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Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis

Oncogene volume 24, pages 7170–7179 (2005)Cite this article

Abstract

Gadd45a, gadd45b and gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress. However, the exact function of Gadd45 proteins in the response of mammalian cells to genotoxic stress is unclear. Here, advantage was taken of gadd45a- and gadd45b-deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. BM cells from gadd45a- and gadd45b-deficient mice were observed to be more sensitive to ultraviolet radiation chemotherapy (UVC), VP-16 and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a- and gadd45b-deficient cells was evident also by enhanced activation of caspase-3 and poly-ADP-ribose polymerase cleavage and decreased expression of c-inhibitor of apoptotic protein-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45-deficient BM cells restored the wt apoptotic phenotype. Both gadd45a- and gadd45b-deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Taken together, these findings identify gadd45a and gadd45b as antiapoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs.

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Acknowledgements

We thank Ms Diana Vesely (graduate student) for construction of MIGW-gadd45a retroviral construct. This work was supported by NIH grants 5 RO1 CA89718-02 (DAL) and RO1 HL 70530-01 (DAL).

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Authors and Affiliations

  1. Fels Institute of Cancer Research and Molecular Biology, Temple University School of Medicine, Room 331, 3307 North Broad Street, Philadelphia, 19140, PA, USA

    Mamta Gupta, Shiv K Gupta, Arthur G Balliet, Barbara Hoffman & Dan A Liebermann

  2. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, 20892, MD, USA

    Mary Christine Hollander & Albert J Fornace Jr

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  1. Mamta Gupta
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Correspondence to Dan A Liebermann.

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Gupta, M., Gupta, S., Balliet, A. et al. Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Oncogene 24, 7170–7179 (2005). https://doi.org/10.1038/sj.onc.1208847

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