GADD45A explained

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.^{[1] [2] [3]}

Function

This gene is a member of a group of genes, the GADD45 genes, whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents (mutagens). The DNA damage-induced transcription of this gene is mediated by both p53-dependent and -independent mechanisms. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase.

Applications

The fact that expression of this gene is an indicator of DNA damage has been exploited to construct an in vitro test for mutagenicity, the GADD45a-GFP GreenScreen HC assay.^[4] This assay consists of a cell line which has been engineered so that expression of GADD45A will lead to expression of green fluorescent protein, which can easily be detected. To test a substance for mutagenicity, it is applied to these cells and fluorescence is measured.

Interactions

GADD45A has been shown to interact with:

• AURKA,^[5]
• Cdk1,^{[6] [7] [8] [9]}
• CCNB1,^{[6] [9]}
• GADD45GIP1^[10]
• MAP3K4,^[11]
• P21,^{[8] [12]} and
• PCNA.^{[8] [13] [14] [15] [16]}

See also

• Gadd45

Further reading

• Hildesheim J, Fornace AJ . Gadd45a: an elusive yet attractive candidate gene in pancreatic cancer. . Clin. Cancer Res. . 8 . 8 . 2475–9 . 2003 . 12171872 .
• Chen IT, Smith ML, O'Connor PM, Fornace AJ . Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA. . Oncogene . 11 . 10 . 1931–7 . 1995 . 7478510 .
• Kearsey JM, Coates PJ, Prescott AR . Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. . Oncogene . 11 . 9 . 1675–83 . 1995 . 7478594 . etal.
• Hall PA, Kearsey JM, Coates PJ . Characterisation of the interaction between PCNA and Gadd45. . Oncogene . 10 . 12 . 2427–33 . 1995 . 7784094 . etal.
• Carrier F, Smith ML, Bae I . Characterization of human Gadd45, a p53-regulated protein. . J. Biol. Chem. . 269 . 51 . 32672–7 . 1995 . 10.1016/S0021-9258(18)31687-9 . 7798274 . etal. free .
• Smith ML, Chen IT, Zhan Q . Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. . Science . 266 . 5189 . 1376–80 . 1994 . 7973727 . 10.1126/science.7973727 . 1994Sci...266.1376S . etal.
• Warbrick E, Lane DP, Glover DM, Cox LS . Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair. . Oncogene . 14 . 19 . 2313–21 . 1997 . 9178907 . 10.1038/sj.onc.1201072 . 29525059 .
• Warbrick E, Heatherington W, Lane DP, Glover DM . PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain. . Nucleic Acids Res. . 26 . 17 . 3925–32 . 1998 . 9705499 . 10.1093/nar/26.17.3925 . 147798 .
• Takekawa M, Saito H . A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. . Cell . 95 . 4 . 521–30 . 1998 . 9827804 . 10.1016/S0092-8674(00)81619-0 . 18980341 . free .
• Carrier F, Georgel PT, Pourquier P . Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. . Mol. Cell. Biol. . 19 . 3 . 1673–85 . 1999 . 10022855 . 10.1128/MCB.19.3.1673. 83961 . etal.
• Zhan Q, Antinore MJ, Wang XW . Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. . Oncogene . 18 . 18 . 2892–900 . 1999 . 10362260 . 10.1038/sj.onc.1202667 . 13112302 . etal.
• Jin S, Antinore MJ, Lung FD . The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. . J. Biol. Chem. . 275 . 22 . 16602–8 . 2000 . 10747892 . 10.1074/jbc.M000284200 . etal. free .
• Vairapandi M, Azam N, Balliet AG . Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. . J. Biol. Chem. . 275 . 22 . 16810–9 . 2000 . 10828065 . 10.1074/jbc.275.22.16810 . etal. free .
• Yi YW, Kim D, Jung N . Gadd45 family proteins are coactivators of nuclear hormone receptors. . Biochem. Biophys. Res. Commun. . 272 . 1 . 193–8 . 2000 . 10872826 . 10.1006/bbrc.2000.2760 . etal.
• Zhao H, Jin S, Antinore MJ . The central region of Gadd45 is required for its interaction with p21/WAF1. . Exp. Cell Res. . 258 . 1 . 92–100 . 2000 . 10912791 . 10.1006/excr.2000.4906 . etal.
• Yang Q, Manicone A, Coursen JD . Identification of a functional domain in a GADD45-mediated G2/M checkpoint. . J. Biol. Chem. . 275 . 47 . 36892–8 . 2001 . 10973963 . 10.1074/jbc.M005319200 . etal. free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination. . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 10.1101/gr.143000 . 310948 .
• Kovalsky O, Lung FD, Roller PP, Fornace AJ . Oligomerization of human Gadd45a protein. . J. Biol. Chem. . 276 . 42 . 39330–9 . 2001 . 11498536 . 10.1074/jbc.M105115200 . free .

