ATM-Dependent DNA Damage Responses and Tumor Suppression. Mol. Cell. Biol. 25: 661-670 [Abstract] [Full Text]  
  • MacLaren, A., Black, E. J., Clark, W., Gillespie, D. A. F. (2004). c-Jun-Deficient Cells Undergo Premature Senescence as a Result of Spontaneous DNA Damage Accumulation. Mol. Cell. Biol. 24: 9006-9018 [Abstract] [Full Text]  
  • Singhi, A. D., Kondratov, R. V., Neznanov, N., Chernov, M. V., Gudkov, A. V. (2004). Selection-subtraction approach (SSA): A universal genetic screening technique that enables negative selection. Proc. Natl. Acad. Sci. USA 101: 9327-9332 [Abstract] [Full Text]  
  • Brodsky, M. H., Weinert, B. T., Tsang, G., Rong, Y. S., McGinnis, N. M., Golic, K. G., Rio, D. C., Rubin, G. M. (2004). Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage. Mol. Cell. Biol. 24: 1219-1231 [Abstract] [Full Text]  
  • Qi, L., Strong, M. A., Karim, B. O., Armanios, M., Huso, D. L., Greider, C. W. (2003). Short Telomeres and Ataxia-Telangiectasia Mutated Deficiency Cooperatively Increase Telomere Dysfunction and Suppress Tumorigenesis. Cancer Res. 63: 8188-8196 [Abstract] [Full Text]  
  • Chao, C., Hergenhahn, M., Kaeser, M. D., Wu, Z., Saito, S.'i., Iggo, R., Hollstein, M., Appella, E., Xu, Y. (2003). Cell Type- and Promoter-specific Roles of Ser18 Phosphorylation in Regulating p53 Responses. J. Biol. Chem. 278: 41028-41033 [Abstract] [Full Text]  
  • Bishop, A. J. R., Hollander, M. C., Kosaras, B., Sidman, R. L., Fornace, A. J. Jr., Schiestl, R. H. (2003). Atm-, p53-, and Gadd45a-Deficient Mice Show an Increased Frequency of Homologous Recombination at Different Stages during Development. Cancer Res. 63: 5335-5343 [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]  
  • Perkins, E. J., Nair, A., Cowley, D. O., Van Dyke, T., Chang, Y., Ramsden, D. A. (2002). Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 16: 159-164 [Abstract] [Full Text]  
  • Fagerlie, S. R., Diaz, J., Christianson, T. A., McCartan, K., Keeble, W., Faulkner, G. R., Bagby, G. C. (2001). Functional correction of FA-C cells with FANCC suppresses the expression of interferon {gamma}-inducible genes. Blood 97: 3017-3024 [Abstract] [Full Text]  
  • Weiss, R. S., Enoch, T., Leder, P. (2000). Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress. Genes Dev. 14: 1886-1898 [Abstract] [Full Text]  
  • Moser, B. A., Brondello, J.-M., Baber-Furnari, B., Russell, P. (2000). Mechanism of Caffeine-Induced Checkpoint Override in Fission Yeast. Mol. Cell. Biol. 20: 4288-4294 [Abstract] [Full Text]  
  • Chao, C., Yang, E. M., Xu, Y. (2000). Rescue of Defective T Cell Development and Function in Atm-/- Mice by a Functional TCR{alpha}{beta} Transgene. J. Immunol. 164: 345-349 [Abstract] [Full Text]  
  • Park, J.-S., Carter, S., Reardon, D. B., Schmidt-Ullrich, R., Dent, P., Fisher, P. B. (1999). Roles for Basal and Stimulated p21Cip-1/WAF1/MDA6 Expression and Mitogen-activated Protein Kinase Signaling in Radiation-induced Cell Cycle Checkpoint Control in Carcinoma Cells. Mol. Biol. Cell 10: 4231-4246 [Abstract] [Full Text]  
  • Dent, P., Reardon, D. B., Park, J. S., Bowers, G., Logsdon, C., Valerie, K., Schmidt-Ullrich, R. (1999). Radiation-induced Release of Transforming Growth Factor alpha Activates the Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase Pathway in Carcinoma Cells, Leading to Increased Proliferation and Protection from Radiation-induced Cell Death. Mol. Biol. Cell 10: 2493-2506 [Abstract] [Full Text]  
  • Liao, M.-J., Yin, C., Barlow, C., Wynshaw-Boris, A., van Dyke, T. (1999). Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction. Mol. Cell. Biol. 19: 3095-3102 [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»