The Experts below are selected from a list of 9453 Experts worldwide ranked by ideXlab platform
Albert J. Fornace - One of the best experts on this subject based on the ideXlab platform.
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Gadd45 in stress signaling, cell cycle control, and apoptosis.
Advances in experimental medicine and biology, 2013Co-Authors: Jesus M. Salvador, Joshua D. Brown-clay, Albert J. FornaceAbstract:The first identified Gadd45 gene, Gadd45a, encodes a ubiquitously expressed protein that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. This protein and the other two members of this small gene family, Gadd45b and Gadd45g, have been implicated in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, and DNA repair. In vivo, many of the prominent roles for the Gadd45 proteins are associated with signaling mediated by p38 mitogen-activated protein kinases (MAPK). Gadd45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction. In vivo, there are important tissue and cell-type-specific differences in the roles for Gadd45 in MAPK signaling. In addition to being p53-regulated, Gadd45a has been found to contribute to p53 activation via p38. Like other stress and signaling proteins, Gadd45 proteins show complex regulation and numerous effectors.
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g2 m arrest by 1 25 dihydroxyvitamin d3 in ovarian cancer cells mediated through the induction of Gadd45 via an exonic enhancer
Journal of Biological Chemistry, 2003Co-Authors: Feng Jiang, Albert J. Fornace, Santo V Nicosia, Wenlong BaiAbstract:1,25-Dihydroxyvitamin D3 suppresses the growth of multiple human cancer cell lines by inhibiting cell cycle progression and inducing cell death. The present study showed that 1,25-dihydroxyvitamin D3 causes cell cycle arrest at the G2/M transition through p53-independent induction of Gadd45 in ovarian cancer cells. Detailed analyses have established Gadd45 as a primary target gene for 1,25-dihydroxyvitamin D3. A DR3-type vitamin D response element was identified in the fourth exon of Gadd45 that forms a complex with the vitamin D receptor·retinoid X receptor heterodimer in electrophoresis mobility shift assays and mediates the dose-dependent induction of luciferase activity by 1,25-dihydroxyvitamin D3 in reporter assays. Chromatin immunoprecipitation assays have shown that the vitamin D receptor is recruited in a ligand-dependent manner to the exonic enhancer but not to the Gadd45 promoter regions. In ovarian cancer cells expressing Gadd45 antisense cDNA or Gadd45-null mouse embryo fibroblasts, 1,25-dihydroxyvitamin D3 failed to induce G2/M arrest. Taken together, these results identify Gadd45 as an important mediator for the tumor-suppressing activity of 1,25-dihydroxyvitamin D3 in human ovarian cancer cells.
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BRCA1 activation of the Gadd45 promoter
Oncogene, 2000Co-Authors: Shunqian Jin, Albert J. Fornace, Hongcheng Zhao, Feiyue Fan, Amy B. Colchagie, Patricia Blanck, Wenhong Fan, Qimin ZhanAbstract:Breast cancer susceptibility gene BRCA1 has been implicated in the control of gene regulation and such regulated genes are thought to mediate the biological role of BRCA1. Overexpression of BRCA1 induces Gadd45, a p53-regulated and stress-inducible gene. However, the molecular mechanism by which BRCA1 induces the expression Gadd45 remains unclear. In this report, we have shown that the Gadd45 promoter is strongly activated following expression of wild-type BRCA1. In contrast, both the tumor-derived BRCA1 mutants (p1749R and Y1853insA) and truncated BRCA1 mutant protein (Δ500–1863 BRCA1), which lack transactivation activity, were unable to activate the Gadd45 promoter, indicating that the BRCA1-mediated activation of the Gadd45 promoter requires normal transcriptional properties of BRCA1. BRCA1 did not induce the c-Jun and c-fos promoters, which rules out a general effect of BRCA1 on other immediate-responsive genes. Expression of the human papillomavirus E6 and the dominant-negative mutant p53 proteins had no effect on the induction of the Gadd45 promoter by BRCA1, suggesting that activation of the Gadd45 promoter by BRCA1 is independent of cellular p53 function. With the 5′-deletion analysis, the BRCA1-responsive element of the Gadd45 promoter was mapped at the region from −121 to −75. Disruption of this region resulted in the abrogation of BRCA1 activation of the Gadd45 promoter. Taken together, these results demonstrate that the mechanism by which BRCA1 induces Gadd45 is mainly through the transactivation of the Gadd45 promoter, further demonstrating the evidence that Gadd45 acts as one of the BRCA1-regulated genes.
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The central region of Gadd45 is required for its interaction with p21/WAF1.
