GATA3
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.[5][6][7]
The GATA3 transcription factor is critical for the embryonic development of various tissues as well as for inflammatory and humoral immune responses and the proper functioning of the endothelium of blood vessels. GATA3 plays central role in allergy and immunity against worm infections.[8][9] GATA3 haploinsufficiency (i.e. loss of one or the two inherited GATA3 genes) results in a congenital disorder termed the Barakat syndrome.[10][11][12]
Current clinical and laboratory research is focusing on determining the benefits of directly or indirectly blocking the action of GATA3 in inflammatory and allergic diseases such as asthma.[10] It is also proposed to be a clinically important marker for various types of cancer, particularly those of the breast. However, the role, if any, of GATA3 in the development of these cancers is under study and remains unclear.[13]
Gene
The GATA3 gene is located close to the end of the short arm of chromosome 10 at position p14. It consists of 8 exons, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2.[14] Expression of GATA3 may be regulated in part or at times by the antisense RNA, GATA3-AS1, whose gene is located close to the GATA3 gene on the short arm of chromosome 10 at position p14.[15] Various types of mutations including point mutations as well as small- and large-scale deletional mutations cause an autosomal dominant genetic disorder, the Barakat syndrome (also termed hypoparathyroidism, deafness, and renal dysplasia syndrome). The location of GATA3 borders that of other critical sites on chromosome 10, particularly a site located at 10p14-p13. Mutations in this site cause the congenital disorder DiGeorge syndrome/velocardiofacial syndrome complex 2 (or DiGeorge syndrome 2).[16] Large-scale deletions in GATA3 may span into the DiGeorge syndrome 2 area and thereby cause a complex syndrome with features of the Barakat syndrome combined with some of those of the DiGeorge syndrome 2.[12][17] Knockout of both GATA3 genes in mice is fatal: these animals die at embryonic days 11 and 12 due to internal bleeding. They also exhibit gross deformities in the brain and spine as well as aberrations in fetal liver hematopoiesis.[18]
Protein
GATA3 variant 1 is a linear protein consisting of 444 amino acids. GATA3 variant 2 protein is an identically structured isoform of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported.[19] With respect to the best studied variant, variant 1, but presumably also variant 2, one of the zinc finger structural motifs, ZNF2, is located at the protein's C-terminus and binds to specific gene promoter DNA sequences to regulate the expression of the genes controlled by these promoters. The other zinc finger, ZNF1, is at the protein's N-terminus and interacts with various nuclear factors, including Zinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1 [i.e. FOG-1]) and ZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.[20]
Pathophysiology
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in physiological as well as pathological humoral inflammatory and allergic responses.[12][10]
Function
GATA3 belongs to the GATA family of transcription factors. Gene-deletion studies in mice indicate that Gata3 (mouse gene equivalent to GATA3) is critical for the embryonic development and/or function of various cell types (e.g. fat cells, neural crest cells, lymphocytes) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland).[11] Studies in humans implicate GATA3 in the following:
- 1) GATA3 is required for the development of the parathyroid gland, sensory component(s) of the auditory system, and the kidney in animals and humans.[12] It may also contribure to the development of the vagina and uterus in humans.[21]
- 2) In humans, GATA3 is required for the development and/or function of innate lymphoid cells (ILCs), particularly Group 2 ILCs as well as for the development of T helper cells,(Th cells), particularly Th2 cells. Group 2 ILCs and Th2 cells, and thereby GATA3, are critical for the development of allergic and humoral immune responses in humans. Comparable studies in animals implicate GATA3 in the development of lymphocytes that mediate allergic and humoral immunity as well as allergic and humeral immune responses.[22][21]
- 3) GATA3 promotes the secretion of IL-4, IL-5, and IL-13 from Th2 cells in humans and has similar actions on comparable mouse lymphocytes. All three of these interleukins serve to promote allergic responses,[23]
- 4) GATA3 induces the maturation of precursor cells into breast epithelial cells and maintains these cells in their mature state in mice and possibly humans.[24][25]
- 5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the thymus, and the nervous system.[26][21]
Clinical significance
Mutations
