Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Gupta, Shiv K.; Gupta, Mamta; Hoffman, Barbara; Liebermann, Dan A.

doi:10.1038/sj.onc.1209555

Cited by 51 publications

(72 citation statements)

References 44 publications

(65 reference statements)

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“…For example, two other genes in the ERK1/2-repressed cohort described by Yamamoto et al, 13 the Mllt3 gene (myeloid/lymphoid or mixed lineage-leukemia translocation to 3 homolog) and Sox6, have been reported to be downregulated selectively by the FLT3-ITD mutant. 11 A role for Gadd45a in promoting granulocytic differentiation has also been suggested from gene ablation studies in mice; where complete loss of Gadd45a results in reduced numbers of granulocytes and increased blasts after GM-CSF treatment 50 consistent with a role in myeloid differentiation. This is also associated with an increased replating ability of CFU-GM from Gadd45aÀ/À bone marrow, suggesting a potential role for Gadd45a as an AML tumor suppressor gene.…”

Section: Gadd45a Repression In Aml M Perugini Et Almentioning

confidence: 83%

“…This is also associated with an increased replating ability of CFU-GM from Gadd45aÀ/À bone marrow, suggesting a potential role for Gadd45a as an AML tumor suppressor gene. 50 Taken together with reports that Gadd45a is a target of C/ EBPa, 51,52 Gadd45a may have an important role in promoting granulocyte differentiation. Gadd45a is also a direct target of C/EBPa in adipocytes 34,35 and thus may have a more general role in coupling growth arrest to induction of differentiation.…”

Section: Gadd45a Repression In Aml M Perugini Et Almentioning

confidence: 99%

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Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

et al. 2009

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The tumor suppressor Gadd45a was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45a as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD þ AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45a mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD þ cell line MV4;11. Knockdown of Gadd45a with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45a in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45a overexpression in FLT3-ITD þ AML cell lines also resulted in reduced growth associated with increased apoptosis and G 1 /S cell cycle arrest. Overexpression of Gadd45a in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45a downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45a by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.

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Section: Gadd45a Repression In Aml M Perugini Et Almentioning

confidence: 83%

Section: Gadd45a Repression In Aml M Perugini Et Almentioning

confidence: 99%

Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

et al. 2009

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“…Finally, gadd45a is induced only at later times. Myeloid enriched BM treated with IL-3, GM-CSF, G-CSF or M-CSF results in rapid induction of all three gadd45 genes, yet the patterns of expression vary during the ensuing myeloid developmental program [3,5,8]. The expression of gadd45b in gadd45a−/− BM and of gadd45a in gadd45b−/− BM was comparable to their expression in wild type BM cells.…”

Section: Expression Of Gadd45 In Myeloid Cells In Response To Cytokinmentioning

confidence: 70%

“…Furthermore, expression of gadd45a, gadd45b and gadd45g is induced in response to multiple environmental and physiological stresses, including MMS, IR, UV, VP-16, daunorubicin (DNR), and inflammatory cytokines [1,[7][8]. In all cases the pattern of expression for each gadd45 gene is unique, consistent with each gadd45 family member playing a different role in response to each source of stress.…”

Section: Introductionmentioning

confidence: 73%

“…In all cases the pattern of expression for each gadd45 gene is unique, consistent with each gadd45 family member playing a different role in response to each source of stress. In addition it was observed that during myeloid differentiation, using either normal bone marrow (BM) stimulated with different hematopoietic cytokines or various hematopoietic cell lines induced to undergo terminal myeloid differentiation, each gadd45 gene has a distinctive pattern of expression [3,8]. Consistent with the distinctive expression patterns, regulation of expression for each gadd45 gene differs.…”

Section: Introductionmentioning

confidence: 86%

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Role of gadd45 in myeloid cells in response to hematopoietic stress

Hoffman

Liebermann

2007

Blood Cells, Molecules, and Diseases

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The gadd45 family of genes is rapidly induced by different stressors, including differentiationinducing 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.

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The Effect of GADD45a on Furazolidone‐Induced S‐Phase Cell‐Cycle Arrest in Human Hepatoma G2 Cells

Sun

Tang

Xiao

2015

J Biochem & Molecular Tox

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In this study, overexpression of GADD45a induced by furazolidone in HepG2 cells could arouse S-phase cell cycle arrest, suppress cell proliferation, and increase the activities of cyclin D1, cyclin D3, and cyclin-dependent kinase 6 (CDK6). To the opposite, GADD45a knockdown cells by RNAi could reduce furazolidone-induced S-phase cell cycle arrest, increase the cell viability, decrease the activities of cyclin D1, cyclin D3, and CDK6; however, cyclin-dependent kinase 4 (CDK4) showed no change. Moreover, data from our current studies show that cyclin D1, cyclin D3, and CDK6 are target genes functioning at the downstream of the GADD45a pathway induced by furazolidone. These results demonstrate that the GADD45a pathway is partially responsible for the furazolidone-induced S-phase cell cycle arrest. GADD45a influences furazolidone-induced S-phase cell cycle arrest in human hepatoma G2 cells via cyclin D1, cyclin D3, and CDK6, but not CDK4.

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Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Cited by 51 publications

References 44 publications

Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

Role of gadd45 in myeloid cells in response to hematopoietic stress

The Effect of GADD45a on Furazolidone‐Induced S‐Phase Cell‐Cycle Arrest in Human Hepatoma G2 Cells

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