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The Johns Hopkins Oncology Center, Baltimore, Maryland 21287 [C. E. C., A. C. W., C-Y C., M. B. K.], and Division of Cancer Therapeutics, National Cancer Institute, Bethesda, Maryland 20892 [A. J. F.]
The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.
1 This work was supported in part by Grant 3187 from the Council for Tobacco Research, Grants ES05777 and T32CA60441 from the NIH, and the Glaxo Research Institute. M. B. K. is The Steven Birnbaum Scholar of the Leukemia Society of America. C. E. C. and A. C. W. contributed equally to this work.
2 To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 2-109, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-5001.
Received 8/18/94. Accepted 8/30/94.
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S. Post, Y.-C. Weng, K. Cimprich, L. B. Chen, Y. Xu, and E. Y.-H. P. Lee Phosphorylation of serines 635 and 645 of human Rad17 is cell cycle regulated and is required for G1/S checkpoint activation in response to DNA damage PNAS, November 6, 2001; 98(23): 13102 - 13107. [Abstract] [Full Text] [PDF]
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