InteractiveFly: GeneBrief

Gadd45: Biological Overview | References


Gene name - Gadd45

Synonyms -

Cytological map position - 43A2-43A2

Function - signaling

Keywords - JNK pathway, oogenesis, immune response

Symbol - Gadd45

FlyBase ID: FBgn0033153

Genetic map position - 2R:3,136,668..3,137,508 [+]

Classification - Ribosomal protein L7Ae/L30e/S12e/Gadd45 family

Cellular location - nuclear



NCBI link: EntrezGene

Gadd45 orthologs: Biolitmine
Recent literature
Camilleri-Robles, C., Serras, F. and Corominas, M. (2019). Role of D-GADD45 in JNK-dependent apoptosis and regeneration in Drosophila. Genes (Basel) 10(5). PubMed ID: 31109086
Summary:
The GADD45 proteins are induced in response to stress and have been implicated in the regulation of several cellular functions, including DNA repair, cell cycle control, senescence, and apoptosis. This study investigated the role of D-GADD45 during Drosophila development and regeneration of the wing imaginal discs. Higher expression of D-GADD45 was found to result in JNK-dependent apoptosis, while its temporary expression does not have harmful effects. Moreover, D-GADD45 is required for proper regeneration of wing imaginal discs. These findings demonstrate that a tight regulation of D-GADD45 levels is required for its correct function both, in development and during the stress response after cell death.
Koval, L., Proshkina, E., Shaposhnikov, M. and Moskalev, A. (2019). The role of DNA repair genes in radiation-induced adaptive response in Drosophila melanogaster is differential and conditional. Biogerontology. PubMed ID: 31624983
Summary:
Studies in human and mammalian cell cultures have shown that induction of DNA repair mechanisms is required for the formation of stimulation effects of low doses of ionizing radiation, named "hormesis". Nevertheless, the role of cellular defense mechanisms in the formation of radiation-induced hormesis at the level of whole organism remains poorly studied. The aim of this work was to investigate the role of genes involved in different mechanisms and stages of DNA repair in radioadaptive response and radiation hormesis by lifespan parameters in Drosophila melanogaster. Genes were studied that control DNA damage sensing (D-Gadd45, Hus1, mnk), nucleotide excision repair (mei-9, mus210, Mus209), base excision repair (Rrp1), DNA double-stranded break repair by homologous recombination (Brca2, spn-B, okr) and non-homologous end joining (Ku80, WRNexo), and the Mus309 gene that participates in several mechanisms of DNA repair. The obtained results demonstrate that in flies with mutations in studied genes radioadaptive response and radiation hormesis are absent or appear to a lesser extent than in wild-type Canton-S flies. Chronic exposure of gamma-radiation in a low dose during pre-imaginal stages of development leads to an increase in expression of the studied DNA repair genes, which is maintained throughout the lifespan of flies. However, the activation of conditional ubiquitous overexpression of DNA repair genes does not induce resistance to an acute exposure to gamma-radiation and reinforces its negative impact.
Weavers, H., Wood, W. and Martin, P. (2019). Injury activates a dynamic cytoprotective network to confer stress resilience and drive repair. Curr Biol 29(22): 3851-3862 PubMed ID: 31668626
Summary:
In healthy individuals, injured tissues rapidly repair themselves following damage. Within a healing skin wound, recruited inflammatory cells release a multitude of bacteriocidal factors, including reactive oxygen species (ROS), to eliminate invading pathogens. Paradoxically, while these highly reactive ROS confer resistance to infection, they are also toxic to host tissues and may ultimately delay repair. Repairing tissues have therefore evolved powerful cytoprotective "resilience" machinery to protect against and tolerate this collateral damage. This study used in vivo time-lapse imaging and genetic manipulation in Drosophila to dissect the molecular and cellular mechanisms that drive tissue resilience to wound-induced stress. A dynamic, cross-regulatory network of stress-activated cytoprotective pathways was identified, linking calcium, JNK, Nrf2, and Gadd45, that act to both "shield" tissues from oxidative damage and promote efficient damage repair. Ectopic activation of these pathways confers stress protection to naive tissue, while their inhibition leads to marked delays in wound closure. Strikingly, the induction of cytoprotection is tightly linked to the pathways that initiate the inflammatory response, suggesting evolution of a fail-safe mechanism for tissue protection each time inflammation is triggered. A better understanding of these resilience mechanisms-their identities and precise spatiotemporal regulation-is of major clinical importance for development of therapeutic interventions for all pathologies linked to oxidative stress, including debilitating chronic non-healing wounds.
BIOLOGICAL OVERVIEW

