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Gene Review

GADD45A  -  growth arrest and DNA-damage-inducible, alpha

Homo sapiens

Synonyms: DDIT-1, DDIT1, DNA damage-inducible transcript 1 protein, GADD45, Growth arrest and DNA damage-inducible protein GADD45 alpha
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Disease relevance of GADD45A


Psychiatry related information on GADD45A


High impact information on GADD45A

  • ChIP analyses have confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on the GADD45 gene following ectopic p53 expression and/or UV irradiation [7].
  • A major BRCA1 target is the DNA damage-responsive gene GADD45 [8].
  • A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK [9].
  • The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation [9].
  • GADD45 is a ubiquitously expressed mammalian gene that is induced by DNA damage and certain other stresses [10].

Chemical compound and disease context of GADD45A


Biological context of GADD45A


Anatomical context of GADD45A


Associations of GADD45A with chemical compounds


Physical interactions of GADD45A

  • Induction requires the binding of wild-type p53 to an evoulutionarily highly conserved putative intronic p53 binding site in intron 3 of GADD45 [25].
  • GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition [26].

Regulatory relationships of GADD45A

  • However, the mechanism(s) by which BRCA1 regulates GADD45 remains unclear [27].
  • The ability of GADD45 to induce a G(2)/M arrest may be caused in part by the inhibition of Cdc2 kinase activity [28].
  • A combination of p53 and WT1 expression vectors strongly induced a GADD45-reporter construct, while mutation of the WT1-Egr1 site in the promoter prevented this induction [29].
  • GADD45 (growth arrest and DNA damage) is a DNA-damage-inducible gene regulated in part by the tumor suppressor p53 [30].
  • CIN85 was also shown to regulate the activation of MEKK4 by GADD45 proteins and promote multi-ubiquitination of MEKK4 [31].

Other interactions of GADD45A

  • Despite this defect in GADD45 induction, we found that all wt p53 melanoma lines exhibited strong G1 arrest and increased levels of p53 protein after IR [17].
  • We chose the GADD45A and EPB41 genes as tumor suppressor candidates based on their function and chromosomal localization [1].
  • Data accumulated suggest that MyD118/GADD45/CR6 serve similar but not identical functions along different apoptotic and growth suppressive pathways [20].
  • BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs [27].
  • GADD45 is a DNA damage responsive gene, induced following BRCA1 expression [32].

