TY - JOUR
T1 - A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
AU - Kastan, Michael B.
AU - Zhan, Qimin
AU - El-Deiry, Wafik S.
AU - Carrier, France
AU - Jacks, Tyler
AU - Walsh, William V.
AU - Plunkett, Beverly S.
AU - Vogelstein, Bert
AU - Fornace, Albert J.
N1 - Funding Information:
This work was supported by grants from the National fnstitutes of Health (ES 05777, CA 43460, CA 09071) The Clayton Fund, and The Preuss Foundation. T. J. is a scholar of the Lucille P. Markey Foundation and was supported in part by National Cancer fnstitute grant 2R35-39826 to Robert Weinberg. We thank Drs. Ralph Weichselbaum, Richard Gatti, and Kathy Cho for helpful discussions. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC Section 1734 solely to indicate this fact.
PY - 1992/11/13
Y1 - 1992/11/13
N2 - Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In addition, cells from patients with the radiosensitive, cancer-prone disease ataxia-telangiectasia (AT) lacked the IR-induced increase in p53 protein levels seen in normal cells. Finally, IR induction of the human GADD45 gene, an induction that is also defective in AT cells, was dependent on wild-type p53 function. Wild-type but not mutant p53 bound strongly to a conserved element in the GADD45 gene, and a p53-containing nuclear factor, which bound this element, was detected in extracts from irradiated cells. Thus, we identified three participants (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
AB - Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In addition, cells from patients with the radiosensitive, cancer-prone disease ataxia-telangiectasia (AT) lacked the IR-induced increase in p53 protein levels seen in normal cells. Finally, IR induction of the human GADD45 gene, an induction that is also defective in AT cells, was dependent on wild-type p53 function. Wild-type but not mutant p53 bound strongly to a conserved element in the GADD45 gene, and a p53-containing nuclear factor, which bound this element, was detected in extracts from irradiated cells. Thus, we identified three participants (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
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U2 - 10.1016/0092-8674(92)90593-2
DO - 10.1016/0092-8674(92)90593-2
M3 - Article
C2 - 1423616
AN - SCOPUS:0026496885
SN - 0092-8674
VL - 71
SP - 587
EP - 597
JO - Cell
JF - Cell
IS - 4
ER -