The mammalian GADD45 (growth arrest and DNA-damage inducible) gene family is composed of three highly homologous small, acidic, nuclear proteins: GADD45α, GADD45β, and GADD45γ. GADD45 proteins are involved in important processes such as regulation of DNA repair, cell cycle control, and apoptosis. Annotation of the Drosophila genome revealed that it contains a single GADD45-like protein (CG11086; D-GADD45). As its mammalian homologs, D-GADD45 is a nuclear protein; however, D-GADD45 expression is not elevated following exposure to genotoxic and nongenotoxic agents in Schneider cells and in adult flies. The D-GADD45 transcript increased following immune response activation, consistent with previous microarray findings. Since upregulation of GADD45 proteins has been characterized as an important cellular response to genotoxic and nongenotoxic agents, the effect of D-GADD45 overexpression on Drosophila development was characterized. Overexpression of D-GADD45 in various tissues led to different phenotypic responses. Specifically, in the somatic follicle cells overexpression caused apoptosis, while overexpression in the germline affected the dorsal-ventral polarity of the eggshell and disrupted the localization of anterior-posterior polarity determinants. This article focused on the role of D-GADD45 overexpression in the germline and it was found that D-GADD45 caused dorsalization of the eggshell. Since mammalian GADD45 proteins are activators of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling pathways, a genetic interaction was tested in Drosophila. It was found that eggshell polarity defects caused by D-GADD45 overexpression are dominantly suppressed by mutations in the JNK pathway, suggesting that the JNK pathway has a novel, D-GADD45-mediated, function in the Drosophila germline (Peretz, 2007).

The GADD45 gene family is composed of three highly homologous (55-58% overall identity at the amino acid level), small, acidic, nuclear proteins: GADD45α, GADD45β (MyD118), and GADD45γ (CR6, cytokine response gene 6). In recent years, evidence has emerged that the proteins encoded by these genes play similar but not identical roles in terminal differentiation and negative growth control, including growth suppression and apoptotic cell death (Azam, 2001; Zhang, 2001; Vairapandi, 2002; Peretz, 2007 and references therein).

One of the well-described responses to genotoxic and nongenotoxic stresses is the rapid upregulation of different GADD45 proteins, which in turn affect cell-cycle regulation, cell survival, and cell death. It has been shown that all the GADD45 proteins mediate cell-cycle regulation through interactions with PCNA (Kelman, 1998; Azam, 2001), the cyclin-dependent kinase inhibitor p21 (Kearsey, 1995), and the Cdk/cyclin B complex (Zhan, 1999; Jin, 2002; Vairapandi, 2002). The potential role of GADD45 proteins in apoptosis emanates from the observation that GADD45 expression is enhanced during apoptosis following induction by a variety of genotoxic agents. Several studies have shown that GADD45 proteins may play a role in apoptosis via activation of the c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK) signaling pathways (Takekawa; 1998; Harkin, 1999). GADD45 proteins physically interact with the MAPKKK, MTK1 (synonym MEKK4), and the ensuing interactions result in the activation of MTK1. Activated MTK1 is thought to further activate its downstream targets JNK and p38 (Takekawa, 1998). It was shown that the N-terminal of MTK1 auto-inactivates its kinase activity and binding of GADD45 proteins to MTK1 relieves this inhibition (Mita, 2002; Miyake, 2007). It has been proposed that in response to genotoxic stress, p53 is activated, which causes transcriptional upregulation of GADD45α, and GADD45α interacts with MTK1 to initiate the JNK/p38-mediated apoptotic pathway (Peretz, 2007 and references therein).

