GADD45A

GADD45A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KG4
Identifiers
Aliases	GADD45A , DDIT1, GADD45, growth arrest and DNA damage inducible alpha
External IDs	OMIM: 126335; MGI: 107799; HomoloGene: 1449; GeneCards: GADD45A; OMA:GADD45A - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1p31.3 Start 67,685,201 bp [1] End 67,688,334 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6|6 C1 Start 67,012,080 bp [2] End 67,014,441 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Descending thoracic aorta vena cava ascending aorta popliteal artery tibial arteries glomerulus metanephric glomerulus human kidney cartilage tissue left coronary artery Top expressed in granulocyte muscle of thigh blood extensor digitorum longus muscle fetal liver hematopoietic progenitor cell transitional epithelium of urinary bladder renal corpuscle interventricular septum duodenum jejunum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding kinase binding protein homodimerization activity protein heterodimerization activity protein N-terminus binding RNA polymerase II core promoter sequence-specific DNA binding Cellular component cytoplasm nucleus nucleoplasm nuclear speck Biological process apoptotic process centrosome cycle regulation of cyclin-dependent protein serine/threonine kinase activity negative regulation of protein kinase activity signal transduction in response to DNA damage response to stress positive regulation of JNK cascade regulation of cell cycle cellular response to DNA damage stimulus cellular response to mechanical stimulus positive regulation of reactive oxygen species metabolic process positive regulation of apoptotic process cellular response to ionizing radiation cell cycle DNA repair positive regulation of p38MAPK cascade DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1647 13197 Ensembl ENSG00000116717 ENSMUSG00000036390 UniProt P24522 P48316 RefSeq (mRNA) NM_001924 NM_001199741 NM_001199742 NM_007836 RefSeq (protein) NP_001186670 NP_001186671 NP_001915 NP_031862 Location (UCSC) Chr 1: 67.69 – 67.69 Mb Chr 6: 67.01 – 67.01 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene. ^{[5] [6] [7]}

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. ^[7]

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. ^[8] 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, ^[9]
• Cdk1, ^{[10] [11] [12] [13]}
• CCNB1, ^{[10] [13]}
• GADD45GIP1 ^[14]
• MAP3K4, ^[15]
• P21, ^{[12] [16]} and
• PCNA. ^{[12] [17] [18] [19] [20]}

See also

• Gadd45

References

1. GRCh38: Ensembl release 89: ENSG00000116717 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000036390 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. doi:10.1128/MCB.11.2.1009. PMC   359769 . PMID   1990262.
6. 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. doi: 10.1016/S0021-9258(20)80537-7 . PMID   8226988.
7. "Entrez Gene: GADD45A growth arrest and DNA-damage-inducible, alpha".
8. Walmsley RM, Tate M (2012). "The GADD45a-GFP GreenScreen HC assay". Genetic Toxicology. Methods in Molecular Biology. Vol. 817. pp. 231–50. doi:10.1007/978-1-61779-421-6_12. ISBN   978-1-61779-420-9. PMID   22147576.
9. 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.
10. 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. S2CID   13112302.
11. 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.
12. 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.
13. 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. S2CID   19138273.
14. 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.
15. 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. S2CID   18980341.
16. 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.
17. 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. Bibcode:1994Sci...266.1376S. doi:10.1126/science.7973727. PMID   7973727.
18. 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.
19. 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.
20. 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. doi: 10.1016/S0021-9258(18)31687-9 . 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. Bibcode:1994Sci...266.1376S. 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. S2CID   29525059.
• 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. S2CID   18980341.
• 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. doi:10.1128/MCB.19.3.1673. 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. S2CID   13112302.
• 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.

External links

• Media related to GADD45A at Wikimedia Commons