DOI: 10.1073/pnas.96.7.3706. GADD45 induction of a G <sub>2</sub> /M cell cycle checkpoint

GADD45 induction of a G 2 /M cell cycle checkpoint

10.1073/pnas.96.7.3706

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

G 1 /S and G 2 /M cell cycle checkpoints maintain genomic stability in eukaryotes in response to genotoxic stress. We report here both genetic and functional evidence of a Gadd45-mediated G 2 /M checkpoint in human and murine cells. Increased expression of Gadd45 via microinjection of an expression vector into primary human fibroblasts arrests the cells at the G 2 /M boundary with a phenotype of MPM2 immunopositivity, 4 n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G 2 /M arrest depends on wild-type p53, because no arrest was observed either in p53-null Li–Fraumeni fibroblasts or in normal fibroblasts coexpressed with p53 mutants. Increased expression of cyclin B1 and Cdc25C inhibited the Gadd45-mediated G 2 /M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G 2 /M checkpoint is at least in part through modulation of the activity of the G 2 -specific kinase, cyclin B1/p34 cdc2 . Genetic and physiological evidence of a Gadd45-mediated G 2 /M checkpoint was obtained by using GADD45 -deficient human or murine cells. Human cells with endogenous Gadd45 expression reduced by antisense GADD45 expression have an impaired G 2 /M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G 2 arrest after ionizing radiation. Lymphocytes from gadd45 -knockout mice ( gadd45 −/−) also retained a G 2 /M checkpoint initiated by ionizing radiation and failed to arrest at G 2 /M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G 2 /M checkpoints in response to specific types of DNA damage.

Bibliography

Wang, X. W., Zhan, Q., Coursen, J. D., Khan, M. A., Kontny, H. U., Yu, L., Hollander, M. C., OâConnor, P. M., Fornace, A. J., & Harris, C. C. (1999). GADD45 induction of a G 2 /M cell cycle checkpoint. Proceedings of the National Academy of Sciences, 96(7), 3706â3711.

Authors 10

Xin Wei Wang (first)
Qimin Zhan (additional)
Jill D. Coursen (additional)
Mohammed A. Khan (additional)
H. Udo Kontny (additional)
Lijia Yu (additional)
M. Christine Hollander (additional)
Patrick M. O’Connor (additional)
Albert J. Fornace (additional)
Curtis C. Harris (additional)

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Dates

Type	When
Created	23 years ago (July 26, 2002, 10:39 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:43 p.m.)
Indexed	4 days, 20 hours ago (Aug. 21, 2025, 1:13 p.m.)
Issued	26 years, 4 months ago (March 30, 1999)
Published	26 years, 4 months ago (March 30, 1999)
Published Online	26 years, 4 months ago (March 30, 1999)
Published Print	26 years, 4 months ago (March 30, 1999)

Funders 0

None

BibTeX

@article{Wang_1999, title={GADD45 induction of a G 2 /M cell cycle checkpoint}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.7.3706}, DOI={10.1073/pnas.96.7.3706}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Wang, Xin Wei and Zhan, Qimin and Coursen, Jill D. and Khan, Mohammed A. and Kontny, H. Udo and Yu, Lijia and Hollander, M. Christine and O’Connor, Patrick M. and Fornace, Albert J. and Harris, Curtis C.}, year={1999}, month=mar, pages={3706–3711} }

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