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Wild-Type p53 Suppresses Transcription of the Human O⁶-Methylguanine-DNA Methyltransferase Gene¹

Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101-0318

High-level expression of the DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) correlates with cellular resistance to the chloroethylnitrosourea (CENU) class of alkylating agents. Consequently, tumors expressing low levels of MGMT are sensitive to CENU chemotherapy, and any mechanism that can be used to reduce MGMT levels could sensitize resistant tumors. We have demonstrated that transient transfection of wild-type, but not mutant, p53 protein into a p53-null cell line, Saos-2, suppresses MGMT promoter activity in a reporter gene system. In addition, following a 24-h transduction of IMR90 fibroblasts with a wild-type p53-adenoviral vector, endogenous MGMT protein is down-regulated and is no longer detectable 5 days following infection. Because p53 is inducible by ionizing radiation, we propose that existing cancer therapy regimens that combine radiotherapy with CENU chemotherapy may be improved by altering scheduling and allowing enough time between the two therapies for the relatively stable MGMT protein to degrade.

¹ This work was supported by NIH Grants CA 14799 and CA 23099, Cancer Center Support (CORE) Grant P30 CA 21765, and the American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, TN 38101-0318. Phone: (901) 495-3440; Fax: (901) 521-1668.

Received 2/23/96. Accepted 3/15/96.

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