GADD45A

Growth arrest and DNA-damage-inducible, alpha
PDB
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2KG4​
Identifiers
Symbols	GADD45A ; DDIT1; GADD45
External IDs	OMIM: 126335 MGI: 107799 HomoloGene: 1449 GeneCards: GADD45A Gene
Gene ontology Molecular function • core promoter binding • protein binding Cellular component • nucleus • cytoplasm Biological process • regulation of cyclin-dependent protein serine/threonine kinase activity • G2/M transition of mitotic cell cycle • activation of MAPKKK activity • DNA repair • negative regulation of protein kinase activity • apoptotic process • cell cycle arrest • centrosome cycle • signal transduction in response to DNA damage • positive regulation of apoptotic process • positive regulation of JNK cascade • cellular response to mechanical stimulus • cellular response to ionizing radiation • mitotic cell cycle arrest • positive regulation of p38MAPK cascade • positive regulation of reactive oxygen species metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1647	13197
Ensembl	ENSG00000116717	ENSMUSG00000036390
UniProt	P24522	P48316
RefSeq (mRNA)	NM_001199741	NM_007836
RefSeq (protein)	NP_001186670	NP_031862
Location (UCSC)	Chr 1: 67.69 – 67.69 Mb	Chr 6: 67.04 – 67.04 Mb
PubMed search

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.^[3]

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][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

References

1. Papathanasiou MA, Kerr NC, Robbins JH, McBride OW, Alamo I Jr, Barrett SF, Hickson ID, Fornace AJ Jr (March 1991). "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. PMC 359769. PMID 1990262.
2. Hollander MC, Alamo I, Jackman J, Wang MG, McBride OW, Fornace AJ Jr (December 1993). "Analysis of the mammalian gadd45 gene and its response to DNA damage". J Biol Chem 268 (32): 24385–93. PMID 8226988.
3. "Entrez Gene: GADD45A growth arrest and DNA-damage-inducible, alpha".
4. Walmsley RM, Tate M (2012). "The GADD45a-GFP GreenScreen HC assay". Methods Mol. Biol. 817: 231–50. doi:10.1007/978-1-61779-421-6_12. PMID 22147576.
5. Sánchez R, Pantoja-Uceda D, Prieto J, Diercks T, Marcaida MJ, Montoya G, Campos-Olivas R, Blanco FJ (July 2010). "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. doi:10.1074/jbc.M109.069344. PMC 2903397. PMID 20460379.
6. Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ (May 1999). "Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45". Oncogene 18 (18): 2892–900. doi:10.1038/sj.onc.1202667. PMID 10362260.
7. Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ, Zhan Q (June 2000). "The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression". J. Biol. Chem. 275 (22): 16602–8. doi:10.1074/jbc.M000284200. PMID 10747892.
8. Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW (November 2000). "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.
9. Vairapandi M, Balliet AG, Hoffman B, Liebermann DA (September 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.
10. 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 (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.
11. Takekawa M, Saito H (November 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.
12. Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, Roller P, Fornace AJ, Zhan Q (July 2000). "The central region of Gadd45 is required for its interaction with p21/WAF1". Exp. Cell Res. 258 (1): 92–100. doi:10.1006/excr.2000.4906. PMID 10912791.
13. Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ (November 1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen". Science 266 (5189): 1376–80. doi:10.1126/science.7973727. PMID 7973727.
14. Chen IT, Smith ML, O'Connor PM, Fornace AJ (November 1995). "Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA". Oncogene 11 (10): 1931–7. PMID 7478510.
15. Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA (June 2000). "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. doi:10.1074/jbc.275.22.16810. PMID 10828065.
16. Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS (June 1995). "Characterisation of the interaction between PCNA and Gadd45". Oncogene 10 (12): 2427–33. PMID 7784094.

Further reading

• Hildesheim J, Fornace AJ (2003). "Gadd45a: an elusive yet attractive candidate gene in pancreatic cancer.". Clin. Cancer Res. 8 (8): 2475–9. PMID 12171872.
• Chen IT, Smith ML, O'Connor PM, Fornace AJ (1995). "Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA.". Oncogene 11 (10): 1931–7. PMID 7478510.
• Kearsey JM, Coates PJ, Prescott AR; et al. (1995). "Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1.". Oncogene 11 (9): 1675–83. PMID 7478594.
• Hall PA, Kearsey JM, Coates PJ; et al. (1995). "Characterisation of the interaction between PCNA and Gadd45.". Oncogene 10 (12): 2427–33. PMID 7784094.
• Carrier F, Smith ML, Bae I; et al. (1995). "Characterization of human Gadd45, a p53-regulated protein.". J. Biol. Chem. 269 (51): 32672–7. PMID 7798274.
• Smith ML, Chen IT, Zhan Q; et al. (1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.". Science 266 (5189): 1376–80. doi:10.1126/science.7973727. PMID 7973727.
• Warbrick E, Lane DP, Glover DM, Cox LS (1997). "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. doi:10.1038/sj.onc.1201072. PMID 9178907.
• Warbrick E, Heatherington W, Lane DP, Glover DM (1998). "PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain.". Nucleic Acids Res. 26 (17): 3925–32. doi:10.1093/nar/26.17.3925. PMC 147798. PMID 9705499.
• Takekawa M, Saito H (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.
• Carrier F, Georgel PT, Pourquier P; et al. (1999). "Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin.". Mol. Cell. Biol. 19 (3): 1673–85. PMC 83961. PMID 10022855.
• Zhan Q, Antinore MJ, Wang XW; et al. (1999). "Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45.". Oncogene 18 (18): 2892–900. doi:10.1038/sj.onc.1202667. PMID 10362260.
• Jin S, Antinore MJ, Lung FD; et al. (2000). "The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression.". J. Biol. Chem. 275 (22): 16602–8. doi:10.1074/jbc.M000284200. PMID 10747892.
• Vairapandi M, Azam N, Balliet AG; et al. (2000). "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. doi:10.1074/jbc.275.22.16810. PMID 10828065.
• 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.
• Zhao H, Jin S, Antinore MJ; et al. (2000). "The central region of Gadd45 is required for its interaction with p21/WAF1.". Exp. Cell Res. 258 (1): 92–100. doi:10.1006/excr.2000.4906. PMID 10912791.
• 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.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Kovalsky O, Lung FD, Roller PP, Fornace AJ (2001). "Oligomerization of human Gadd45a protein.". J. Biol. Chem. 276 (42): 39330–9. doi:10.1074/jbc.M105115200. PMID 11498536.