|Growth arrest and DNA-damage-inducible, gamma|
Rendering based on PDB .
|Symbols||; CR6; DDIT2; GADD45gamma; GRP17|
|RNA expression pattern|
Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer.
GADD45G was originally cloned by Beadling under the name CR6 in 1993. In this experiment, several genes including GADD45G were noted for being induced by IL-2, and they were identified as immediate early response genes in T lymphocytes. Its role as a tumor suppressor was discovered in 1999 by Zhang. It received the name OIG37 from Nakayama due to its regulation by Oncostatin M, which was found to be able to inhibit growth. Finally, it also became known as Gadd-related protein 17 during its isolation from a cDNA library by Suzuki due to its homology with Gadd45.
Structure and function
GADD45G is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase. GADD45G is in turn regulated upstream by NF-κB.
The crystal structure of GADD45G reveals a dimer made of four parallel helices. The central region contains a highly acidic patch where it allows for interaction with cdc2, PCNA, and p21. The parallel isoform of GADD45G is the active form.
This gene plays a role in cell cycle regulation. GADD45G prevents the kinase ability of the cyclin b1/Cdk1 complex in a fashion that does not break apart the complex. It plays a role in the activation of the S and G2/M checkpoints.
In the male sexual development pathway, GADD45G is essential for activating SRY, leading to proper formation of the gonads and sex-determination. This could occur through GADD45G interaction with the p38 MAPK signaling pathway.
Deletion of an enhancer close to the GADD45G gene is correlated to increased proliferation of neuronal cells, which could account for part of the difference in neural development between humans and other species. The deletion of the enhancer reduces the expression of the gene in the forebrain allowing for more brain growth in humans.
GADD45G is involved with dental epithelial cell proliferation. GADD45G is expressed in enamel knots, where it regulates gene expression and cell growth. The gene modulates p21-mediated epithelial cell proliferation by activating the p38 MAPK pathway during the development of teeth.
There is differential expression of the Xenopus homolog of GADD45G in embryonic development. It plays a large role in neural and brain development with GADD45A. GADD45G and GADD45A knockdowns are related to improper gastrulation, defective head growth, and shorter axes. GADD45G and GADD45A act redundantly to control cell growth, allow the cells to move from pluripotentcy helping cells differentiate.
GADD45G carries out its many previously stated functions with many different interactions. GADD45G was found to inhibit Cdk1 kinase activity, which would cause disruption of cell growth. It also interacts with CRIF, which causes the inhibition of Cdc2-cyclin B1 and Cdk-cyclin E. GADD45 also works with the cyclin-dependent kinase inhibitor p21, which can cause growth arrest as well. GADD45G is found to be involved with the p38 MAPK pathway through interactions with MAP3K4, which can be important in sex-determination. Additionally, GADD45G regulates DNA replication and repair through its interactions with PCNA.
In humans, GADD45G is expressed most in the skeletal muscle, kidney and liver. This gene has a low expression in the heart, brain, spleen, lung and testis. GADD45G is highly expressed in the placenta.
In numerous kinds of cancerous cells, GADD45G is down regulated. There is a low expression due to methylation of the GADD45G promotor. This low expression can also be explained by increased NF-κB activation.
GADD45G methylation is seen in many cancers. In esophageal cancer the expression level and methylation status of the gene are involved in the prognosis of esophageal squamous cell carcinoma. Demethylation of the gene can have some beneficial effects. Similar circumstances are seen in gastric cardio adenocarcinomas where GADD45G is silenced. GADD45G methylation levels are also measured in the diagnosis of pancreatic and colorectal cancers.
In the pituitary gland, GADD45G is a growth suppressor. There is a loss of expression of the gene in many pituitary cancerous masses. The gene plays a role in prostate cancer as a tumor suppressor as well. In these cancerous cells, Vitamin D can induce the expression of GADD45G. GADD45G could possibly be a target of therapeutic benefit for prostate cancer. 
In cancerous liver cells, GADD45G is down regulated.It participates in negatively regulating the Jak-Stat3 signaling pathway. It acts as a tumor suppressor in HCC cells by promoting cell death or growth arrest. When GADD45G expression is low, liver cells may be able to bypass the growth arrest stage, leading to cancerous cells.
- Suzuki M, Watanabe TK, Fujiwara T, Nakamura Yp6, Takahashi E, Tanigami A; Watanabe; Fujiwara; Nakamura; Takahashi; Tanigami (Oct 1999). "Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118". J Hum Genet 44 (5): 300–3. doi:10.1007/s100380050164. PMID 10496071.
- Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM; González-Silva; Carramolino; Flores; Torres; Salvador (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLoS ONE 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.
- McLean CY, Reno PL, Pollen AA et al. (March 2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129.
- Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF; De Vasconcellos; Sarkar; Libermann; Fisher; Zerbini (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. PMC 3797964. PMID 22515981.
