Abstract
The gadd45 family of gene(s) is rapidly induced by genotoxic stress or by differentiation-inducing cytokines. Using bone marrow (BM) from gadd45a−/−, gadd45b−/− and wild-type (wt) mice, we investigated their role in stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelotoxic agents and inflammatory substances. Bone marrow cells from gadd45a−/− and gadd45b−/− mice displayed compromised myeloid differentiation and higher apoptosis in vitro, following acute stimulation with a variety of differentiating cytokines. Intriguingly, gadd45a−/− and gadd45b−/− colony forming units granulocyte/macrophage progenitors displayed prolonged proliferation capacity compared to wt controls upon re-plating in methylcellulose supplemented with interleukin-3. The recovery of the BM myeloid compartment following 5-Fluorouracil-induced myelo-ablation was much slower in gadd45a−/− and gadd45b−/− mice compared to wt controls. Furthermore, the response of myeloid cells to inflammatory stress, inflicted via intraperitoneal administration of sodium caseinate was impaired in gadd45a−/− and gadd45b−/− mice compared to age-matched wt mice, as indicated by lower percentage of Gr-1-positive cells in the BM and lower number of myeloid cells in peritoneal exudates. Overall, these data indicate that both gadd45a and gadd45b play a role in modulating physiological stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelo-ablation and inflammation. These findings should aid in understanding the response of normal and malignant hematopoietic cells to physiological and chemical stressors including anticancer agents.
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We thank Dr Albert Fornace Jr for the Gadd45a−/− mice. This work was supported by RO1 HL70530-03 (DL).
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Gupta, S., Gupta, M., Hoffman, B. et al. Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation. Oncogene 25, 5537–5546 (2006). https://doi.org/10.1038/sj.onc.1209555
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DOI: https://doi.org/10.1038/sj.onc.1209555
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