Several model systems have been used to analyze the role of GADD45 proteins during development. GADD45α-null mice exhibit several phenotypes including genomic instability, increased radiation carcinogenesis, and a low frequency of exencephaly (Hollander, 1999). GADD45γ-deficient mice develop normally and are indistinguishable from their littermates, possibly due to functional redundancy among the GADD45 family members (Hoffeyer, 2001). In the fish, Oryzias latipes, ectopic expression of GADD45γ leads to cell cycle arrest without inducing apoptosis. Loss of function of GADD45γ causes a significant increase in apoptosis, suggesting that GADD45γ is an important component of the molecular pathway that coordinates cell cycle vs. apoptosis decisions during vertebrate development (Candal, 2004). The zebrafish GADD45β genes were found to be periodically expressed as paired stripes in the anterior presomitic mesoderm. Both knockdown and overexpression of GADD45β genes caused somite defects with different consequences for marker gene expression, indicating that the regulated expression of GADD45β genes is required for somite segmentation (Kawahara, 2005). The possible functional redundancy among the GADD45 proteins in these model systems makes the analysis of the molecular function of GADD45 difficult. Annotation of the Drosophila genome revealed that it contains only one GADD45-like protein (Peretz, 2007).

Since upregulation of GADD45 proteins may affect cell cycle regulation, cell survival, and cell death, the effect was studied of D-GADD45 overexpression on D. melanogaster oogenesis. Overexpression of D-GADD45 in the somatic follicle cells led to apoptosis of the entire egg chamber. In contrast, overexpression of D-GADD45 in the germline did not cause apoptosis but affected the dorsal-ventral polarity of the eggshell. Moreover, D-GADD45 also affected anterior-posterior polarity determinants. However, anterior oocyte nuclear migration and bcd localization were unaffected. Finally, it was found that mutations in the MAPK-JNK pathway dominantly suppressed the egg asymmetric defects in D-GADD45 overexpression ovaries, suggesting a novel, D-GADD45-mediated function for the JNK pathway in the germline (Peretz, 2007).

In Drosophila D-GADD45 preserves the nuclear localization property, but unlike its mammalian homologs its expression is not elevated following exposure to different stress stimuli. This result is supported by the Drosophila whole genome microarray analysis which did not identify D-GADD45 as a gene whose expression is increased following various genotoxic and nongenotoxic treatments. Although a number of stress treatments were tried, it is possible that D-GADD45 expression would rise only following exposure to as yet untested stressful conditions (Peretz, 2007).

D-GADD45 was identified as a gene whose expression is induced following microbial infection (De Gregorio, 2001). It was also shown that D-GADD45 expression may be regulated by the NF-BkappaB-like transcription factor, Dorsal, which has an optimal binding site 3 kb upstream to D-GADD45 transcription start site. These results are consistent with those found by De Gregorio (2001) and further strengthen a possible function for D-GADD45 in the immune response. Given that Drosophila is devoid of an adaptive immune system and relies only on innate immune reactions for its defense, D-GADD45 may play an important role during infection (Peretz, 2007).

Ubiquitous overexpression of D-GADD45 was lethal, most likely due to apoptosis, as was directly demonstrated in the follicle cells. However, the results suggest that apoptosis induced by overexpression of D-GADD45 is tissue specific since overexpression of D-GADD45 in other somatic tissues, such as the eye and wing, did not lead to apoptosis. Also, overexpression in the germline did not cause cell death; rather, it affected egg chamber asymmetric development. The apparent phenotypic differences in overexpression of D-GADD45 in the germline as opposed to somatic derived tissues probably reflect the complexity of the biological functions of GADD45, which may be subject to tissue- and/or signal-specific regulation that ultimately dictate their output. Similarly, it has been shown that individual members of the GADD45 family play critical roles in negative growth control in some tissues while in others they are associated with uncontrolled cell growth and tumor development. GADD45α was identified as an important mediator of tumor suppression in human ovarian cancer cells (Jiang, 2003). While in pancreatic ductal adenocarcinoma GADD45α was found to be overexpressed at the mRNA and protein level. Downregulation of GADD45α by means of RNAi reduced proliferation and induced apoptosis in pancreatic cancer cells implying that GADD45α contributes to pancreatic cancer cell proliferation and viability (Schneider, 2006; Peretz, 2007).