Notes and References

1. Papathanasiou MA, Kerr NC, Robbins JH, McBride OW, ((Alamo I Jr)), Barrett SF, Hickson ID, ((Fornace AJ Jr)) . Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C . Mol Cell Biol . 11 . 2 . 1009–16 . March 1991 . 1990262 . 359769 . 10.1128/MCB.11.2.1009.
2. Hollander MC, Alamo I, Jackman J, Wang MG, McBride OW, ((Fornace AJ Jr)) . Analysis of the mammalian gadd45 gene and its response to DNA damage . J Biol Chem . 268 . 32 . 24385–93 . December 1993 . 10.1016/S0021-9258(20)80537-7 . 8226988 . free .
3. Web site: Entrez Gene: GADD45A growth arrest and DNA-damage-inducible, alpha.
4. Book: Walmsley RM, Tate M . Genetic Toxicology . The GADD45a-GFP GreenScreen HC assay . 817 . 231–50 . 2012 . 22147576 . 10.1007/978-1-61779-421-6_12 . Methods in Molecular Biology . 978-1-61779-420-9 .
5. July 2010 . Sánchez R, Pantoja-Uceda D, Prieto J, Diercks T, Marcaida MJ, Montoya G, Campos-Olivas R, Blanco FJ . Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase . J. Biol. Chem. . 285 . 29 . 22196–201 . 20460379 . 2903397 . 10.1074/jbc.M109.069344. free .
6. May 1999 . Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ . Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 . Oncogene . 18 . 18 . 2892–900 . 10362260 . 10.1038/sj.onc.1202667. 13112302 .
7. June 2000 . Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ, Zhan Q . The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression . J. Biol. Chem. . 275 . 22 . 16602–8 . 10747892 . 10.1074/jbc.M000284200. free .
8. November 2000 . Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW . Identification of a functional domain in a GADD45-mediated G2/M checkpoint . J. Biol. Chem. . 275 . 47 . 36892–8 . 10973963 . 10.1074/jbc.M005319200. free .
9. September 2002 . Vairapandi M, Balliet AG, Hoffman B, Liebermann DA . 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 . 12124778 . 10.1002/jcp.10140. 19138273 .
10. July 2003 . Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H, Park KC, Song JH, Kim DW, Hwang ES, Yoon SH, Bae YS, Kim JM, Bae I, Shong M . CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle . J. Biol. Chem. . 278 . 30 . 28079–88 . 12716909 . 10.1074/jbc.M212835200. free .
11. November 1998 . Takekawa M, Saito H . A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK . Cell . 95 . 4 . 521–30 . 9827804 . 10.1016/s0092-8674(00)81619-0. 18980341 . free .
12. July 2000 . Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, Roller P, Fornace AJ, Zhan Q . The central region of Gadd45 is required for its interaction with p21/WAF1 . Exp. Cell Res. . 258 . 1 . 92–100 . 10912791 . 10.1006/excr.2000.4906.
13. November 1994 . Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ . Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen . Science . 266 . 5189 . 1376–80 . 7973727 . 10.1126/science.7973727. 1994Sci...266.1376S .
14. November 1995 . Chen IT, Smith ML, O'Connor PM, Fornace AJ . Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA . Oncogene . 11 . 10 . 1931–7 . 7478510 .
15. June 2000 . Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA . Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control . J. Biol. Chem. . 275 . 22 . 16810–9 . 10828065 . 10.1074/jbc.275.22.16810. free .
16. June 1995 . Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS . Characterisation of the interaction between PCNA and Gadd45 . Oncogene . 10 . 12 . 2427–33 . 7784094 .