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Wang, X. et al.

Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure.

GADD45a is a transcription target of the breast tumor suppressor gene BRCA. It was recently shown that mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of Brca1 (Brca1(Delta11/Delta11)) or a Gadd45A-null mutation (Gadd45a(-/-)) suffer centrosome amplification. To study genetic interactions between these genes during centrosome duplication, we generated Brca1(Delta11/Delta)(11)Gadd45a(-/-) mice by crossing each mutant. We found that all Brca1(Delta11/Delta11)Gadd45a(-/-) embryos at embryonic days 9.5-10.5 were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of BAX, BCL-2, and p53. The trigger for these events is likely the genetic instability arising from centrosome amplification that is associated, at least in part, with decreased expression of the NIMA-related kinase NEK2. We demonstrate that small interfering RNA-mediated suppression of Brca1 decreased Nek2 more dramatically in Gadd45a(-/-) cells than in wild-type cells and, conversely, that overexpression of Brca1 and/or Gadd45a up-regulated transcription of Nek2. Furthermore, we show that overexpression of Nek2 in Brca1-specific small interfering RNA-treated wild-type and Gadd45a(-/-) cells repressed abnormal centrosome amplification. These observations suggest that NEK2 plays a role in mediating the actions of BRCA1 and GADD45a in regulating centrosome duplication and in maintaining genetic stability.[1]

References

Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. Wang, X., Wang, R.H., Li, W., Xu, X., Hollander, M.C., Fornace, A.J., Deng, C.X. J. Biol. Chem. (2004) [Pubmed]

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