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GADD45

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GADD45 Family Members and Synonyms

Cytokine responsive 6 (CR6); DDIT1 (DNA-damage inducible transcript 1); GADD45A: GADD45α; GADD45B: GADD45β; GADD45G: Gadd45γ; Myd118

Historical Background

The first GADD45 gene, now referred to as GADD45A, was originally isolated from Chinese hamster CHO-K1 cells in 1988 as a subset of transcripts that were consistently upregulated after exposure to ultraviolet (UV) radiation and several other DNA-damaging agents, including the alkylating agent methyl methane sulfonate (MMS), hydrogen peroxide, and N-acetoxy-2-acetylaminofluorene (Fornace et al. 1988). They were also found to be induced by other growth cessation signals, such as medium depletion (starvation) or hydroxyurea. This subgroup of transcripts was termed gadd, for growth arrest and DNA damage inducible (Fornace et al. 1989). GADD45A, as well as another gadd gene GADD153 (CHOP, DDIT3), was particularly interesting in that it could be induced in an ATM-dependent and protein kinase...

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References

  • Amanullah A, Azam N, Balliet A, Hollander C, Hoffman B, Fornace A, et al. Cell signalling: cell survival and a Gadd45-factor deficiency. Nature. 2003;424:741. discussion 742

    Article  PubMed  CAS  Google Scholar 

  • Arab K, Park YJ, Lindroth AM, Schäfer A, Oakes C, Weichenhan D, et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell. 2014;55:604–14.

    Article  PubMed  CAS  Google Scholar 

  • Barreto G, Schäfer A, Marhold J, Stach D, Swaminathan SK, Handa V, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007;445:671–5.

    Article  PubMed  CAS  Google Scholar 

  • Brown J, Bothma H, Veale R, Willem P. Genomic imbalances in esophageal carcinoma cell lines involve Wnt pathway genes. World J Gastroenterol. 2011;17:2909–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bulavin DV, Kovalsky O, Hollander MC, Fornace AJJ. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Mol Cell Biol. 2003;23:3859–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cantone I, Fisher AG. Epigenetic programming and reprogramming during development. Nat Struct Mol Biol. 2013;20:282–9.

    Article  PubMed  CAS  Google Scholar 

  • Carrier F, Georgel PT, Pourquier P, Blake M, Kontny HU, Antinore MJ, et al. Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol Cell Biol. 1999;19:1673–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen H, Fan J, Shou Q, Zhang L, Ma H, Fan Y. Hypermethylation of glucocorticoid receptor gene promoter results in glucocorticoid receptor gene low expression in peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Rheumatol Int. 2015;35:1335–42.

    Article  PubMed  CAS  Google Scholar 

  • Chi H, Lu B, Takekawa M, Davis RJ, Flavell RA. GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. EMBO J. 2004;23:1576–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chiou HY, Liu SY, Lin CH, Lee EH. Hes-1 SUMOylation by protein inhibitor of activated STAT1 enhances the suppressing effect of Hes-1 on GADD45α expression to increase cell survival. J Biomed Sci. 2014;21:53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cho HJ, Park SM, Hwang EM, Baek KE, Kim IK, Nam IK, et al. Gadd45b mediates Fas-induced apoptosis by enhancing the interaction between p38 and retinoblastoma tumor suppressor. J Biol Chem. 2010;285:25500–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011;146:67–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cretu A, Sha X, Tront J, Hoffman B, Liebermann DA. Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer Ther. 2009;7:268–76.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Duan MR, Smerdon MJ. UV damage in DNA promotes nucleosome unwrapping. J Biol Chem. 2010;285:26295–303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Engel N, Tront JS, Erinle T, Nguyen N, Latham KE, Sapienza C, et al. Conserved DNA methylation in Gadd45a(-/-) mice. Epigenetics. 2009;4:98–9.

    Article  PubMed  CAS  Google Scholar 

  • Fornace AJ, Alamo I, Hollander MC. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci U S A. 1988;85:8800–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fornace AJJ, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J, et al. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989;9:4196–203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Frau M, Simile MM, Tomasi ML, Demartis MI, Daino L, Seddaiu MA, et al. An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis. Cell Oncol (Dordr). 2012;35:163–73.

    Article  CAS  Google Scholar 

  • Gao M, Guo N, Huang C, Song L. Diverse roles of GADD45alpha in stress signaling. Curr Protein Pept Sci. 2009;10:388–94.

    Article  PubMed  CAS  Google Scholar 

  • Gao M, Li X, Dong W, Jin R, Ma H, Yang P, et al. Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation. Nucleic Acids Res. 2013;41:5210–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gonzalez-Martin A, Adams BD, Lai M, Shepherd J, Salvador-Bernaldez M, Salvador JM, et al. The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat Immunol. 2016;17:433–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo W, Zhu T, Dong Z, Cui L, Zhang M, Kuang G. Decreased expression and aberrant methylation of Gadd45G is associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma. Clin Exp Metastasis. 2013;30:977–92.