Experimental cell research, 2000Co-Authors: Hongcheng Zhao, Albert J. Fornace, Shunqian Jin, Michael J. Antinore, Feng-di T. Lung, Feiyue Fan, Patricia Blanck, Peter P. Roller, Qimin ZhanAbstract:Abstract Cell cycle arrest represents an important response to genotoxic stress and the tumor suppressor p53 has been described to act as a critical effector in this biological event. Upon stress, p53 becomes transcriptionally active and up-regulates the transcription of downstream effector genes, which contain p53 recognition sites in their regulatory regions. Among the genes activated are p21 and Gadd45, each of which independently exhibits growth-suppressive activity. The Gadd45 protein has been described to form a complex with p21, and thus, work was undertaken to map the regions of Gadd45 involved in this interaction and to examine the roles of those two proteins in growth suppression. In this report, a Gadd45 overlapping peptide library and a series of Gadd45 deletion mutants were used to define the domains of Gadd45 involved in the association with p21. Results using both in vitro and in vivo methods have shown that the interaction of Gadd45 with p21 involves a central region of Gadd45. Interestingly, the p21-binding domain of Gadd45 also encodes the Cdc2-binding activity, indicating that the central region of Gadd45 may serve as an important “core,” through which Gadd45 protein is able to present cross-talk with other cell cycle regulators. In addition, Gadd45 inhibition of Cdc2 kinase activity was compared with Myd118 and CR6, two other members of the Gadd45 family. Gadd45 was shown to generate the strongest inhibitory effect on Cdc2 activity. Finally, results from short-term survival assays further demonstrated that p21 and Gadd45 act upon different cellular pathways to exert their growth-suppressive function.
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the central region of Gadd45 is required for its interaction with p21 waf1
Experimental Cell Research, 2000Co-Authors: Hongcheng Zhao, Albert J. Fornace, Shunqian Jin, Michael J. Antinore, Feng-di T. Lung, Feiyue Fan, Patricia Blanck, Peter P. Roller, Qimin ZhanAbstract:Abstract Cell cycle arrest represents an important response to genotoxic stress and the tumor suppressor p53 has been described to act as a critical effector in this biological event. Upon stress, p53 becomes transcriptionally active and up-regulates the transcription of downstream effector genes, which contain p53 recognition sites in their regulatory regions. Among the genes activated are p21 and Gadd45, each of which independently exhibits growth-suppressive activity. The Gadd45 protein has been described to form a complex with p21, and thus, work was undertaken to map the regions of Gadd45 involved in this interaction and to examine the roles of those two proteins in growth suppression. In this report, a Gadd45 overlapping peptide library and a series of Gadd45 deletion mutants were used to define the domains of Gadd45 involved in the association with p21. Results using both in vitro and in vivo methods have shown that the interaction of Gadd45 with p21 involves a central region of Gadd45. Interestingly, the p21-binding domain of Gadd45 also encodes the Cdc2-binding activity, indicating that the central region of Gadd45 may serve as an important “core,” through which Gadd45 protein is able to present cross-talk with other cell cycle regulators. In addition, Gadd45 inhibition of Cdc2 kinase activity was compared with Myd118 and CR6, two other members of the Gadd45 family. Gadd45 was shown to generate the strongest inhibitory effect on Cdc2 activity. Finally, results from short-term survival assays further demonstrated that p21 and Gadd45 act upon different cellular pathways to exert their growth-suppressive function.
Mutsuhiro Takekawa - One of the best experts on this subject based on the ideXlab platform.
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Gadd45β Gadd45γ and mekk4 comprise a genetic pathway mediating stat4 independent ifnγ production in t cells
The EMBO Journal, 2004Co-Authors: Hongbo Chi, Mutsuhiro Takekawa, Roger J Davis, Richard A FlavellAbstract:The stress-inducible molecules Gadd45β and Gadd45γ have been implicated in regulating IFNγ production in CD4 T cells. However, how Gadd45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with Gadd45 in vitro. Here we generated MEKK4-deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4−/− mice have reduced p38 activity and defective IFNγ synthesis. Expression of Gadd45β or Gadd45γ promotes IFNγ production in MEKK4+/+ T cells, but not in MEKK4−/− cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of Gadd45β and Gadd45γ on p38 activation and IFNγ production. During Th1 differentiation, the Gadd45β/Gadd45γ/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNγ production in a process independent of STAT4.
