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Separate Pathways for p53 Induction by Ionizing Radiation and N-(Phosphonoacetyl)-L-aspartate¹

The Johns Hopkins Oncology Center, Baltimore, Maryland 21205 [C-Y. M. C., M. B. K.]; Department of Pathology, University of California, San Francisco, San Francisco, California 94143 [I. H., T. D. T.]; and Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709 [T. J. L., T. M. G.]

The tumor suppressor gene product, p53, appears to be a significant participant in signaling pathways that mediate cellular responses to cytotoxic stresses. In particular, p53 appears to be a critical determinant of whether the cell lives or dies and how it progresses through the cell cycle after the cytotoxic exposure. Many of the molecular details for these signaling pathways remain to be elucidated, and whether all cytotoxic signals utilize the same pathway to increase p53 expression is not clear. Here, we demonstrate the existence of cell types in which the induction of p53 and associated G₁ arrest by the antimetabolite, N-(phosphonoacetyl)-L-aspartate (PALA), is defective, whereas p53 induction and G₁ arrest induced by ionizing radiation are intact. These observations demonstrate the existence of genetic defects that can alter p53 induction and associated cellular outcomes after some, but not all, cytotoxic insults and suggest distinct pathways of p53 induction by PALA and ionizing radiation.

¹ This work was supported in part by NIH Grants ES05777 and CA61949 (to M. B. K.) and Grants CA58413 and CA51912 (to T. D. T.).

² To whom requests for reprints may be addressed, at The Johns Hopkins Hospital, 720 Rutland Avenue, 345 Ross Building, Baltimore, MD 21205. Phone: (410) 955-4967; Fax: (410) 614-4095; E-mail: mbkastan@welchlink.welch.jhu.edu (M. B. K.); or at University of California, San Francisco, Pathology Dept., P.O. Box 0506, San Francisco, CA 94143-0506. Phone: (415) 502-6116; Fax: (415) 502-6163 (T. D. T.).

³ M. B. K. is the Steven Birnbaum Scholar of The Leukemia Society of America.

Received 6/ 6/96. Accepted 6/29/96.

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