Inactivating mutations in one of the two parental GATA3 genes cause the congenital disorder of hypoparathyroidism with sensorineural deafness and kidney malformations, i.e. the Barakat syndrome. This rare syndrome may occur in families or as a new mutation in an individual from a family with no history of the disorder. Mutations in GATA3 cause variable degrees of hypoparathyroidism, deafness, and kidney disease birth defects because of 1) individual differences in the penetrance of the mutation, 2) a sporadic, and as yet unexplained, association with malformation of uterus and vagina, and 3) mutations which extend beyond the GATA3 gene into chromosomal areas where mutations are responsible for developing other types of abnormalities which are characteristics of the DeGeorge syndrome 2. The Barakat syndrome is due to a haploinsufficiency in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues during embryogenesis.[11][12][17]
Allergy
Mouse studies indicate that inhibiting the expression of GATA3 using antisense RNA methods suppresses allergic inflammation. The protein is overexpressed in the afflicted tissues of individuals with various forms of allergy including asthma, rhinitis, nasal polyps, and atopic eczema. This suggests that it may have a role in promoting these disorders.[27] In a phase IIA clinical study of individuals suffering allergen-induced asthma, inhalation of Deoxyribozyme ST010, which specifically inactivates GATA3 messenger RNA, for 28 days reduced early and late immune lung responses to inhaled allergen. The clinical benefit of inhibiting GATA3 in this disorder is thought to be due to interfering with the function of Group 2 ILCs and Th2 cells by, for example, reducing there production of IL-4, IL-13, and especially IL-5. Reduction in these eosinophil-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses.[10][28] For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.[27]
Tumors
Breast tumors
Development
GATA3 is one of the three genes mutated in >10% of breast cancers (Cancer Genome Atlas).[29] Studies in mice indicate that the gene is critical for the normal development of breast tissue and directly regulates luminal cell (i.e. cells lining mammary ducts) differentiation in experimentally induced breast cancer.[18][30] Analytic studies of human breast cancer tissues suggest that GATA3 is required for specific type of low risk breast cancer (i.e. luminal A), is integral to the expression of estrogen receptor alpha, and (in estrogen receptor negative/androgen receptor positive cancers) androgen receptor signaling.[31][32][33] These studies suggest that GATA3 is involved in the development of at least certain types of breast cancer in humans. However, there is disagreement on this, with some studies suggesting that the expression of the GATA3 acts to inhibit and other studies suggesting that it acts to promote the development, growth, and/or spread of this cancer. Further studies are needed to elucidate the role, if any, of GATA3 in the development of breast cancer.[18]
Marker
Immuocytochemical analysis of GATA3 protein in breast cells is a valuable marker for diagnosing primary breast cancer, being tested as positive in up to 94% of cases. It is especially valuable for estrogen receptor positive breast cancers but is less sensitive (435-66% elevated), although still more valuable than many other markers, for diagnosing triple-negative breast cancers. This analysis is widely used as a clinically valuable marker for breast cancer.[34][35]
Other tumor types
Similar to breast tumors, the role of GATA3 in the genesis of other tumor types is unclear but detection of its transcription factor product may be diagnostically useful. Immuocytochemical analysis of GATA3 protein is considered a valuable marker for certain types of urinary bladder and urethral cancers as well as for parathyroid gland tumors (cancerous or benign), Single series reports suggest that this analysis might also be of value for diagnosing salivary gland tumors, salivary duct carcinomas, mammary analog secretory carcinomas, benign ovarian Brenner tumors, benign Walthard cell rests, and paragangliomas.[36][13]
Interactions
GATA3 has been shown to interact with the following transcription factor regulators: ZFPM1 and ZFPM2;[20] LMO1;[37][38] and FOXA1.[39] These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.
See also
References
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Further reading
- Naylor MJ, Ormandy CJ (2007). "Gata-3 and mammary cell fate". Breast Cancer Research. 9 (2): 302. doi:10.1186/bcr1661. PMC 1868924. PMID 17381824.
- Ho IC, Vorhees P, Marin N, Oakley BK, Tsai SF, Orkin SH, Leiden JM (May 1991). "Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene". The EMBO Journal. 10 (5): 1187–92. doi:10.1002/j.1460-2075.1991.tb08059.x. PMC 452772. PMID 1827068.
- Marine J, Winoto A (Aug 1991). "The human enhancer-binding protein Gata3 binds to several T-cell receptor regulatory elements". Proceedings of the National Academy of Sciences of the United States of America. 88 (16): 7284–8. Bibcode:1991PNAS...88.7284M. doi:10.1073/pnas.88.16.7284. PMC 52279. PMID 1871134.
- Ko LJ, Yamamoto M, Leonard MW, George KM, Ting P, Engel JD (May 1991). "Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer". Molecular and Cellular Biology. 11 (5): 2778–84. doi:10.1128/mcb.11.5.2778. PMC 360054. PMID 2017177.