    Article  PubMed  CAS  Google Scholar 

  • Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, et al. Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res. 2002;62:7305–15.

    PubMed  CAS  Google Scholar 

  • Hollander MC, Fornace AJ. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a. Oncogene. 2002;21:6228–33.

    Article  PubMed  CAS  Google Scholar 

  • Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI, et al. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci U S A. 2005;102:13200–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ishiguro H, Kimura M, Takahashi H, Tanaka T, Mizoguchi K, Takeyama H. GADD45A expression is correlated with patient prognosis in esophageal cancer. Oncol Lett. 2016;11:277–82.

    Article  PubMed  CAS  Google Scholar 

  • Jackson JG, Pereira-Smith OM. p53 is referentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res. 2006;66:8356–60.

    Article  PubMed  CAS  Google Scholar 

  • Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert S, Albrecht S, et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res. 2011;17:4650–60.

    Article  PubMed  CAS  Google Scholar 

  • Jarome TJ, Butler AA, Nichols JN, Pacheco NL, Lubin FD. NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation. Front Mol Neurosci. 2015;8:54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jinawath N, Vasoontara C, Yap KL, Thiaville MM, Nakayama K, Wang TL, et al. NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. Oncogene. 2009;28:1941–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jirmanova L, Jankovic D, Fornace AJJ, Ashwell JD. Gadd45alpha regulates p38-dependent dendritic cell cytokine production and Th1 differentiation. J Immunol. 2007;178:4153–8.

    Article  PubMed  CAS  Google Scholar 

  • Johnson D, Hastwell PW, Walmsley RM. The involvement of WT1 in the regulation of GADD45a in response to genotoxic stress. Mutagenesis. 2013;28:393–9.

    Article  PubMed  CAS  Google Scholar 

  • Ju S, Zhu Y, Liu L, Dai S, Li C, Chen E, et al. Gadd45b and Gadd45g are important for anti-tumor immune responses. Eur J Immunol. 2009;39:3010–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Karger S, Weidinger C, Krause K, Sheu SY, Aigner T, Gimm O, et al. FOXO3a: a novel player in thyroid carcinogenesis? Endocr Relat Cancer. 2009;16:189–99.

    Article  PubMed  CAS  Google Scholar 

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71:587–97.

    Article  PubMed  CAS  Google Scholar 

  • Kearsey JM, Coates PJ, Prescott AR, Warbrick E, Hall PA. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene. 1995;11:1675–83.

    PubMed  CAS  Google Scholar 

  • Kim HL, Kim SU, Seo YR. A novel role for Gadd45α in base excision repair: modulation of APE1 activity by the direct interaction of Gadd45α with PCNA. Biochem Biophys Res Commun. 2013;434:185–90.

    Article  PubMed  CAS  Google Scholar 

  • Kodama S, Negishi M. Pregnane X receptor PXR activates the GADD45beta gene, eliciting the p38 MAPK signal and cell migration. J Biol Chem. 2011;286:3570–8.

    Article  PubMed  CAS  Google Scholar 

  • Lei W, Luo Y, Lei W, Luo Y, Yan K, Zhao S, et al. Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand J Rheumatol. 2009;38:369–74.

    Article  PubMed  CAS  Google Scholar 

  • Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature. 2000;406:210–5.

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Zhao M, Yin H, Gao F, Wu X, Luo Y, et al. Overexpression of the growth arrest and DNA damage-induced 45alpha gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis Rheum. 2010;62:1438–47.

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Gu TP, Weber AR, Shen JZ, Li BZ, Xie ZG, et al. Gadd45a promotes DNA demethylation through TDG. Nucleic Acids Res. 2015;43:3986–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lin CR, Yang CH, Huang CE, Wu CH, Chen YS, Sheen-Chen SM, et al. GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury. J Neurosci Res. 2011;89:689–99.

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Suyeoka G, Papa S, Franzoso G, Neufeld AH. Growth arrest and DNA damage protein 45b (Gadd45b) protects retinal ganglion cells from injuries. Neurobiol Dis. 2009;33:104–10.

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Zhang YH, Jiang Y, Li LL, Chen Q, He GQ, et al. Gadd45b is a novel mediator of neuronal apoptosis in ischemic stroke. Int J Biol Sci. 2015;11:353–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu CC, Ou TT, Wu CC, Li RN, Lin YC, Lin CH, et al. Global DNA methylation, DNMT1, and MBD2 in patients with systemic lupus erythematosus. Lupus. 2011;20:131–6.

