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PMID:10097101

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Citation

Wang, XW, Zhan, Q, Coursen, JD, Khan, MA, Kontny, HU, Yu, L, Hollander, MC, O'Connor, PM, Fornace, AJ Jr and Harris, CC (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc. Natl. Acad. Sci. U.S.A. 96:3706-11

Abstract

G1/S and G2/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 G2/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 G2/M boundary with a phenotype of MPM2 immunopositivity, 4n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G2/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 G2/M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G2/M checkpoint is at least in part through modulation of the activity of the G2-specific kinase, cyclin B1/p34(cdc2). Genetic and physiological evidence of a Gadd45-mediated G2/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 G2/M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G2 arrest after ionizing radiation. Lymphocytes from gadd45-knockout mice (gadd45 -/-) also retained a G2/M checkpoint initiated by ionizing radiation and failed to arrest at G2/M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G2/M checkpoints in response to specific types of DNA damage.

Links

PubMed PMC22358

Keywords

Animals; Cell Cycle/physiology; Cell Cycle Proteins; Cell Line; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins/genetics; DNA Damage; DNA-Binding Proteins; Fibroblasts/cytology; Fibroblasts/physiology; G2 Phase; Genes, p53; Humans; Intracellular Signaling Peptides and Proteins; Lymphocytes/cytology; Lymphocytes/physiology; Mice; Mice, Inbred Strains; Mitosis; Protein-Serine-Threonine Kinases; Proteins/genetics; Proteins/physiology; Recombinant Proteins/metabolism; Spleen/cytology; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GA45A

GO:0071850: mitotic cell cycle arrest

ECO:0000314:

P

Figure one shows that Gadd-45 arrests human fibroblasts in the G2/M cell cycle phase.

complete
CACAO 7555

HUMAN:GA45A

involved_in

GO:0071850: mitotic cell cycle arrest

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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