Overexpression of D-GADD45 in the germline results in dorsalization of the chorion due to defects in grk localization and translation. The posterior markers osk and Kin:β-gal were mislocalized during mid-oogenesis. In contrast, D-GADD45 overexpression does not affect the localization of anterior end markers such as bcd and Nod:β-gal and also the anterior oocyte nuclear migration is unaffected. Similar results have reported in mutants of squid (sqd) which encodes a heterogeneous nuclear ribonucleoprotein (hnRNP). In these mutants grk mRNA is mislocalized along the anterior ring, leading to dorsalization of the eggshell. Furthermore, loss of sqd function causes an aberrant localization of osk and Kin:β-gal, but does not affect bcd localization and oocyte nucleus migration. It was shown that in sqd mutant oocytes short microtubules (MTs) around the entire oocyte cortex are retained, including at the posterior pole, unlike wild-type MTs which emanate mostly from the anterior. It has been suggested that the primary MT defect in sqd mutants is the failure to eliminate cortical sites of MT nucleation beyond stage 7. It is possible that D-GADD45 overexpression also affects MT organization in the oocyte. This possibility is further supported by the finding that GADD45α interacts with elongation factor 1α (EF-1α), a microtubule-severing protein that plays an important role in maintaining microtubule cytoskeletal stability (Tong, 2005). To test whether D-GADD45 affects MT organization, the ovaries were stained with anti-tubulin. Using this tool, no gross morphological changes were detected in the MT network. Given that the patterning defect seen in D-GADD45 overexpression is weaker than that in sqd mutants, it could be that this kind of staining is not sensitive enough to identify the MT network alterations in D-GADD45 overexpression flies (Peretz, 2007).

A genetic interaction was found between D-GADD45 and proteins of the MAPK-JNK pathway. Mutations in the JNKK, hemipterous, dominantly suppres the dorsalized eggshell phenotype. This genetic interaction is supported by the finding that in human cells GADD45 proteins act as initiators of JNK/p38 signaling via their interaction with the MAPKKK, MTK1 (Takekawa, 1998). It was shown that the N-terminal of MTK1 inhibits its C-terminal kinase domain by preventing the kinase domain from interacting with its substrate, MKK6, and binding of GADD45 proteins relieves this auto-inhibition (Mita, 2002; Miyake, 2007; Peretz, 2007).

Up until now the only roles attributed to the JNK pathway during oogenesis were in the follicle cells and included morphogenesis of the dorsal appendages and the micropyle (Suzanne, 2001). It was also reported that the JNK pathway is involved in the morphogenetic process of dorsal closure during embryogenesis. Surprisingly, it was found that eggshell patterning defects caused by D-GADD45 overexpression are dominantly suppressed in a hep deficient background suggesting an additional role for the JNK pathway in the germline. This novel function may have gone unnoticed in the past while studying JNK loss-of-function alleles due to redundancy with some other pathway. In this study, overexpression of the JNK activator, D-GADD45, may have unmasked this new role during oogenesis (Peretz, 2007).

Gene induction following wounding of wild-type versus macrophage-deficient Drosophila embryos.

By using a microarray screen to compare gene responses after sterile laser wounding of wild-type and 'macrophageless' serpent mutant Drosophila embryos, this study showed wound-induced programs that were independent of a pathogenic response, and macrophage dependent genes were distinguished. The evolutionarily conserved nature of this response is highlighted by the finding that one such new inflammation-associated gene, growth arrest and DNA damage-inducible gene 45 (GADD45), is upregulated in both Drosophila and murine repair models. Comparison of unwounded wild-type and serpent mutant embryos also shows a portfolio of 'macrophage-specific' genes, which suggest analogous functions with vertebrate inflammatory cells. Besides identifying the various classes of wound- and macrophage-related genes, these data indicate that sterile injury per se, in the absence of pathogens, triggers induction of a 'pathogen response', which might prime the organism for what is likely to be an increased risk of infection (Stramer, 2008).

Drosophila GADD45 is robustly induced by wounding wild-type embryos, and in situ hybridization showed that this gene was strongly inflammation dependent. The data suggest that Drosophila macrophages might secrete signals that are necessary for full GADD45 induction in the wounded epithelium. There is precedent for a paracrine signalling role for haemocytes during an immune response; after septic injury, an unpaired (Upd)-like cytokine is secreted by haemocytes and is necessary for Jak/Stat signalling in the fat body. Although GADD45 is not a known Jak/Stat target, it is responsive to Toll signalling. However, Toll mutants showed a similar epithelial wound induction of GADD45, and expression of an activated form of the Toll ligand, spatzle (spz), in the epithelium of Drosophila embryos failed to induce GADD45 expression, suggesting that GADD45 induction following wounding is Toll independent (Stramer, 2008).

