Myeloid Differentiation (MyD)/Growth Arrest DNA Damage (GADD) genes in tumor suppression, immunity and inflammation

Liebermann, Dan A.; Hoffman, Barbara

doi:10.1038/sj.leu.2402477

Cited by 78 publications

(52 citation statements)

References 202 publications

(214 reference statements)

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“…As the Per2 gene is regulated by Clock, it is possible that the expression of this protein might be involved in DNA damage-induced apoptosis. The analysis of the expression profile showed that several DNA damage-inducible genes such as members of the growth-arrest and DNA damage (GADD) family that block cell-cycle progression (Liebermann and Hoffman, 2002) and cyclin genes were controlled by circadian regulators (Fu et al, 2002). Taken together, these results indicate that the cell cycle-regulating mechanism in cisplatin-resistant cells is regulated by Clock.…”

Section: Discussionmentioning

confidence: 91%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

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Section: Discussionmentioning

confidence: 91%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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“…We also suggest that mitochondrial ROS and CHOP-10/GADD153 belong to the intracellular O 2 sensing mechanism of adipose cells. This signaling pathway could be involved in limiting growth of adipose tissue as described in other tissues (32,33). Moreover, ROS generation linked to mitochondrial dysfunction could be directly involved in adipose tissues alterations associated with metabolic disorders (34).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Reactive Oxygen Species Control the Transcription Factor CHOP-10/GADD153 and Adipocyte Differentiation

Carrière

Carmona

Fernandez

et al. 2004

Journal of Biological Chemistry

215

146

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Recent reports emphasize the importance of mitochondria in white adipose tissue biology. In addition to their crucial role in energy homeostasis, mitochondria are the main site of reactive oxygen species generation. When moderately produced, they function as physiological signaling molecules. Thus, mitochondrial reactive oxygen species trigger hypoxia-dependent gene expression. Therefore the present study tested the implication of mitochondrial reactive oxygen species in adipocyte differentiation and their putative role in the hypoxiadependent effect on this differentiation. Pharmacological manipulations of mitochondrial reactive oxygen species generation demonstrate a very strong and negative correlation between changes in mitochondrial reactive oxygen species and adipocyte differentiation of 3T3-F442A preadipocytes. Moreover, mitochondrial reactive oxygen species positively and specifically control expression of the adipogenic repressor CHOP-10/ GADD153. Hypoxia (1% O 2 ) strongly increased reactive oxygen species generation, hypoxia-inducible factor-1 and CHOP-10/GADD153 expression, and inhibited adipocyte differentiation. All of these hypoxia-dependent effects were partly prevented by antioxidants. By using hypoxia-inducible factor-1␣ (HIF-1␣)-deficient mouse embryonic fibroblasts, HIF-1␣ was shown not to be required for hypoxia-mediated CHOP-10/GADD153 induction. Moreover, the comparison of hypoxia and CoCl 2 effects on adipocyte differentiation of wild type or HIF-1␣ deficient mouse embryonic fibroblasts suggests the existence of at least two pathways dependent or not on the presence of HIF-1␣. Together, these data demonstrate that mitochondrial reactive oxygen species control CHOP-10/GADD153 expression, are antiadipogenic signaling molecules, and trigger hypoxia-dependent inhibition of adipocyte differentiation.White adipose tissue is the main energy store in adult mammals and displays great plasticity according to the energy needs of the organism. Adipocyte differentiation results from a subtle balance of sequential and interdependent transcription factors expression that activate or inhibit promoters of adipogenic genes.

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“…The GADD45 proteins share 55 to 58% sequence identity. The three GADD45 genes are all inducible by cellular stresses, although optimal stimuli for each gene appear to be different (25). The expression profiles of the three GADD45 genes are also distinct in various tissues (34).…”

mentioning

confidence: 99%

“…The GADD45 gene was originally identified as a UV-inducible gene in Chinese hamster cells (14). The human genome encodes three GADD45-like proteins, GADD45␣ (the original GADD45), GADD45␤ (MyD118), and GADD45␥ (CR6 or OIG37) (25,44). These will be referred to collectively as the GADD45 proteins.…”

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confidence: 99%

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Activation of MTK1/MEKK4 by GADD45 through Induced N-C Dissociation and Dimerization-Mediated trans Autophosphorylation of the MTK1 Kinase Domain

Miyake

Takekawa

et al. 2007

Molecular and Cellular Biology

100

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The mitogen-activated protein kinase (MAPK) module, composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK), is a cellular signaling device that is conserved throughout the eukaryotic world. In mammalian cells, various extracellular stresses activate two major subfamilies of MAPKs, namely, the Jun N-terminal kinases and the p38/stress-activated MAPK (SAPK). MTK1 (also called MEKK4) is a stress-responsive MAPKKK that is bound to and activated by the stress-inducible GADD45 family of proteins (GADD45␣/␤/␥). Here, we dissected the molecular mechanism of MTK1 activation by GADD45 proteins. The MTK1 N terminus bound to its C-terminal segment, thereby inhibiting the C-terminal kinase domain. This N-C interaction was disrupted by the binding of GADD45 to the MTK1 N-terminal GADD45-binding site. GADD45 binding also induced MTK1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of MTK1 at Thr-1493 in the kinase activation loop. An MTK1 alanine substitution mutant at Thr-1493 has a severely reduced activity. Thus, we conclude that GADD45 binding induces MTK1 N-C dissociation, dimerization, and autophosphorylation at Thr-1493, leading to the activation of the kinase catalytic domain. Constitutively active MTK1 mutants induced the same events, but in the absence of GADD45.

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Myeloid Differentiation (MyD)/Growth Arrest DNA Damage (GADD) genes in tumor suppression, immunity and inflammation

Cited by 78 publications

References 202 publications

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

Mitochondrial Reactive Oxygen Species Control the Transcription Factor CHOP-10/GADD153 and Adipocyte Differentiation

Activation of MTK1/MEKK4 by GADD45 through Induced N-C Dissociation and Dimerization-Mediated trans Autophosphorylation of the MTK1 Kinase Domain

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