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A Family of Stress-Inducible Gadd45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK
Cell, 1998Co-Authors: Mutsuhiro Takekawa, Haruo SaitoAbstract:The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, Gadd45alpha (= Gadd45), Gadd45, (= MyD118), and Gadd45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The Gadd45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the Gadd45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the Gadd45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
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a family of stress inducible Gadd45 like proteins mediate activation of the stress responsive mtk1 mekk4 mapkkk
Cell, 1998Co-Authors: Mutsuhiro Takekawa, Haruo SaitoAbstract:The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, Gadd45alpha (= Gadd45), Gadd45, (= MyD118), and Gadd45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The Gadd45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the Gadd45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the Gadd45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
Haruo Saito - One of the best experts on this subject based on the ideXlab platform.
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A Family of Stress-Inducible Gadd45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK
Cell, 1998Co-Authors: Mutsuhiro Takekawa, Haruo SaitoAbstract:The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, Gadd45alpha (= Gadd45), Gadd45, (= MyD118), and Gadd45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The Gadd45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the Gadd45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the Gadd45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
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a family of stress inducible Gadd45 like proteins mediate activation of the stress responsive mtk1 mekk4 mapkkk
Cell, 1998Co-Authors: Mutsuhiro Takekawa, Haruo SaitoAbstract:The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, Gadd45alpha (= Gadd45), Gadd45, (= MyD118), and Gadd45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The Gadd45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the Gadd45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the Gadd45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
Dan A. Liebermann - One of the best experts on this subject based on the ideXlab platform.
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Gadd45 Stress Sensors in Malignancy and Leukemia
Critical reviews in oncogenesis, 2011Co-Authors: Dan A. Liebermann, Jennifer S. Tront, Xiogen Sha, Kaushiki Mukherjee, Alisha Mohamed-hadley, Barbara HoffmanAbstract:Gadd45 proteins, including Gadd45a, Gadd45b and Gadd45g, have been implicated in stress signaling in response to physiological and environmental stress, including oncogenic stress, which can result in cell cycle arrest, DNA repair, cell survival, senescence, and apoptosis. The function of Gadd45 as a stress sensor is mediated via a complex interplay of physical interactions with other cellular proteins implicated in cell cycle regulation and the response of cells to stress, notably PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Altered expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Using genetically engineered mouse models and bone-marrow transplantation, evidence has been obtained indicating that Gadd45 proteins can function to either promote or suppress tumor development and leukemia; this is dependent on the molecular nature of the activated oncogene and the cell type, via engagement of different signaling pathways.
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Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells.
Journal of cellular physiology, 2009Co-Authors: Barbara Hoffman, Dan A. LiebermannAbstract: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-κB 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. J. Cell. Physiol. 218: 26–31, 2009. © 2008 Wiley-Liss, Inc.
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Stress sensor Gadd45 genes as therapeutic targets in cancer.
Cancer therapy, 2009Co-Authors: Alexandra Cretu, Barbara Hoffman, Jennifer S. Tront, Xiaojin Sha, Dan A. LiebermannAbstract:Gadd45 genes have been implicated in stress signaling responses to various physiological or environmental stressors, resulting in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated up to date suggests that Gadd45 proteins function as stress sensors, mediating their activity through 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. Disregulated expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Also, evidence has accumulated that Gadd45 proteins are intrinsically associated with the response of tumor cells to a variety of cancer therapeutic agents. Thus, Gadd45 proteins may represent a novel class of targets for therapeutic intervention in cancer. Additional research is needed to better understand which of the Gadd45 stress response functions may be targeted for chemotherapeutic drug design in cancer therapy.
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Gadd45 Genes Participate in Myeloid Cell Fate Determination.
Blood, 2007Co-Authors: John D. Gibbs, Alisha Mohamed-hadley, Dan A. Liebermann, Barbara HoffmanAbstract:The Gadd45 family of genes is rapidly induced by different stressors, including differentiation-inducing cytokines, and there is a large body of evidence that their cognate proteins are key players in cellular stress responses. Gadd45 gene(s) were found to be primary response gene(s) to IL-6 mediated terminal differentiation of M1 monocytic leukemia cells, as well as to G-CSF mediated terminal differentiation of 32Dcl3 cells; furthermore, Gadd45 gene(s) were induced by myeloid differentiation inducing cytokines such as IL-3 and GM-CSF in primary murine bone marrow (BM) cells (Zhang et al., Oncogene18:4899–4907, 1999; Abdollahi et al, Oncogene6:165–167, 1990). 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 BM or peripheral blood compartments of mice deficient for either Gadd45a or Gadd45b. Both BM and Hoxb8 immortalized macrophage progenitors induced to differentiate in vitro revealed that deficiency in either Gadd45a or Gadd45b resulted in loss of macrophages and an increase in neutrophils compared to cells derived from wild type mice. How Gadd45a and Gadd45b influence the expression and activation of transcription factors that regulate myeloid cell determination will be discussed.
