Gadd45 in stress signaling

Liebermann, Dan A.; Hoffman, Barbara

doi:10.1186/1750-2187-3-15

Cited by 188 publications

(177 citation statements)

References 74 publications

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“…Gadd45a also functions as a stress sensor, which 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. 17 Gupta et al 37 reported that Gadd45a-deficient hematopoietic cells demonstrated an impaired DDR response. They found myeloidenriched BM cells from Gadd45a-or Gadd45b-deficient mice were defective in G2/M arrest following exposure to UV and VP-16 and these cells were sensitized to genotoxic-stressinduced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

et al. 2011

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Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation(s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. cH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage À Sca1 þ c-kit þ (LSK) cells than in mock-transduced LSK cells both in a steady state and after c-ray treatment. Expression profiling by real-time -PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

“…As for this mechanism, we found that RUNX1dC suppresses the transcription of a sensor of DNA stress, Gadd45a. 17 Moreover, bone marrow (BM) cells from MDS/ AML patients harboring a RUNX1-C-terminal mutation showed significantly lower GADD45A expression than those from MDS/ AML patients with WT RUNX1. These results suggest RUNX1…”

Section: Introductionmentioning

confidence: 99%

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

et al. 2011

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“…15,46,47 Cell cycle analysis of FDB1 cells and AML cell lines (MOLM-13 and MV4;11) overexpressing Gadd45a shows that arrest occurs at G1/S. The Gadd proteins interact directly with a number of cell cycle proteins including PCNA, p21 and cdc2/ CyclinB1 linking DNA damage to cell cycle arrest (reviewed in Hoffman and Liebermann 16,17 ). All Gadd family members have been shown to induce G2/M cell cycle arrest by various mechanisms (reviewed in Hoffman and Liebermann 16,17 ) and mounting evidence has also implicated Gadd family members in G1/S arrest.…”

Section: Gadd45a Repression In Aml M Perugini Et Almentioning

confidence: 99%

“…13 It is a member of the Gadd gene family (Gadd45a, b and g) which encode small, acidic, nuclear proteins that interact with a number of cell cycle proteins linking DNA damage to cell cycle arrest and apoptosis. [14][15][16][17] Gadd45a is directly activated by the tumor suppressors p53, C/EBPa and Egr-1 and is repressed by c-Myc. 18 Direct mutation or epigenetic modification of the Gadd45a locus has been reported in pancreatic and breast cancers.…”

Section: Introductionmentioning

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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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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“…GADD45␤, is an immediate-early response gene induced by various physiological and environmental stressors, including cytokines and genotoxic stresses (13). Through protein-protein interactions with numerous signal molecules, GADD45␤ can regulate cellular signals for cell cycle, DNA repair, and apoptosis, depending on the types of stimuli and cells that are stimulated (14 -17).…”

mentioning

confidence: 99%

Pregnane X Receptor PXR Activates the GADD45β Gene, Eliciting the p38 MAPK Signal and Cell Migration

Kodama

Negishi

2011

Journal of Biological Chemistry

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Pregnane X receptor (PXR) was originally characterized as a transcription factor that induces hepatic drug metabolism by activating cytochrome P450 genes. Here we have now demonstrated a novel function of PXR, that of eliciting p38 mitogenactivated protein kinase (MAPK) phosphorylation for cell migration. Upon xenobiotic activation of ectopic human PXR, human hepatocellular carcinoma HepG2 cells were found to exhibit increased phosphorylation of p38 MAPK and to subsequently change morphology and migrate. p38 MAPK was responsible for the regulation of these morphological changes and cell migration because the p38 MAPK inhibitor SB239063 repressed both. Prior to this phosphorylation, PXR directly activated the early response GADD45␤ gene by binding to a distal direct repeat 4 site of the GADD45␤ promoter. Ectopic expression of GADD45␤ increased p38 MAPK phosphorylation, whereas siRNA knockdown of GADD45␤ decreased the PXR-induced p38 MAPK phosphorylation, confirming that GADD45␤ can regulate PXR-induced p38 MAPK phosphorylation in HepG2 cells. These results indicate that PXR activates the GADD45␤ gene, increasing p38 MAPK phosphorylation, and leading HepG2 cells to change morphology and migrate. The GADD45␤ gene is a direct target for PXR, eliciting cell signals to regulate various cellular functions.

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Gadd45 in stress signaling

Cited by 188 publications

References 74 publications

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

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

Pregnane X Receptor PXR Activates the GADD45β Gene, Eliciting the p38 MAPK Signal and Cell Migration

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