- Siegel MD, Zhang DH, Ray P, Ray A (Oct 1995). "Activation of the interleukin-5 promoter by cAMP in murine EL-4 cells requires the GATA-3 and CLE0 elements". The Journal of Biological Chemistry. 270 (41): 24548–55. doi:10.1074/jbc.270.41.24548. PMID 7592673.
- Labastie MC, Bories D, Chabret C, Grégoire JM, Chrétien S, Roméo PH (May 1994). "Structure and expression of the human GATA3 gene". Genomics. 21 (1): 1–6. doi:10.1006/geno.1994.1217. PMID 8088776.
- Ono Y, Fukuhara N, Yoshie O (Feb 1997). "Transcriptional activity of TAL1 in T cell acute lymphoblastic leukemia (T-ALL) requires RBTN1 or -2 and induces TALLA1, a highly specific tumor marker of T-ALL". The Journal of Biological Chemistry. 272 (7): 4576–81. doi:10.1074/jbc.272.7.4576. PMID 9020185.
- Ono Y, Fukuhara N, Yoshie O (Dec 1998). "TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3". Molecular and Cellular Biology. 18 (12): 6939–50. doi:10.1128/MCB.18.12.6939. PMC 109277. PMID 9819382.
- Yang GP, Ross DT, Kuang WW, Brown PO, Weigel RJ (Mar 1999). "Combining SSH and cDNA microarrays for rapid identification of differentially expressed genes". Nucleic Acids Research. 27 (6): 1517–23. doi:10.1093/nar/27.6.1517. PMC 148347. PMID 10037815.
- Blumenthal SG, Aichele G, Wirth T, Czernilofsky AP, Nordheim A, Dittmer J (Apr 1999). "Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1". The Journal of Biological Chemistry. 274 (18): 12910–6. doi:10.1074/jbc.274.18.12910. PMID 10212281.
- Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (Jul 2000). "GATA3 haplo-insufficiency causes human HDR syndrome". Nature. 406 (6794): 419–22. Bibcode:2000Natur.406..419V. doi:10.1038/35019088. PMID 10935639. S2CID 4327212.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T (Jun 2001). "GATA3 abnormalities and the phenotypic spectrum of HDR syndrome". Journal of Medical Genetics. 38 (6): 374–80. doi:10.1136/jmg.38.6.374. PMC 1734904. PMID 11389161.
- Crawford SE, Qi C, Misra P, Stellmach V, Rao MS, Engel JD, Zhu Y, Reddy JK (Feb 2002). "Defects of the heart, eye, and megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family of transcription factors". The Journal of Biological Chemistry. 277 (5): 3585–92. doi:10.1074/jbc.M107995200. PMID 11724781.
- Kieffer LJ, Greally JM, Landres I, Nag S, Nakajima Y, Kohwi-Shigematsu T, Kavathas PB (Apr 2002). "Identification of a candidate regulatory region in the human CD8 gene complex by colocalization of DNase I hypersensitive sites and matrix attachment regions which bind SATB1 and GATA-3". Journal of Immunology. 168 (8): 3915–22. doi:10.4049/jimmunol.168.8.3915. PMID 11937547.
- Asnagli H, Afkarian M, Murphy KM (May 2002). "Cutting edge: Identification of an alternative GATA-3 promoter directing tissue-specific gene expression in mouse and human". Journal of Immunology. 168 (9): 4268–71. doi:10.4049/jimmunol.168.9.4268. PMID 11970965.
- Steenbergen RD, OudeEngberink VE, Kramer D, Schrijnemakers HF, Verheijen RH, Meijer CJ, Snijders PJ (Jun 2002). "Down-regulation of GATA-3 expression during human papillomavirus-mediated immortalization and cervical carcinogenesis". The American Journal of Pathology. 160 (6): 1945–51. doi:10.1016/S0002-9440(10)61143-1. PMC 1850837. PMID 12057898.
- Höfer T, Nathansen H, Löhning M, Radbruch A, Heinrich R (Jul 2002). "GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model". Proceedings of the National Academy of Sciences of the United States of America. 99 (14): 9364–8. Bibcode:2002PNAS...99.9364H. doi:10.1073/pnas.142284699. PMC 123146. PMID 12087127.
- Karunaratne A, Hargrave M, Poh A, Yamada T (Sep 2002). "GATA proteins identify a novel ventral interneuron subclass in the developing chick spinal cord". Developmental Biology. 249 (1): 30–43. doi:10.1006/dbio.2002.0754. PMID 12217316.
External links
- GATA3+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook GATA3
This article incorporates text from the United States National Library of Medicine, which is in the public domain.