GATA2
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Location (UCSC) | Chr 3: 128.48 – 128.49 Mb | Chr 6: 88.17 – 88.18 Mb | |||||||
PubMed search | [3] | [4] |
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GATA2 or GATA-binding factor 2 is a
Inactivating mutations of the GATA2 gene cause a reduction in the cellular levels of GATA2 and the development of a wide range of familial hematological, immunological, lymphatic, and/or other disorders that are grouped together into a common disease termed GATA2 deficiency. Less commonly, these disorders are associated with non-familial (i.e. sporadic or acquired) GATA inactivating mutations. GATA2 deficiency often begins with seemingly benign abnormalities but if untreated progresses to life-threatening opportunistic infections, virus-induced cancers, lung failure, the myelodysplastic syndrome (i.e. MDS), and/or acute myeloid leukemia, principally acute myeloid leukemia (AML), less commonly chronic myelomonocytic leukemia (CMML), and rarely a lymphoid leukemia.[6][7]
Overexpression of the GATA2 transcription factor that is not due to mutations in the GATA2 gene appears to be a secondary factor that promotes the aggressiveness of non-familial EVI1 positive AML as well as the progression of prostate cancer.[8][9][10][11]
GATA2 gene
The GATA2 gene is a member of the evolutionarily conserved
The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in
The human GATA2 gene is
The Gata2 gene in mice has a structure similar to its human counterpart, Deletion of both parental Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the
Mutations
Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's C-ZnF, N-ZnF, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.[6][17]
One GATA2 mutation is a gain of function type, i.e. it is associated with an increase in the activity rather than levels of GATA2. This mutation substitutes valine for leucine in the 359 amino acid position (i.e. within the N-ZnF site) of the transcription factor and has been detected in individuals undergoing the blast crisis of chronic myelogenous leukemia.[9][20]
Pathological inhibition
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promoter. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency.[19]
Pathological stimulation
Non-mutational stimulation of GATA2 expression and consequential aggressiveness in EVI1-positive AML appears due to the ability of
GATA2
The full length GATA2 transcription factor is a moderately sized protein consisting of 480 amino acids. Of its two zinc fingers, C-ZnF (located toward the protein's
GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but for unknown reasons GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2, particularly with referenced to its interactions with many other gene-regulating factors, in controlling its target genes is extremely complex and not fully understood.[6][14][15][16]
Inactivating GATA2 mutations
Familial and sporadic inactivating mutations in one of the two parental GATA2 genes causes a reduction, i.e. a haploinsufficiency, in the cellular levels of the GATA2 transcription factor. In consequence, individuals commonly develop a disease termed GATA2 deficiency. GATA2 deficiency is a grouping of various clinical presentations in which GATA2 haploinsufficiency results in the development over time of hematological, immunological, lymphatic, and/or other presentations that may begin as apparently benign abnormalities but commonly progress to life-threatening opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemias, particularly AML.[6][7] The various presentations of GATA2 deficiency include all cases of Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC) and the Emberger syndrome as well as a significant percentage of cases of familial myelodysplastic syndrome/acute myeloid leukemia, congenital neutropenia, chronic myelomonocytic leukemia, aplastic anemia, and several other presentations.[6][7][29][30]
Activating GATA2 mutation
The L359V gain of function mutation (see above section on mutation) increases the activity of the GATA2 transcription factor. The mutation occurs during the blast crisis of chronic myelogenous leukemia and is proposed to play a role in the transformation of the chronic and/or accelerated phases of this disease to its blast crisis phase.[9][20]
Repression of GATA2
The repression of GATA2 expression due to
Overexpression of GATA2
Elevated levels of GATA2 transcription factor due to overexpression of its gene GATA2 is a common finding in AML. It is associated with a poor prognosis, appears to promote progression of the disease, and therefore proposed to be a target for therapeutic intervention. This overexpression is not due to mutation but rather caused at least in part by the overexpression of
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000179348 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015053 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1714909.
- ^ PMID 28179280.
- ^ PMID 28643018.
- ^ PMID 21904383.
- ^ PMID 25619630.
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- ^ PMID 28264478.
- ^ PMID 23048181.
- ^ "GATA2 GATA binding protein 2 [Homo sapiens (human)] - Gene - NCBI".
- ^ PMID 28637621.
- ^ PMID 28179282.
- ^ PMID 27235756.
- ^ PMID 24227816.
- S2CID 3557136.
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Further reading
- Minegishi N (2002). "[Transcription factors regulating hematopoiesis: researches spanning from molecule to whole body]". Seikagaku. 74 (5): 398–402. PMID 12073612.
