This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Westphal, C. H. Articles by Leder, P. Search for Related Content PubMed PubMed Citation Articles by Westphal, C. H. Articles by Leder, P.

Genetic Interactions between atm and p53 Influence Cellular Proliferation and Irradiation-induced Cell Cycle Checkpoints¹

Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School [C. H. W., P. L.], and Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School [C. S., S. R., D. E. F.], and Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100 Israel [A. E.]

Ataxia-telangiectasia and Li-Fraumeni syndrome, pleiotropic disorders caused by mutations in the genes atm and p53, share a marked increase in cancer rates. A number of studies have argued for an interaction between these two genes (for comprehensive reviews, see M. S. Meyn, Cancer Res., 55: 5991–6001, 1995, and M. F. Lavin and Y. Shiloh, Annu. Rev., Immunol., 15: 177–202, 1996). Specifically, atm is placed upstream of p53 in mediating G₁-S cell cycle checkpoint control, and both atm and p53 are believed to influence cellular proliferation. To analyze the genetic interactions of atm and p53, mouse embryonic fibroblasts (MEFs) homozygously deficient for both atm and p53 were used to assess cell cycle and growth control. These double-null fibroblasts proliferate rapidly and fail to exhibit the premature growth arrest seen with atm-null MEFs. MEFs null for both atm and p53 do not express any p21^cipl/wafl, showing that p53 is required for p21^cipl/wafl expression in an atm-null background. By contrast, homozygous loss of either atm, p53, or both results in similar abnormalities of the irradiation-induced G₁-S cell cycle checkpoint. Our results suggest two separate pathways of interaction between atm and p53, one linear, involving G₁-S cell cycle control, and another more complex, involving aspects of growth regulation.

¹ This work was supported by the Howard Hughes Medical Institute (to P. L.) and by NIH Grants CA69531 and AR43369 (to D. E. F.). D. E. F. is a Pew Foundation scholar and a scholar of the James S. McDonnall Foundation. C. H. W. is a Sandoz Fellow. C. S. is the recipient of a scholarship from the Deutsche Forschungsgemeinschaft. S. R. is supported by a predoctoral fellowship from the Howard Hughes Medical Institute. A. E. is an Alon Fellow and the incumbent of the Adolfo and Evelyn Blum Chair.

² To whom requests for reprints should be addressed, at Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.

Received 2/26/97. Accepted 3/24/97.

This article has been cited by other articles:

				I. R. Matei, R. A. Gladdy, L. M. J. Nutter, A. Canty, C. J. Guidos, and J. S. Danska ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes Blood, March 1, 2007; 109(5): 1887 - 1896. [Abstract] [Full Text] [PDF]

				N. Rasheed, X. Wang, Q.-T. Niu, J. Yeh, and B. Li Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis Hum. Mol. Genet., June 15, 2006; 15(12): 1938 - 1948. [Abstract] [Full Text] [PDF]

				J. Dahl, J. You, and T. L. Benjamin Induction and Utilization of an ATM Signaling Pathway by Polyomavirus J. Virol., October 15, 2005; 79(20): 13007 - 13017. [Abstract] [Full Text] [PDF]

				K. C. Shen, H. Heng, Y. Wang, S. Lu, G. Liu, C.-X. Deng, S.C. Brooks, and Y. A. Wang ATM and p21 Cooperate to Suppress Aneuploidy and Subsequent Tumor Development Cancer Res., October 1, 2005; 65(19): 8747 - 8753. [Abstract] [Full Text] [PDF]

				I. A. Stasinopoulos, Y. Mironchik, A. Raman, F. Wildes, P. Winnard Jr., and V. Raman HOXA5-Twist Interaction Alters p53 Homeostasis in Breast Cancer Cells J. Biol. Chem., January 21, 2005; 280(3): 2294 - 2299. [Abstract] [Full Text] [PDF]

				H. K. Sluss, H. Armata, J. Gallant, and S. N. Jones Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice Mol. Cell. Biol., February 1, 2004; 24(3): 976 - 984. [Abstract] [Full Text] [PDF]

				A. Fedier, M. Schlamminger, V. A. Schwarz, U. Haller, S. B. Howell, and D. Fink Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites Ann. Onc., June 1, 2003; 14(6): 938 - 945. [Abstract] [Full Text] [PDF]

				K. Gronbak, J. Worm, E. Ralfkiaer, V. Ahrenkiel, P. Hokland, and P. Guldberg ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma Blood, July 30, 2002; 100(4): 1430 - 1437. [Abstract] [Full Text] [PDF]

				S. Peretz, R. Jensen, R. Baserga, and P. M. Glazer ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response PNAS, February 1, 2001; (2001) 41416598. [Abstract] [Full Text]

				R. Khosravi, R. Maya, T. Gottlieb, M. Oren, Y. Shiloh, and D. Shkedy Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage PNAS, December 21, 1999; 96(26): 14973 - 14977. [Abstract] [Full Text] [PDF]

				E. C. Gosink, M. J. Chong, and P. J. McKinnon Ataxia Telangiectasia Mutated Deficiency Affects Astrocyte Growth but not Radiosensitivity Cancer Res., October 1, 1999; 59(20): 5294 - 5298. [Abstract] [Full Text] [PDF]

				T. Shigeta, M. Takagi, D. Delia, L. Chessa, S. Iwata, Y. Kanke, M. Asada, M. Eguchi, and S. Mizutani Defective Control of Apoptosis and Mitotic Spindle Checkpoint in Heterozygous Carriers of ATM Mutations Cancer Res., June 1, 1999; 59(11): 2602 - 2607. [Abstract] [Full Text] [PDF]

				T. Kamijo, E. van de Kamp, M. J. Chong, F. Zindy, J. A. Diehl, C. J. Sherr, and P. J. McKinnon Loss of the ARF Tumor Suppressor Reverses Premature Replicative Arrest but not Radiation Hypersensitivity Arising from Disabled Atm Function Cancer Res., May 1, 1999; 59(10): 2464 - 2469. [Abstract] [Full Text] [PDF]

				M.-J. Liao, C. Yin, C. Barlow, A. Wynshaw-Boris, and T. van Dyke Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction Mol. Cell. Biol., April 1, 1999; 19(4): 3095 - 3102. [Abstract] [Full Text] [PDF]

				Y. A. Wang, A. Elson, and P. Leder Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice PNAS, December 23, 1997; 94(26): 14590 - 14595. [Abstract] [Full Text] [PDF]

				S. Peretz, R. Jensen, R. Baserga, and P. M. Glazer ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response PNAS, February 13, 2001; 98(4): 1676 - 1681. [Abstract] [Full Text] [PDF]

				S. H. Khan, J. Moritsugu, and G. M. Wahl Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion PNAS, March 28, 2000; 97(7): 3266 - 3271. [Abstract] [Full Text] [PDF]