The data suggest that GADD45 is an 'inflammation-associated' wound response gene in insects. To determine whether this response is conserved in mammals, microarray data was analyzed from an analogous experiment in mice comparing the gene profiles of wounds in the presence and absence of an inflammatory response. These data showed that a murine homologue of Drosophila GADD45 was upregulated rapidly after wounding and that this response was much reduced in PU.1 null mice in which inflammatory cells were missing. The expression of GADD45 protein after injury was examined by western blotting, and rapid and transient induction was shown by 1 day after wounding. Furthermore, immunostaining showed that, as in Drosophila, murine GADD45 was induced in the wound epithelium. This finding provided further evidence for an evolutionarily conserved repair response in flies and vertebrates, and highlights how useful Drosophila might be in elucidating new mechanisms regulating various aspects of vertebrate tissue repair (Stramer, 2008).

Injury activates a dynamic cytoprotective network to confer stress resilience and drive repair

In healthy individuals, injured tissues rapidly repair themselves following damage. Within a healing skin wound, recruited inflammatory cells release a multitude of bacteriocidal factors, including reactive oxygen species (ROS), to eliminate invading pathogens. Paradoxically, while these highly reactive ROS confer resistance to infection, they are also toxic to host tissues and may ultimately delay repair. Repairing tissues have therefore evolved powerful cytoprotective 'resilience' machinery to protect against and tolerate this collateral damage. This study used in vivo time-lapse imaging and genetic manipulation in Drosophila to dissect the molecular and cellular mechanisms that drive tissue resilience to wound-induced stress. This study identified a dynamic, cross-regulatory network of stress-activated cytoprotective pathways, linking calcium, JNK, Nrf2, and Gadd45, that act to both 'shield' tissues from oxidative damage and promote efficient damage repair. Ectopic activation of these pathways confers stress protection to naive tissue, while their inhibition leads to marked delays in wound closure. Strikingly, the induction of cytoprotection is tightly linked to the pathways that initiate the inflammatory response, suggesting evolution of a fail-safe mechanism for tissue protection each time inflammation is triggered. A better understanding of these resilience mechanisms-their identities and precise spatiotemporal regulation-is of major clinical importance for development of therapeutic interventions for all pathologies linked to oxidative stress, including debilitating chronic non-healing wounds (Weavers, 2019).

Reactive oxygen species (ROS) are universal injury-induced signals, produced by NADPH oxidases as an immediate response to tissue damage. At low levels, ROS can function as attractants for the recruitment of innate immune cells and to promote efficient wound angiogenesis; however, incoming inflammatory cells generate additional ROS in a 'respiratory burst' to eliminate invading pathogens and confer resistance to infection. Although this bacteriocidal response is clearly beneficial, excessive ROS levels can cause substantial bystander damage to host tissue; indeed, excessive oxidative stress is thought to be a key player in the pathogenesis of chronic non-healing wounds of patients in the clinic (Weavers, 2019).

To counter inflammatory stress, host tissues must employ powerful cytoprotective machinery to limit the 'collateral' damage and prevent immunopathology. Mammalian wound studies have identified a number of signaling pathways that may promote protection against oxidative stress, but such investigations have been complicated by the intricacy of the protection machinery and relative genetic intractability of vertebrate models. Nevertheless, a better understanding of these protective mechanisms will be crucial to enable the development of improved therapeutic interventions for a wide range of oxidative stress-related diseases, including chronic non-healing wounds. Also in the context of wound repair, therapeutic activation of cytoprotective pathways in the clinic could also offer an exciting approach to 'precondition' patient tissues prior to elective surgery (Weavers, 2019).

