A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Abstract
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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GADD45A can induce G2/M cell cycle arrest.
“The p53 target genes BTG236, 154, 155 and GADD45A13, 156 can also induce G1/S and G2/M cell cycle arrest, respectively.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [13]
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- Authors
- Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J.
- Affiliations
- Johns Hopkins University (US)
- National Cancer Institute (US)
- Massachusetts Institute of Technology (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1992-11
- Volume
- 71
- Issue
- 4
- Pages
- 587-597
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1986179131
- Cited by
- 3,047
- References
- 64
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 17 · 2023: 20 · 2022: 23 · 2021: 23 · 2020: 24 · 2019: 16 · 2018: 31 · 2017: 34 · 2016: 35 · 2015: 43 · 2014: 44 · 2013: 30 · 2012: 48
- FWCI
- 86.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 09071, CA43460, T32CA009071)
- National Institute of Environmental Health Sciences (ES05777)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- ataxia telangiectasia, p53, GADD45, cell cycle checkpoints, G1/S checkpoint, ionizing radiation, DNA damage response, cell cycle arrest, signal transduction, cancer susceptibility, radiosensitivity
- MeSH terms
- Amino Acid Sequence, Animals, Ataxia Telangiectasia, Base Sequence, Cell Cycle, Cell Line, Cloning, Molecular, DNA Damage, DNA Repair, Gene Expression Regulation, Humans, Molecular Sequence Data, Genes, p53, Mutagenesis, Mice
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