- Ohneda K, Yamamoto M (2003). "Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage". Acta Haematol. 108 (4): 237–45. S2CID 29966039.
- Dorfman DM, Wilson DB, Bruns GA, Orkin SH (1992). "Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells". J. Biol. Chem. 267 (2): 1279–85. PMID 1370462.
- Page RL, Wharton JM, Wilkinson WE, Friedman IM, Claypool WD, Karim A, Kowalski KG, McDonald SJ, Gardiner P, Pritchett EL (1992). "Bidisomide (SC-40230), a new antiarrhythmic agent: initial study of tolerability and pharmacokinetics". Clin. Pharmacol. Ther. 51 (4): 371–8. S2CID 21141791.
- Lee ME, Temizer DH, Clifford JA, Quertermous T (1991). "Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells". J. Biol. Chem. 266 (24): 16188–92. PMID 1714909.
- Zhang R, Min W, Sessa WC (1995). "Functional analysis of the human endothelial nitric oxide synthase promoter. Sp1 and GATA factors are necessary for basal transcription in endothelial cells". J. Biol. Chem. 270 (25): 15320–6. PMID 7541039.
- Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH (1995). "Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9585–9. PMID 7568177.
- Towatari M, May GE, Marais R, Perkins GR, Marshall CJ, Cowley S, Enver T (1995). "Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3". J. Biol. Chem. 270 (8): 4101–7. PMID 7876160.
- Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH (1994). "An early haematopoietic defect in mice lacking the transcription factor GATA-2". Nature. 371 (6494): 221–6. S2CID 4235579.
- Briegel K, Lim KC, Plank C, Beug H, Engel JD, Zenke M (1993). "Ectopic expression of a conditional GATA-2/estrogen receptor chimera arrests erythroid differentiation in a hormone-dependent manner". Genes Dev. 7 (6): 1097–109. PMID 8504932.
- Towatari M, Kanei Y, Saito H, Hamaguchi M (1998). "Hematopoietic transcription factor GATA-2 activates transcription from HIV-1 long terminal repeat". AIDS. 12 (3): 253–9. S2CID 45961447.
- Dasen JS, O'Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG (1999). "Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types". Cell. 97 (5): 587–98. S2CID 15737684.
- Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS, Auron PE, Tenen DG, Sun Z (1999). "Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8705–10. PMID 10411939.
- Wieser R, Volz A, Vinatzer U, Gardiner K, Jäger U, Mitterbauer M, Ziegler A, Fonatsch C (2000). "Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia". Biochem. Biophys. Res. Commun. 273 (1): 239–45. PMID 10873593.
- Tsuzuki S, Towatari M, Saito H, Enver T (2000). "Potentiation of GATA-2 Activity through Interactions with the Promyelocytic Leukemia Protein (PML) and the t(15;17)-Generated PML-Retinoic Acid Receptor α Oncoprotein". Mol. Cell. Biol. 20 (17): 6276–86. PMID 10938104.
- Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA (2001). "Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP". J. Biol. Chem. 276 (16): 12645–53. PMID 11278891.
- Ozawa Y, Towatari M, Tsuzuki S, Hayakawa F, Maeda T, Miyata Y, Tanimoto M, Saito H (2001). "Histone deacetylase 3 associates with and represses the transcription factor GATA-2". Blood. 98 (7): 2116–23. PMID 11567998.
- Zhang SB, He QY, Zhao H, Gui CY, Jiang C, Qian RL (2002). "Function of GATA transcription factors in hydroxyurea-induced HEL cells". Cell Res. 11 (4): 301–10. PMID 11787775.
- Tsuzuki S, Enver T (2002). "Interactions of GATA-2 with the promyelocytic leukemia zinc finger (PLZF) protein, its homologue FAZF, and the t(11;17)-generated PLZF-retinoic acid receptor alpha oncoprotein". Blood. 99 (9): 3404–10. S2CID 35192406.
- Hirasawa R, Shimizu R, Takahashi S, Osawa M, Takayanagi S, Kato Y, Onodera M, Minegishi N, Yamamoto M, Fukao K, Taniguchi H, Nakauchi H, Iwama A (2002). "Essential and Instructive Roles of GATA Factors in Eosinophil Development". J. Exp. Med. 195 (11): 1379–86. PMID 12045236.
External links
- GATA2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook GATA2
- Overview of all the structural information available in the PDB for UniProt: P23769 (Endothelial transcription factor GATA-2) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.