This study has characterized the temporal and spatial dynamics of the stress 'resilience' mechanisms that are induced downstream of wounding and dissect the underlying molecular and cellular mechanisms driving tissue protection. A complex cross-regulatory network of cytoprotective pathways were identified, involving calcium, JNK, Nrf2, and Gadd45, which collectively 'shield' tissues from ROS-induced damage and promote efficient damage repair. RNAi-mediated inhibition of either Nrf2 or Gadd45 delays wound repair, which is further exacerbated if both pathways are inhibited. Interestingly, it was found that these cytoprotective pathways are activated downstream of the same calcium signaling pathway that initiates the inflammatory response, suggesting the existence of a 'fail-safe' mechanism for cytoprotection whenever inflammation is triggered. Finally, ectopic activation of these protective pathways can confer stress resilience to naive unwounded tissue, and in the case of Gadd45, can even accelerate the rate of wound repair. Prolonged activation of Nrf2, however, caused marked delays in wound repair, suggesting that the optimal level of cytoprotection required for the most efficient tissue repair will be a finely tuned spatiotemporal balance of cytoprotective signaling (Weavers, 2019).

Until now, research on cytoprotective factors in wound repair has mainly focused on how antioxidant systems directly minimize ROS-induced damage following injury. However, tissues will undoubtedly have evolved a diverse range of 'resilience' mechanisms acting on different cellular targets and working in a highly coordinated manner to collectively reduce damage. This study shows that injury activates a cytoprotective signaling network that targets multiple different components to protect the repairing epithelial tissue, including both the upregulation of antioxidant defense machinery and DNA repair mechanisms. In this way, tissue resilience mechanisms can both shield the tissue from damage by directly dampening ROS levels and enhance DNA repair mechanisms (thus making wounded tissues more tolerant to any DNA damage caused by residual ROS). The presence of multiple, partially redundant protective mechanisms ensures effective resilience and thus minimizes delays in tissue repair; indeed, this study found that simultaneous knockdown of Nrf2 and Gadd45 exaggerates wound repair defects compared to individual knockouts alone (Weavers, 2019).

Since both Nrf2 and Gadd45α are upregulated within mammalian skin wounds, similar networks of wound-induced resilience mechanisms are likely to be well conserved from flies to man. Drosophila, with its advanced genetic tractability, capacity for live-imaging, and opportunity for large-scale genetic screening, thus offers an exciting new model for dissecting the mechanisms governing tissue resilience to stress, particularly those during wound repair. These studies may also have important implications for cancer therapy, as cancer cells could hijack this resilience machinery to protect the tumor from host immune attack, as well as confer resistance to clinical therapies such as chemo- or radio-therapy. Indeed, it is known that Gadd45α deficiency sensitizes epithelial cancer cells to ionizing radiation in vivo, implicating cytoprotective genes such as Gadd45a as potential drug targets in management of cancer radiotherapy treatments (Weavers, 2019).

For nearly 30 years, experimental biologists and clinicians have observed the remarkable but mysterious phenomenon of 'preconditioning,' whereby a brief period of sub-lethal tissue damage triggers adaptive mechanisms that confer subsequent cytoprotection against further insult, either within the same tissue or more remotely. Indeed, recent work in zebrafish has shown that superficial insult (via thoracotomy) preconditions adjacent cardiac tissue and renders it more resilient to subsequent cryoinjury (modeling an infarct) by upregulation of cardioprotective factors. Remarkably, activation of cardioprotective signaling by injection of exogenous ciliary neurotrophic factor just prior to ventricular cryoinjury had beneficial regenerative effects and rendered the heart more resilient to injury. In this regard, therapeutic activation of some or all of these resilience pathways could offer exciting 'pre-conditioning' strategies in the clinic to protect patient tissues during surgery or following organ transplant (Weavers, 2019).

A better understanding of resilience pathways and their long-term effects (including an analysis of 'cost') is clearly crucial for their full application in a clinical setting, given that excessive and long-term activation of resilience machinery could potentially have adverse effects. Indeed, while this study found that ectopic expression of Gadd45 prior to wounding could accelerate wound repair, long-term overexpression of dNrf2 within the epithelium caused marked delays in wound closure. Previous work suggests that prolonged Nrf2 activation may make cells less 'competitive' than their neighbors and can also induce certain skin defects (such as hyperkeratosis) and fibroblast senescence. Given the role for wound-induced ROS in inflammatory cell recruitment and angiogenesis, it is envisioned that achieving an optimal transient and balanced activation of this endogenous resilience machinery will be the key to unlocking its enormous therapeutic benefits, conferring valuable stress resilience without reaching levels that might otherwise be detrimental to repair or later tissue health (Weavers, 2019).


