Integral role of Noxa in p53-mediated apoptotic response.
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 p21(WAF1/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.
Shibue
Tsukasa
T
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Takeda
Kiyoshi
K
Oda
Eri
E
Tanaka
Hiroshi
H
Murasawa
Hideki
H
Takaoka
Akinori
A
Morishita
Yasuyuki
Y
Akira
Shizuo
S
Taniguchi
Tadatsugu
T
Tanaka
Nobuyuki
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004249:DNA Damage; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein