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RESEARCH COMMUNICATION
1 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan , 2 Department of Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan , 3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka 565-0871, Japan , 4 Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Nakahara-ku, Kawasaki-shi 211-8533, Japan
The tumor suppressor p53 exerts its versatile function to maintain the genomic integrity of a cell, and the life of cancerous cells with DNA damage is often terminated by induction of apoptosis. We studied the role of Noxa, one of the transcriptional targets of p53 that encodes a proapoptotic protein of the Bcl-2 family, by the gene-targeting approach. Mouse embryonic fibroblasts deficient in Noxa [Noxa-/- mouse embryonic fibroblasts (MEFs)] showed notable resistance to oncogene-dependent apoptosis in response to DNA damage, which was further increased by introducing an additional null zygosity for Bax. These MEFs also showed increased sensitivity to oncogene-induced cell transformation in vitro. Furthermore, Noxa is also involved in the oncogene-independent gradual apoptosis induced by severe genotoxic stresses, under which p53 activates both survival and apoptotic pathways through induction of p21WAF1/Cip1 and Noxa, respectively. Noxa-/- mice showed resistance to X-ray irradiation-induced gastrointestinal death, accompanied with impaired apoptosis of the epithelial cells of small intestinal crypts, indicating the contribution of Noxa to the p53 response in vivo.
[Keywords: p53; apoptosis; Bcl-2 family; DNA damage; oncogene]
Received April 14, 2003; revised version accepted July 10, 2003.
Supplemental material is available at http://www.genesdev.org.
5 Corresponding author.
E-MAIL tada{at}m.u-tokyo.ac.jp; FAX 81-3-5841-3450.
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