- Liebermann DA, Hoffman B; Hoffman (2007). "Gadd45 in the response of hematopoietic cells to genotoxic stress". Blood Cells Mol. Dis. 39 (3): 329–35. doi:10.1016/j.bcmd.2007.06.006. PMC 3268059. PMID 17659913.
- Zhang L, Yang Z, Ma A, Qu Y, Xia S, Xu D, Ge C, Qiu B, Xia Q, Li J, Liu Y; Yang; Ma; Qu; Xia; Xu; Ge; Qiu; Xia; Li; Liu (January 2014). "Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma". Hepatology 59 (1): 178–89. doi:10.1002/hep.26628. PMID 23897841.
- Beadling C, Johnson KW, Smith KA; Johnson; Smith (April 1993). "Isolation of interleukin 2-induced immediate-early genes". Proc. Natl. Acad. Sci. U.S.A. 90 (7): 2719–23. doi:10.1073/pnas.90.7.2719. PMC 46167. PMID 7681987.
- Zhang W, Bae I, Krishnaraju K, Azam N, Fan W, Smith K, Hoffman B, Liebermann DA; Bae; Krishnaraju; Azam; Fan; Smith; Hoffman; Liebermann (September 1999). "CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control". Oncogene 18 (35): 4899–907. doi:10.1038/sj.onc.1202885. PMID 10490824.
- Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A; Hara; Hibi; Hirano; Miyajima (August 1999). "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth". J. Biol. Chem. 274 (35): 24766–72. doi:10.1074/jbc.274.35.24766. PMID 10455148.
- Takekawa M, Saito H; Saito (Dec 1998). "A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK". Cell 95 (4): 521–30. doi:10.1016/S0092-8674(00)81619-0. PMID 9827804.
- Zhang W, Fu S, Liu X, Zhao X, Zhang W, Peng W et al. (2011). "Crystal structure of human Gadd45γ [corrected] reveals an active dimer". Protein Cell 2 (10): 814–26. doi:10.1007/s13238-011-1090-6. PMID 22058036.
- Vairapandi M, Balliet AG, Hoffman B, Liebermann DA; Balliet; Hoffman; Liebermann (2002). "GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress". J. Cell. Physiol. 192 (3): 327–38. doi:10.1002/jcp.10140. PMID 12124778.
- Iskow, Rebecca C.; Gokcumen, Omer; Lee, Charles (2012). "Exploring the role of copy number variants in human adaptation". Trends in Genetics 28 (6): 245–257. doi:10.1016/j.tig.2012.03.002. ISSN 0168-9525. PMID 22483647.
- Ishida K, Yuge Y, Hanaoka M, Yasukawa M, Minami Y, Ogawa M, Masumoto KH, Shigeyoshi Y, Saito M, Tsuji T; Yuge; Hanaoka; Yasukawa; Minami; Ogawa; Masumoto; Shigeyoshi; Saito; Tsuji (August 2013). "Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression". Genes Cells 18 (8): 660–71. doi:10.1111/gtc.12067. PMID 23751077.
- Kaufmann, Lilian T.; Niehrs, Christof (2011). "Gadd45a and Gadd45g regulate neural development and exit from pluripotency in Xenopus". Mechanisms of Development 128 (7–10): 401–411. doi:10.1016/j.mod.2011.08.002. ISSN 0925-4773. PMID 21854844.
- Chung HK, Yi YW, Jung NC et al. (July 2003). "CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle". J. Biol. Chem. 278 (30): 28079–88. doi:10.1074/jbc.M212835200. PMID 12716909.
- Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA; Vairapandi; Zhang; Hoffman; Liebermann (Jan 2001). "Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control". J. Biol. Chem. 276 (4): 2766–74. doi:10.1074/jbc.M005626200. PMID 11022036.
- Warr N, Carre GA, Siggers P et al. (November 2012). "Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression". Dev. Cell 23 (5): 1020–31. doi:10.1016/j.devcel.2012.09.016. PMC 3526779. PMID 23102580.
- "Entrez Gene: GADD45G growth arrest and DNA-damage-inducible, gamma".
- Kaufmann, Lilian T.; Gierl, Mathias S.; Niehrs, Christof (2011). "Gadd45a, Gadd45b and Gadd45g expression during mouse embryonic development". Gene Expression Patterns 11 (8): 465–470. doi:10.1016/j.gep.2011.07.005. ISSN 1567-133X. PMID 21843656.
- Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B; Tront; Sha; Mukherjee; Mohamed-Hadley; Hoffman (2011). "Gadd45 stress sensors in malignancy and leukemia". Crit Rev Oncog 16 (1–2): 129–40. doi:10.1615/critrevoncog.v16.i1-2.120. PMC 3268054. PMID 22150313.