    Article  PubMed  CAS  Google Scholar 

  • Lo Nigro C, Monteverde M, Riba M, Lattanzio L, Tonissi F, Garrone O, et al. Expression profiling and long lasting responses to chemotherapy in metastatic gastric cancer. Int J Oncol. 2010;37:1219–28.

    Article  PubMed  CAS  Google Scholar 

  • Lu B. The molecular mechanisms that control function and death of effector CD4+ T cells. Immunol Res. 2006;36:275–82.

    Article  PubMed  CAS  Google Scholar 

  • Lu Q, Shen N, Li XM, Chen SL. Genomic view of IFN-alpha response in pre-autoimmune NZB/W and MRL/lpr mice. Genes Immun. 2007;8:590–603.

    Article  PubMed  CAS  Google Scholar 

  • Lucas A, Mialet-Perez J, Daviaud D, Parini A, Marber MS, Sicard P. Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling. Cardiovasc Res. 2015;108:254–67.

    Article  PubMed  CAS  Google Scholar 

  • Luo Y, Boyle DL, Hammaker D, Edgar M, Franzoso G, Firestein GS. Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice. Arthritis Rheum. 2011;63:2949–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009;323:1074–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maekawa T, Sano Y, Shinagawa T, Rahman Z, Sakuma T, Nomura S, et al. ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors. Oncogene. 2008;27:1045–54.

    Article  PubMed  CAS  Google Scholar 

  • Mitra S, Sammani S, Wang T, Boone DL, Meyer NJ, Dudek SM, et al. Role of growth arrest and DNA damage-inducible α in Akt phosphorylation and ubiquitination after mechanical stress-induced vascular injury. Am J Respir Crit Care Med. 2011;184:1030–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Na YK, Lee SM, Hong HS, Kim JB, Park JY, Kim DS. Hypermethylation of growth arrest DNA-damage-inducible gene 45 in non-small cell lung cancer and its relationship with clinicopathologic features. Mol Cell. 2010;30:89–92.

    Article  CAS  Google Scholar 

  • Ou DL, Shyue SK, Lin LI, Feng ZR, Liou JY, Fan HH, et al. Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma. Oncotarget. 2015;6:27953–65.

    PubMed  PubMed Central  Google Scholar 

  • Papa S, Monti SM, Vitale RM, Bubici C, Jayawardena S, Alvarez K, et al. Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. J Biol Chem. 2007;282:19029–41.

    Article  PubMed  CAS  Google Scholar 

  • Papa S, Zazzeroni F, Fu YX, Bubici C, Alvarez K, Dean K, et al. Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J Clin Invest. 2008;118:1911–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Park MA, Seok YJ, Jeong G, Lee JS. SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy. Nucleic Acids Res. 2008;36:263–83.

    Article  PubMed  CAS  Google Scholar 

  • Paruthiyil S, Cvoro A, Tagliaferri M, Cohen I, Shtivelman E, Leitman DC. Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast Cancer Res Treat. 2011;129:777–84.

    Article  PubMed  CAS  Google Scholar 

  • Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perugini M, Iarossi DG, Kok CH, Cummings N, Diakiw SM, Brown AL, et al. GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1/2 and DNMT3A mutations. Leukemia. 2013;27(7):1588–92.

    Article  PubMed  CAS  Google Scholar 

  • Qiu W, Zhou B, Zou H, Liu X, Chu PG, Lopez R, et al. Hypermethylation of growth arrest DNA damage-inducible gene 45 beta promoter in human hepatocellular carcinoma. Am J Pathol. 2004;165:1689–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rajput P, Pandey V, Kumar V. Stimulation of ribosomal RNA gene promoter by transcription factor Sp1 involves active DNA demethylation by Gadd45-NER pathway. Biochim Biophys Acta. 2016;1859:953–63.

    Article  PubMed  CAS  Google Scholar 

  • Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, et al. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol Cell. 2010;40:34–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reis IM, Ramachandran K, Speer C, Gordian E, Singal R. Serum GADD45a methylation is a useful biomarker to distinguish benign vs malignant prostate disease. Br J Cancer. 2015;113:460–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sabag O, Zamir A, Keshet I, Hecht M, Ludwig G, Tabib A, et al. Establishment of methylation patterns in ES cells. Nat Struct Mol Biol. 2014;21:110–2.

    Article  PubMed  CAS  Google Scholar 

  • Salerno DM, Tront JS, Hoffman B, Liebermann DA. Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling. J Cell Physiol. 2012;227:3613–20.

    Article  PubMed  CAS  Google Scholar 

  • Salvador JM, Mittelstadt PR, Belova GI, Fornace AJJ, Ashwell JD. The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway. Nat Immunol. 2005;6:396–402.

    Article  PubMed  CAS  Google Scholar 

  • Schäfer A, Karaulanov E, Stapf U, Döderlein G, Niehrs C. Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3. Genes Dev. 2013;27:261–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schmitz KM, Schmitt N, Hoffmann-Rohrer U, Schäfer A, Grummt I, Mayer C. TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation. Mol Cell. 2009;33:344–53.

