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 Yount, G. L. Articles by Israel, M. A. Search for Related Content PubMed PubMed Citation Articles by Yount, G. L. Articles by Israel, M. A.

Cell Cycle Synchrony Unmasks the Influence of p53 Function on Radiosensitivity of Human Glioblastoma Cells¹

Preuss Laboratory, Brain Tumor Research Center, Departments of Neurological Surgery [G. L. Y., D. A. H-K., M. A. I.] and Pediatrics [M. A. I.], and Department of Radiation Oncology [D. A. H-K., C. A. V., W. C. D.], School of Medicine, University of California, San Francisco, San Francisco, California 94143, and Department of Biology, University of California, San Diego, San Diego, California 92093 [M. H.]

Although ionizing radiation causes DNA damage that can play a role in tumorigenesis, such irradiation is also an important modality of cancer therapy. We studied the radiation response of the U-87 MG human glioblastoma cell line and transfected derivatives in which p53 function had been inactivated. Although little effect of p53 on the radiation sensitivity of asynchronously growing cultures could be detected, inactivation of p53 resulted in a large increase in clonogenic survival when cells synchronized by mitotic selection were irradiated in early G₁. The radiation dose sufficient to reduce cellular clonogenicity by 1 log in cells expressing functional p53 was 3.26 ± 0.12 Gy, whereas a much higher dose (7.41 ± 0.44 Gy) was required to achieve the same killing effect in cells in which p53 was inactivated. Apoptosis was excluded as a probable mechanism contributing to the radiosensitivity of these cells. Fluorescence-activated cell sorter analysis, continuous labeling with tritiated thymidine, and time-lapse videomicroscopy documented the first example of a prolonged p53-dependent G₁ arrest induced by ionizing radiation during the first postirradiation cell cycle of tumor cells, suggesting a role for G₁ arrest in determining the sensitivity of these cells to irradiation.

¹ This work is supported in part by the Robert Steel Foundation for Pediatric Cancer Research and by Public Health Service Grants CA09215 and CA61019 from the National Cancer Institute to the Department of Radiation Oncology and NS31076, CA13525, and CA64898 to the Brain Tumor Research Center, University of California, San Francisco. The investigators are also appreciative of support for this research from the Betz Foundation, the Price Family Foundation, and the Preuss Foundation.

² To whom requests for reprints should be addressed, at Brain Tumor Research Center, Department of Neurosurgery, University of California, San Francisco, HSE 722, 513 Parnassus Avenue, San Francisco, CA 94143-0520. Phone: (415) 476-6662; Fax: (415) 476-0388.

Received 10/ 2/95. Accepted 12/14/95.

This article has been cited by other articles:

				C. G. Hadjipanayis and N. A. DeLuca Inhibition of DNA Repair by a Herpes Simplex Virus Vector Enhances the Radiosensitivity of Human Glioblastoma Cells Cancer Res., June 15, 2005; 65(12): 5310 - 5316. [Abstract] [Full Text] [PDF]

				I. M. Hussaini, J. E. Carpenter, G. T. Redpath, J. J. Sando, M. E. Shaffrey, and S. R. VandenBerg Protein kinase C-{eta} regulates resistance to UV- and {gamma}-irradiation-induced apoptosis in glioblastoma cells by preventing caspase-9 activation Neuro-oncol, January 1, 2002; 4(1): 9 - 21. [Abstract] [PDF]

				J. A. Cerrato, W.K. A. Yung, and T.-J. Liu Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis Neuro-oncol, April 1, 2001; 3(2): 113 - 122. [Abstract] [PDF]

				L. J. Ostruszka and D. S. Shewach The Role of Cell Cycle Progression in Radiosensitization by 2',2'-Difluoro-2'-deoxycytidine Cancer Res., November 1, 2000; 60(21): 6080 - 6088. [Abstract] [Full Text]

				H.-K. G. Shu, C. M. Julin, F. Furman, G. L. Yount, D. Haas-Kogan, and M. A. Israel Overexpression of E2F1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation Neuro-oncol, January 1, 2000; 2(1): 16 - 21. [Abstract] [PDF]

				H.-S. Hwang, T. W. Davis, J. A. Houghton, and T. J. Kinsella Radiosensitivity of Thymidylate Synthase-deficient Human Tumor Cells Is Affected by Progression through the G1 Restriction Point into S-Phase: Implications for Fluoropyrimidine Radiosensitization Cancer Res., January 1, 2000; 60(1): 92 - 100. [Abstract] [Full Text]

				R. Mirzayans, S. Bashir, D. Murray, and M. C. Paterson Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response Carcinogenesis, June 1, 1999; 20(6): 941 - 946. [Abstract] [Full Text] [PDF]

				M. Nozaki, M. Tada, H. Kobayashi, C.-L. Zhang, Y. Sawamura, H. Abe, N. Ishii, and E. G. Van Meir Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression Neuro-oncol, April 1, 1999; 1(2): 124 - 137. [Abstract] [PDF]

				J. M. Brown and B. G. Wouters Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents Cancer Res., April 1, 1999; 59(7): 1391 - 1399. [Abstract] [Full Text] [PDF]

				R. G. Syljuasen, B. Krolewski, and J. B. Little Loss of Normal G1 Checkpoint Control Is an Early Step in Carcinogenesis, Independent of p53 Status Cancer Res., March 1, 1999; 59(5): 1008 - 1014. [Abstract] [Full Text] [PDF]

				G. L. Yount, K. S. Levine, H. Kuriyama, D. A. Haas-Kogan, and M. A. Israel Fas (APO-1/CD95) Signaling Pathway Is Intact in Radioresistant Human Glioma Cells Cancer Res., March 1, 1999; 59(6): 1362 - 1365. [Abstract] [Full Text] [PDF]

				H. B. Forrester, C. A. Vidair, N. Albright, C. C. Ling, and W. C. Dewey Using Computerized Video Time Lapse for Quantifying Cell Death of X-irradiated Rat Embryo Cells Transfected with c-myc or c-Ha-ras Cancer Res., February 1, 1999; 59(4): 931 - 939. [Abstract] [Full Text] [PDF]

				H.-K. G. Shu, M. M. Kim, P. Chen, F. Furman, C. M. Julin, and M. A. Israel The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21BAX expression PNAS, November 24, 1998; 95(24): 14453 - 14458. [Abstract] [Full Text] [PDF]

				N. S. Pellegata, R. J. Antoniono, J. L. Redpath, and E. J. Stanbridge DNA damage and p53-mediated cell cycle arrest: A reevaluation PNAS, December 24, 1996; 93(26): 15209 - 15214. [Abstract] [Full Text] [PDF]