Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells

Abstract

Gadd45 proteins modulate signaling in response to physiological and environmental stressors. Expression of gadd45 genes is rapidly induced by different stressors, including differentiation-inducing cytokines and genotoxic stress. Induction of gadd45 genes at the onset of myeloid differentiation suggested that Gadd45 protein(s) play a role in hematopoiesis, yet no apparent abnormalities were observed in either the bone marrow (BM) or peripheral blood compartments of mice deficient for either gadd45a or gadd45b. However, under conditions of hematological stress, including acute stimulation with cytokines, myelo-ablation and inflammation, both gadd45a-deficient and gadd45b-deficient mice exhibited deficiencies. This is discussed within the context of what is known about Gadd45 proteins in stress signaling, hematopoietic development and the innate immune response. Furthermore, myeloid enriched BM cells from gadd45a and gadd45b deficient mice were observed to be more sensitive to ultraviolet radiation (UVC), VP-16 and daunorubicin (DNR) induced apoptosis compared to wild-type (WT) cells, displaying defective G2/M arrest following exposure to UVC and VP-16, but not to DNR. Novel mechanisms that mediate the pro-survival functions of Gadd45 in hematopoietic cells following UV irradiation were demonstrated, involving activation of the Gadd45a-p38-NF-kappaB survival pathway and Gadd45b mediated inhibition of the stress response MKK4-JNK apoptotic pathway. The ramifications regarding the pathogenesis of different leukemias and the response of normal and malignant hematopoietic cells to chemo- and radiation-therapy, as well as other challenges to the hematopoietic compartment, are discussed.