NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45α and γ is essential for cancer cell survival

Zerbini, Luiz F.; Wang, Yihong; Czibere, Akos; Correa, Ricardo G.; Cho, Je‐Yoel; Ijiri, Kosei; Wei, Wanjang; Joseph, Marie; Gu, Xuesong; Grall, Franck; Goldring, Mary B.; Zhou, Jin-Rhong; Libermann, Towia A.

doi:10.1073/pnas.0402069101

Cited by 148 publications

(195 citation statements)

References 27 publications

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“…Also, using the gadd45aÀ/À mice, it has been reported that gadd45a promotes UV-induced apoptosis in skin keratinocytes (Maeda et al, 2002). Additional evidence for a proapoptotic function of gadd45a and gadd45g has been documented recently using either overexpression of these proteins in prostate and breast cancer cell lines or siRNA-mediated knockdown that was observed to block IkB-mediated apoptosis in these cell lines (Zerbini et al, 2004). On the other hand, our results are consistent with an earlier report where it was shown that p53 null MEFS that lack gadd45a are sensitized to UV-and cisplatin-induced cell death (Smith et al, 2000).…”

Section: Discussionmentioning

confidence: 87%

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

et al. 2005

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Section: Discussionmentioning

confidence: 87%

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

et al. 2005

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“…Also, using the gadd45a-/-mice, it has been reported that gadd45a promotes UV induced apoptosis in skin keratinocytes (57). Additional evidence for a pro-apoptotic function of gadd45a and gadd45g has been documented using either overexpression of these proteins in prostate and breast cancer cell lines or siRNA-mediated knockdown that was observed to block IkB mediated apoptosis in these cell lines (58). On the other hand, our results are consistent with an earlier report where it was shown that p53 null MEFS that lack gadd45a are sensitized to UV and cisplatin induced cell death (24).…”

Section: Hematopoietic Cells From Gadd45a and Gadd45b Deficient Mice mentioning

confidence: 95%

Gadd45 in the response of hematopoietic cells to genotoxic stress

Liebermann

Hoffman

2007

Blood Cells, Molecules, and Diseases

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Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in either cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Recently we have taken advantage 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. 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. The increased apoptosis in gadd45a and gadd45b deficient cells was evident also by enhanced activation of caspase-3 and PARP cleavage and decreased expression of cIAP-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. Additional work conducted in this laboratory has shown that in hematopoietic cells exposed to UV radiation gaddd45a and gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the Gadd45a-p38-NF-kB mediated survival pathway and Gadd45b mediated inhibition of the stress response MKK4-JNK pathway (59). These data reveal novel mechanisms that mediate the pro-survival functions of gadd45a and gadd45b in hematopoietic cells following UV irradiation. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs. This knowledge should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukaemias and response of normal and malignant hematopoietic cells to chemo and radiation therapy. These observations set the stage to evaluate, in clinically relevant settings, the impact that the status of gadd45a and gadd45b might have on the efficacy of DNR or VP-16 in killing leukemic cells.

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“…Whereas GADD45α and GADD45γ are strictly proapoptotic proteins [23,31], the involvement of GADD45β in the apoptotic process is debated. The present study demonstrates an anti-apoptotic effect of Gadd45b expression in beta cells exposed to IL-1β, and we have previously shown that enhanced Gadd45b expression prevents apoptosis [22,24,32] in other cell types.…”

Section: Discussionmentioning

confidence: 99%

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

et al. 2006

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Aims/hypothesis: IL-1β is a candidate mediator of apoptotic beta cell destruction, a process that leads to type 1 diabetes and progression of type 2 diabetes. IL-1β activates beta cell c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38, all of which are members of the mitogen-activated protein kinase (MAPK) family. Inhibition of JNK prevents IL-1β-mediated beta cell destruction. In mouse embryo fibroblasts and 3DO T cells, overexpression of the gene encoding growth arrest and DNA-damage-inducible 45β (Gadd45b) downregulates pro-apoptotic JNK signalling. The aim of this study was to investigate if Gadd45b prevents IL-1β-induced beta cell MAPK signalling and apoptosis. Materials: Rat insulinoma INS-1E cells and mouse beta-TC3 cells stably expressing Gadd45b were generated. The effects of Gadd45b expression on signalling by JNK, ERK and p38 were assessed by Western blotting and kinase assays. Apoptosis rate was measured by terminal deoxynucleotidyl-mediated dUTP-biotin nick end-labelling (TUNEL) and an ELISA designed to detect apoptotic nucleosomes. Expression of endogenous Gadd45b mRNA was measured by RT-PCR. Results: In INS-1E and beta-TC3 cells, expression ofGadd45b inhibited IL-1β-induced activation of JNK and ERK, but augmented IL-1β-mediated p38 activity. IL-1β-induced nitric oxide production and decreases in insulin content and secretion were reduced by GADD45β. IL-1β-induced apoptosis was reduced by GADD45β by up to 77%. Although IL-1β stimulated the time-dependent induction of endogenous Gadd45b in INS-1E cells and rat islets, expression levels were lower in these cells than in IL-1β-exposed NIH-3T3 and 3DO T cells.

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NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45α and γ is essential for cancer cell survival

Cited by 148 publications

References 27 publications

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

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

Gadd45 in the response of hematopoietic cells to genotoxic stress

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

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