Analytical, diagnostic and therapeutic context of GADD45A


  1. GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis. Piaskowski, S., Rieske, P., Szybka, M., Wozniak, K., Bednarek, A., Płuciennik, E., Jaskolski, D., Sikorska, B., Liberski, P.P. Cancer Genet. Cytogenet. (2005) [Pubmed]
  2. UVB-induced G2 arrest of human melanocytes involves Cdc2 sequestration by Gadd45a in nuclear speckles. Fayolle, C., Pourchet, J., Cohen, A., Pedeux, R., Puisieux, A., de Fromentel, C.C., Dorè, J.F., Voeltzel, T. Cell Cycle (2006) [Pubmed]
  3. PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway. Han, C., Demetris, A.J., Michalopoulos, G.K., Zhan, Q., Shelhamer, J.H., Wu, T. Hepatology (2003) [Pubmed]
  4. p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells. Takemoto, S., Trovato, R., Cereseto, A., Nicot, C., Kislyakova, T., Casareto, L., Waldmann, T., Torelli, G., Franchini, G. Blood (2000) [Pubmed]
  5. The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. Artuso, M., Esteve, A., Brésil, H., Vuillaume, M., Hall, J. Oncogene (1995) [Pubmed]
  6. GADD45 is induced in Alzheimer's disease, and protects against apoptosis in vitro. Torp, R., Su, J.H., Deng, G., Cotman, C.W. Neurobiol. Dis. (1998) [Pubmed]
  7. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. An, W., Kim, J., Roeder, R.G. Cell (2004) [Pubmed]
  8. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Harkin, D.P., Bean, J.M., Miklos, D., Song, Y.H., Truong, V.B., Englert, C., Christians, F.C., Ellisen, L.W., Maheswaran, S., Oliner, J.D., Haber, D.A. Cell (1999) [Pubmed]
  9. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa, M., Saito, H. Cell (1998) [Pubmed]
  10. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Smith, M.L., Chen, I.T., Zhan, Q., Bae, I., Chen, C.Y., Gilmer, T.M., Kastan, M.B., O'Connor, P.M., Fornace, A.J. Science (1994) [Pubmed]
  11. Combined GADD45A and thymidine phosphorylase expression levels predict response and survival of neoadjuvant-treated gastric cancer patients. Napieralski, R., Ott, K., Kremer, M., Specht, K., Vogelsang, H., Becker, K., Müller, M., Lordick, F., Fink, U., Rüdiger Siewert, J., Höfler, H., Keller, G. Clin. Cancer Res. (2005) [Pubmed]
  12. Peroxynitrite induces GADD34, 45, and 153 VIA p38 MAPK in human neuroblastoma SH-SY5Y cells. Oh-Hashi, K., Maruyama, W., Isobe, K. Free Radic. Biol. Med. (2001) [Pubmed]
  13. Induction of GADD45 and GADD153 in neuroblastoma cells by dopamine-induced toxicity. Stokes, A.H., Freeman, W.M., Mitchell, S.G., Burnette, T.A., Hellmann, G.M., Vrana, K.E. Neurotoxicology (2002) [Pubmed]
  14. Bitter gourd seed fatty acid rich in 9c,11t,13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPARgamma in human colon cancer Caco-2 cells. Yasui, Y., Hosokawa, M., Sahara, T., Suzuki, R., Ohgiya, S., Kohno, H., Tanaka, T., Miyashita, K. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  15. Molecular characterization of Coriolus versicolor PSP-induced apoptosis in human promyelotic leukemic HL-60 cells using cDNA microarray. Zeng, F., Hon, C.C., Sit, W.H., Chow, K.Y., Hui, R.K., Law, I.K., Ng, V.W., Yang, X.T., Leung, F.C., Wan, J.M. Int. J. Oncol. (2005) [Pubmed]
  16. Differential responses of stress genes to low dose-rate gamma irradiation. Amundson, S.A., Lee, R.A., Koch-Paiz, C.A., Bittner, M.L., Meltzer, P., Trent, J.M., Fornace, A.J. Mol. Cancer Res. (2003) [Pubmed]
  17. An abnormality in the p53 pathway following gamma-irradiation in many wild-type p53 human melanoma lines. Bae, I., Smith, M.L., Sheikh, M.S., Zhan, Q., Scudiero, D.A., Friend, S.H., O'Connor, P.M., Fornace, A.J. Cancer Res. (1996) [Pubmed]
  18. p53 Is Preferentially Recruited to the Promoters of Growth Arrest Genes p21 and GADD45 during Replicative Senescence of Normal Human Fibroblasts. Jackson, J.G., Pereira-Smith, O.M. Cancer Res. (2006) [Pubmed]
  19. Radiation-induced G1 arrest is selectively mediated by the p53-WAF1/Cip1 pathway in human thyroid cells. Namba, H., Hara, T., Tukazaki, T., Migita, K., Ishikawa, N., Ito, K., Nagataki, S., Yamashita, S. Cancer Res. (1995) [Pubmed]
  20. Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control. Azam, N., Vairapandi, M., Zhang, W., Hoffman, B., Liebermann, D.A. J. Biol. Chem. (2001) [Pubmed]
  21. Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway. Hsu, C.A., Rishi, A.K., Su-Li, X., Gerald, T.M., Dawson, M.I., Schiffer, C., Reichert, U., Shroot, B., Poirer, G.C., Fontana, J.A. Blood (1997) [Pubmed]
  22. A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. Russo, T., Zambrano, N., Esposito, F., Ammendola, R., Cimino, F., Fiscella, M., Jackman, J., O'Connor, P.M., Anderson, C.W., Appella, E. J. Biol. Chem. (1995) [Pubmed]
  23. Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress. Zhan, Q., Kontny, U., Iglesias, M., Alamo, I., Yu, K., Hollander, M.C., Woodworth, C.D., Fornace, A.J. Oncogene (1999) [Pubmed]
  24. Down-regulation of proliferating cell nuclear antigen gene expression occurs during cell cycle arrest induced by human fecal water in colonic HT-29 cells. Zeng, H., Davis, C.D. J. Nutr. (2003) [Pubmed]
  25. A polymorphism but no mutations in the GADD45 gene in breast cancers. Blaszyk, H., Hartmann, A., Sommer, S.S., Kovach, J.S. Hum. Genet. (1996) [Pubmed]
  26. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mita, H., Tsutsui, J., Takekawa, M., Witten, E.A., Saito, H. Mol. Cell. Biol. (2002) [Pubmed]
  27. BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. Fan, W., Jin, S., Tong, T., Zhao, H., Fan, F., Antinore, M.J., Rajasekaran, B., Wu, M., Zhan, Q. J. Biol. Chem. (2002) [Pubmed]
  28. Identification of a functional domain in a GADD45-mediated G2/M checkpoint. Yang, Q., Manicone, A., Coursen, J.D., Linke, S.P., Nagashima, M., Forgues, M., Wang, X.W. J. Biol. Chem. (2000) [Pubmed]
  29. Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. Zhan, Q., Chen, I.T., Antinore, M.J., Fornace, A.J. Mol. Cell. Biol. (1998) [Pubmed]
  30. Characterization of human Gadd45, a p53-regulated protein. Carrier, F., Smith, M.L., Bae, I., Kilpatrick, K.E., Lansing, T.J., Chen, C.Y., Engelstein, M., Friend, S.H., Henner, W.D., Gilmer, T.M. J. Biol. Chem. (1994) [Pubmed]
  31. CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Aissouni, Y., Zapart, G., Iovanna, J.L., Dikic, I., Soubeyran, P. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  32. Clinicopathological significance of GADD45 gene alterations in human familial breast carcinoma. Sensi, E., Tancredi, M., Aretini, P., Cipollini, G., Collecchi, P., Naccarato, A.G., Viacava, P., Bevilacqua, G., Caligo, M.A. Breast Cancer Res. Treat. (2004) [Pubmed]
  33. GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. Gramantieri, L., Chieco, P., Giovannini, C., Lacchini, M., Treré, D., Grazi, G.L., Venturi, A., Bolondi, L. Hum. Pathol. (2005) [Pubmed]
  34. Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. Buzek, J., Latonen, L., Kurki, S., Peltonen, K., Laiho, M. Nucleic Acids Res. (2002) [Pubmed]
  35. Both the basal transcriptional activity of the GADD45A gene and its enhancement after ionizing irradiation are mediated by AP-1 element. Daino, K., Ichimura, S., Nenoi, M. Biochim. Biophys. Acta (2006) [Pubmed]
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