    Article  PubMed  CAS  Google Scholar 

  • Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature. 2010;463:563–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science. 1994;266:1376–80.

    Article  PubMed  CAS  Google Scholar 

  • Snyder AR, Morgan WF. Gene expression profiling after irradiation: clues to understanding acute and persistent responses. Cancer Metastasis Rev. 2004;23:259–68.

    Article  PubMed  CAS  Google Scholar 

  • Song L, Li J, Hu M, Huang C. Both IKKalpha and IKKbeta are implicated in the arsenite-induced AP-1 transactivation correlating with cell apoptosis through NF-kappaB activity-independent manner. Exp Cell Res. 2008;314:2187–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sultan FA, Wang J, Tront J, Liebermann DA, Sweatt JD. Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. J Neurosci. 2012;32:17059–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Svensson CI, Inoue T, Hammaker D, Fukushima A, Papa S, Franzoso G, et al. Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling. Arthritis Rheum. 2009;60:3229–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tao H, Umek RM. Reciprocal regulation of gadd45 by C/EBP alpha and c-Myc. DNA Cell Biol. 1999;18:75–84.

    Article  PubMed  CAS  Google Scholar 

  • Thalheimer FB, Wingert S, De Giacomo P, Haetscher N, Rehage M, Brill B, et al. Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells. Stem Cell Rep. 2014;3:34–43.

    Article  CAS  Google Scholar 

  • Thyss R, Virolle V, Imbert V, Peyron JF, Aberdam D, Virolle T. NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death. EMBO J. 2005;24:128–37.

    Article  PubMed  CAS  Google Scholar 

  • Tian J, Huang H, Hoffman B, Liebermann DA, Ledda-Columbano GM, Columbano A, et al. Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice. J Clin Invest. 2011;121:4491–502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A, Tralau-Stewart C, et al. Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors. Cancer Cell. 2014;26:495–508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJJ, DiStefano PS, et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002;296:530–4.

    Article  PubMed  CAS  Google Scholar 

  • Tront JS, Huang Y, Fornace AJJ, Hoffman B, Liebermann DA. Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress. Cancer Res. 2010;70:9671–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vercelli A, Biggi S, Sclip A, Repetto IE, Cimini S, Falleroni F, et al. Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury. Cell Death Dis. 2015;6:e1854.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang B, Yin BL, He B, Chen C, Zhao M, Zhang W, et al. Overexpression of DNA damage-induced 45 α gene contributes to esophageal squamous cell cancer by promoter hypomethylation. J Exp Clin Cancer Res. 2012a;31:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang L, Xiao X, Li D, Chi Y, Wei P, Wang Y, et al. Abnormal expression of GADD45B in human colorectal carcinoma. J Transl Med. 2012b;10:215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, et al. GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A. 1999;96:3706–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wingert S, Thalheimer FB, Haetscher N, Rehage M, Schroeder T, Rieger MA. DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival. Stem Cells. 2016;34:699–710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yamamoto Y, Moore R, Flavell RA, Lu B, Negishi M. Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS One. 2010;5:e10121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM. IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced IFN-gamma production. Nat Immunol. 2001;2:157–64.

    Article  PubMed  CAS  Google Scholar 

  • Yang XR, Xiong Y, Duan H, Gong RR. Identification of genes associated with methotrexate resistance in methotrexate-resistant osteosarcoma cell lines. J Orthop Surg Res. 2015;10:136.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Song L, Huang C. Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets. 2009;9:915–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yi YW, Kim D, Jung N, Hong SS, Lee HS, Bae I. Gadd45 family proteins are coactivators of nuclear hormone receptors. Biochem Biophys Res Commun. 2000;272:193–8.

    Article  PubMed  CAS  Google Scholar 

  • Yoo J, Ghiassi M, Jirmanova L, Balliet AG, Hoffman B, Fornace AJJ, et al. Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J Biol Chem. 2003;278:43001–7.

    Article  PubMed  CAS  Google Scholar 

  • Zhan Q, Chen IT, Antinore MJ, Fornace AJJ. Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. Mol Cell Biol. 1998;18:2768–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang W, Li T, Shao Y, Zhang C, Wu Q, Yang H, et al. Semi-quantitative detection of GADD45-gamma methylation levels in gastric, colorectal and pancreatic cancers using methylation-sensitive high-resolution melting analysis. J Cancer Res Clin Oncol. 2010;136:1267–73.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge all the scientists who contributed to characterization of the role, function, and regulation of the GADD45 genes and protein products, but whose works could not be cited due to space concerns.

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Correspondence to Albert J. Fornace Jr. .

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Brown-Clay, J.D., Fornace, A.J. (2018). GADD45. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_8

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