REFERENCES

Search PubMed for articles about Drosophila Gadd45

Azam, N., et al. (2001). Interaction of CR6 (GADD45) with proliferating cell nuclear antigen impedes negative growth control. J. Biol. Chem. 276: 2766-2774. PubMed ID: 11022036

Candal, E., et al. (2004). Medaka as a model system for the characterisation of cell cycle regulators: a functional analysis of Ol-Gadd45 during early embryogenesis. Mech. Dev. 121: 945-958. PubMed ID: 15210198

De Gregorio, E., et al. (2001). Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proc. Natl. Acad. Sci. USA 98(22): 12590-12595. PubMed ID: 11606746

Harkin, D. P., et al. (1999). Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97(5): 575-86. PubMed ID: 10367887

Hoffeyer, A., et al. (2001). Gadd45gamma is dispensable for normal mouse development and T-cell proliferation. Mol. Cell. Biol. 9: 3137-3143. PubMed ID: 11287618

Hollander, M. C., et al. (1999). Genomic instability in Gadd45a-deficient mice. Nat. Genet. 23: 176-184. PubMed ID: 10508513

Jiang, F., et al. (2003). G2/M arrest by 1,25-dihydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J. Biol. Chem. 278: 48030-48040. PubMed ID: 14506229

Jin, S., et al. (2002). GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene 21(57): 8696-704. PubMed ID: 12483522

Kawahara, A., et al. (2005). Zebrafish GADD45β genes are involved in somite segmentation. Proc. Natl. Acad. Sci. USA 102(2): 361-366. PubMed ID: 15623554

Kelman, Z., and Hurwitz, J. (1998). Protein-PCNA interactions: a DNA-scanning mechanism? Trends Biochem. Sci. 23: 236-238. PubMed ID: 9697409

Kearsey, J. M., et al. (1995). Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 11(9): 1675-83. PubMed ID: 7478594

Mita, H., et al. (2002). Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol. Cell. Biol. 22: 4544-4555. PubMed ID: 12052864

Miyake, Z., et al. (2007). Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol. Cell. Biol. 27(7): 2765-2776. PubMed ID: 17242196

Peretz, G., Bakhrat, A. and Abdu, U. (2007). Expression of the Drosophila melanogaster GADD45 homolog (CG11086) affects egg asymmetric development that is mediated by the c-Jun N-terminal kinase pathway. Genetics 177(3): 1691-702. PubMed ID: 18039880

Schneider, G., et al. (2006). GADD45a is highly expressed in pancreatic ductal adenocarcinoma cells and required for tumor cell viability. Int. J. Cancer 118: 2405-2411. PubMed ID: 16353139

Stramer, B., et al. (2008). Gene induction following wounding of wild-type versus macrophage-deficient Drosophila embryos. EMBO Rep. [Epub ahead of print]. PubMed ID: 18344972

Suzanne, M., Perrimon, N. and Noselli, S. (2001). The Drosophila JNK pathway controls the morphogenesis of the egg dorsal appendages and micropyle. Dev. Biol. 237: 282-294. PubMed ID: 11543614

Takekawa, M., and Saito, H. (1998). A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521-530. PubMed ID: 9827804

Tong, T., et al. (2005). Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria. Mol. Cell. Biol. 25(11): 4488-4500. PubMed ID: 15899854

Vairapandi, M., et al. (2002). GADD45β and GADD45β are cdc2/CyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J. Cell. Physiol. 192: 327-338. PubMed ID: 12124778

Weavers, H., Wood, W. and Martin, P. (2019). Injury activates a dynamic cytoprotective network to confer stress resilience and drive repair. Curr Biol. PubMed ID: 31668626

Zhan, Q., et al. (1999). Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18: 2892-2900. PubMed ID: 10362260

Zhang, W., Hoffman, B. and Liebermann, D. A. (2001). Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis. Int. J. Oncol. 18: 749-757. PubMed ID: 11251170


Biological Overview

date revised: 3 January 2020

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