- Guo, Wei; Dong, Zhiming; Guo, Yanli; Chen, Zhifeng; Kuang, Gang; Yang, Zhibin (2013). "Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma". International Journal of Cancer 133 (9): 2043–2053. doi:10.1002/ijc.28223. ISSN 0020-7136.
- Zhang W, Li T, Shao Y, Zhang C, Wu Q, Yang H, Zhang J, Guan M, Yu B, Wan J; Li; Shao; Zhang; Wu; Yang; Zhang; Guan; Yu; Wan (August 2010). "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. 136 (8): 1267–73. doi:10.1007/s00432-010-0777-z. PMID 20111973.
- Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B et al. (2002). "Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis". J Clin Endocrinol Metab 87 (3): 1262–7. doi:10.1210/jcem.87.3.8315. PMID 11889197.
- Flores O, Burnstein KL; Burnstein (2010). "GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells". Endocrinology 151 (10): 4654–64. doi:10.1210/en.2010-0434. PMC 2946153. PMID 20739400.
- Liebermann DA, Hoffman B; Hoffman (October 2011). "Prostate cancer: JunD, Gadd45a and Gadd45g as therapeutic targets". Cell Cycle 10 (20): 3428. doi:10.4161/cc.10.20.17528. PMID 22030693.
- Yu S, Cho J, Park I, Kim SJ, Kim H, Shin GT; Cho; Park; Kim; Kim; Shin (2009). "Urinary GADD45gamma expression is associated with progression of lgA nephropathy". Am J Nephrol 30 (2): 135–9. doi:10.1159/000209317. PMID 19293565.
- Karine Plourde, Yvan Labrie; Geneviève Ouellette, Johanne Ouellet; Fernand Labrie, Céline Martel; Francine Durocher, Georges Pelletier (2012). "Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments". Endocrinology & Metabolic Syndrome 01 (S4). doi:10.4172/2161-1017.S4-005. ISSN 2161-1017.
- Ivanga, Mahinè; Labrie, Yvan; Calvo, Ezequiel; Belleau, Pascal; Martel, Céline; Pelletier, Georges; Morissette, Jean; Labrie, Fernand; Durocher, Francine (2009). "Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus". Molecular Reproduction and Development 76 (3): 278–288. doi:10.1002/mrd.20949. ISSN 1040-452X. PMID 18671277.
- Fan W, Richter G, Cereseto A et al. (2000). "Cytokine response gene 6 induces p21 and regulates both cell growth and arrest". Oncogene 18 (47): 6573–82. doi:10.1038/sj.onc.1203054. PMID 10597261.
- Gong R, Yu L, Zhang H et al. (2000). "Assignment of human GADD45G to chromosome 9q22.1→q22.3 by radiation hybrid mapping". Cytogenet. Cell Genet. 88 (1–2): 95–6. doi:10.1159/000015496. PMID 10773677.
- Yi YW, Kim D, Jung N et al. (2000). "Gadd45 family proteins are coactivators of nuclear hormone receptors". Biochem. Biophys. Res. Commun. 272 (1): 193–8. doi:10.1006/bbrc.2000.2760. PMID 10872826.
- Yang Q, Manicone A, Coursen JD et al. (2001). "Identification of a functional domain in a GADD45-mediated G2/M checkpoint". J. Biol. Chem. 275 (47): 36892–8. doi:10.1074/jbc.M005319200. PMID 10973963.
- Wan Y, Wang Z, Shao Y et al. (2001). "UV-induced expression of GADD45 is mediated by an oxidant sensitive pathway in cultured human keratinocytes and in human skin in vivo". Int. J. Mol. Med. 6 (6): 683–8. doi:10.3892/ijmm.6.6.683. PMID 11078829.
- Kovalsky O, Lung FD, Roller PP, Fornace AJ; Lung; Roller; Fornace Jr (2001). "Oligomerization of human Gadd45a protein". J. Biol. Chem. 276 (42): 39330–9. doi:10.1074/jbc.M105115200. PMID 11498536.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Sun L, Gong R, Wan B et al. (2004). "GADD45gamma, down-regulated in 65% hepatocellular carcinoma (HCC) from 23 Chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for hepatoma Hep-G2 cell lines". Mol. Biol. Rep. 30 (4): 249–53. doi:10.1023/A:1026370726763. PMID 14672412.
- Jiang F, Wang Z; Wang (2004). "Gadd45gamma is androgen-responsive and growth-inhibitory in prostate cancer cells". Mol. Cell. Endocrinol. 213 (2): 121–9. doi:10.1016/j.mce.2003.10.050. PMID 15062559.
- Zerbini LF, Wang Y, Czibere A et al. (2004). "NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival". Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13618–23. doi:10.1073/pnas.0402069101. PMC 518803. PMID 15353598.
- Goehler H, Lalowski M, Stelzl U et al. (2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Mol. Cell 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276.