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Role of Gadd45 in myeloid cells in response to hematopoietic stress.
Blood cells molecules & diseases, 2007Co-Authors: Barbara Hoffman, Dan A. LiebermannAbstract:The Gadd45 family of genes is rapidly induced by different stressors, including differentiation-inducing cytokines, and there is a large body of evidence that their cognate proteins are key players in cellular stress responses. 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 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 topic is discussed within the context of what is known about Gadd45 proteins in stress signaling, hematopoietic development and the innate immune response.
Barbara Hoffman - One of the best experts on this subject based on the ideXlab platform.
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Gadd45 Stress Sensors in Malignancy and Leukemia
Critical reviews in oncogenesis, 2011Co-Authors: Dan A. Liebermann, Jennifer S. Tront, Xiogen Sha, Kaushiki Mukherjee, Alisha Mohamed-hadley, Barbara HoffmanAbstract:Gadd45 proteins, including Gadd45a, Gadd45b and Gadd45g, have been implicated in stress signaling in response to physiological and environmental stress, including oncogenic stress, which can result in cell cycle arrest, DNA repair, cell survival, senescence, and apoptosis. The function of Gadd45 as a stress sensor is mediated via a complex interplay of physical interactions with other cellular proteins implicated in cell cycle regulation and the response of cells to stress, notably PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Altered expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Using genetically engineered mouse models and bone-marrow transplantation, evidence has been obtained indicating that Gadd45 proteins can function to either promote or suppress tumor development and leukemia; this is dependent on the molecular nature of the activated oncogene and the cell type, via engagement of different signaling pathways.
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Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells.
Journal of cellular physiology, 2009Co-Authors: Barbara Hoffman, Dan A. LiebermannAbstract: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-κB 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. J. Cell. Physiol. 218: 26–31, 2009. © 2008 Wiley-Liss, Inc.
-
Stress sensor Gadd45 genes as therapeutic targets in cancer.
Cancer therapy, 2009Co-Authors: Alexandra Cretu, Barbara Hoffman, Jennifer S. Tront, Xiaojin Sha, Dan A. LiebermannAbstract:Gadd45 genes have been implicated in stress signaling responses to various physiological or environmental stressors, resulting in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated up to date suggests that Gadd45 proteins function as stress sensors, mediating their activity through 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. Disregulated expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Also, evidence has accumulated that Gadd45 proteins are intrinsically associated with the response of tumor cells to a variety of cancer therapeutic agents. Thus, Gadd45 proteins may represent a novel class of targets for therapeutic intervention in cancer. Additional research is needed to better understand which of the Gadd45 stress response functions may be targeted for chemotherapeutic drug design in cancer therapy.
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Gadd45 Genes Participate in Myeloid Cell Fate Determination.
Blood, 2007Co-Authors: John D. Gibbs, Alisha Mohamed-hadley, Dan A. Liebermann, Barbara HoffmanAbstract:The Gadd45 family of genes is rapidly induced by different stressors, including differentiation-inducing cytokines, and there is a large body of evidence that their cognate proteins are key players in cellular stress responses. Gadd45 gene(s) were found to be primary response gene(s) to IL-6 mediated terminal differentiation of M1 monocytic leukemia cells, as well as to G-CSF mediated terminal differentiation of 32Dcl3 cells; furthermore, Gadd45 gene(s) were induced by myeloid differentiation inducing cytokines such as IL-3 and GM-CSF in primary murine bone marrow (BM) cells (Zhang et al., Oncogene18:4899–4907, 1999; Abdollahi et al, Oncogene6:165–167, 1990). 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 BM or peripheral blood compartments of mice deficient for either Gadd45a or Gadd45b. Both BM and Hoxb8 immortalized macrophage progenitors induced to differentiate in vitro revealed that deficiency in either Gadd45a or Gadd45b resulted in loss of macrophages and an increase in neutrophils compared to cells derived from wild type mice. How Gadd45a and Gadd45b influence the expression and activation of transcription factors that regulate myeloid cell determination will be discussed.
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Role of Gadd45 in myeloid cells in response to hematopoietic stress.
Blood cells molecules & diseases, 2007Co-Authors: Barbara Hoffman, Dan A. LiebermannAbstract:The Gadd45 family of genes is rapidly induced by different stressors, including differentiation-inducing cytokines, and there is a large body of evidence that their cognate proteins are key players in cellular stress responses. 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 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 topic is discussed within the context of what is known about Gadd45 proteins in stress signaling, hematopoietic development and the innate immune response.
