GADD45B

GADD45B Background

The GADD45B gene was originally identified as a myeloid differentiation (MyD)-responsive gene in IL-6-treated M1 myeloid leukemia cells ^[1]. This gene encodes growth arrest and DNA-damage-inducible protein beta ^[2], one of the GADD45 family proteins associated with cell growth control, apoptosis, and DNA damage repair response. GADD45B has a role in the mediation of TGFβ-induced apoptosis. GADD45B is activated upon TGFβ-induced apoptosis ^[11]. Selvakumaran et al. have reported that blocking GADD45B expression impaired transforming growth factor-beta (TGFβ)-induced cell death in myeloid leukemia cells ^[3]. Contrary to its pro-apoptotic activity, GADD45B has also been identified to contribute to cell survival under certain physiological or stress conditions. De Smaele et al. reported that the upregulation of GADD45B downregulates JNK signaling induced by the cytokine tumor necrosis factor α (TNFα) through an NF-κB-dependent mechanism in mouse embryonic fibroblast (MEF) cells and 3DO T cells ^[4]. It was further shown that GADD45B over-expression suppresses IL-1β-induced apoptosis in insulin-producing cells ^{[5]. Additionally, GADD45B attenuates UV-induced apoptosis in hematopoietic cells by suppressing the JNK cascade [6]. Recent studies have reported that GADD45B may play an important role in the carcinogenesis of human hepatocellular carcinoma and pituitary gonadotrope tumors [7-9]. Chang Hoon Cho et al. demonstrated that GADD45B is a player in neuroprotection by regulating Bcl-2, Bax, and mitochondrial function in global ischemia and identified that GADD45B as a potential therapeutic target for the amelioration of hippocampal neurodegeneration [10].}

[1] Abdollahi A, Azam N, et al. Cell Signalling: Cell Survival and a Gadd45-Factor Deficiency [J]. Nature. 2003;424:741.
[2] Abdollahi A, Lord KA, et al. Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines [J]. Oncogene. 1991, 6 (1): 165–7.
[3] Selvakumaran M, Lin HK, et al. The Novel Primary Response Gene Myd118 and the Proto-Oncogenes Myb, Myc and Bcl-2 Modulate Transforming Growth Factor β1-Induced Apoptosis of Myeloid Leukemia Cells [J]. Mol Cell Biol. 1994;14:2352–2360.
[4] De Smaele E, Zazzeroni F, et al. Induction of Gadd45beta by Nf-Kappab Downregulates Pro-Apoptotic Jnk Signalling [J]. Nature. 2001;414:308–313.
[5] Larsen CM, Døssing MG, et al. Growth Arrest- and DNA-Damage-Inducible 45β Gene Inhibits C-Jun N-Terminal Kinase and Extracellular Signal-Regulated Kinase and Decreases Il-1β-Induced Apoptosis in Insulin-Producing Ins-1e Cells [J]. Diabetologia. 2006;49:980–989.
[6] Gupta M, Gupta SK, et al. Hematopoietic Cells from Gadd45α- and Gadd45β-Deficient Mice Are Sensitized to Genotoxic-Stress-Induced Apoptosis [J]. Oncogene. 2005;24:7170–7179.
[7] Michaelis KA, Knox AJ, et al. Identification of growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor in pituitary gonadotrope tumors [J]. Endocrinology. 2011, 152: 3603-3613.
[8] Ou DL, Shen YC, et al. Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells [J]. Cancer Res. 2010, 70: 9309-9318.
[9] Qiu W, David D, et al. Down-regulation of growth arrest DNA damage-inducible gene 45beta expression is associated with human hepatocellular carcinoma [J]. Am J Pathol. 2003, 162: 1961-1974.
[10] Chang Hoon Cho, et al. Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death [J]. Int Neurourol J 2019; 23(Suppl 1): S11-21.
[11] Selvakumaran M, Lin HK, et al. The Novel Primary Response Gene Myd118 and the Proto-Oncogenes Myb, Myc and Bcl-2 Modulate Transforming Growth Factor β1-Induced Apoptosis of Myeloid Leukemia Cells. Mol Cell Biol. 1994;14:2352–2360.