GATA3
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| Location (UCSC) | Chr 10: 8.05 – 8.08 Mb | Chr 2: 9.86 – 9.89 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
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
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
Protein
GATA3 variant 1 is a
Pathophysiology
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in
Function
GATA3 belongs to the
- 1) GATA3 is required for the development of the parathyroid gland, sensory components of the auditory system, and the kidney in animals and humans.[12] It may also contribute 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 humoral 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
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 their 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
Interactions
GATA3 has been shown to
These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000107485 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015619 – 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 2050118.
- PMID 15087456.
- ^ "Entrez Gene: GATA3 GATA binding protein 3".
- S2CID 18342599.
- PMID 27207805.
- ^ S2CID 4647119.
- ^ a b c "OMIM Entry - * 131320 - GATA-BINDING PROTEIN 3; GATA3". omim.org.
- ^ PMID 27387476.
- ^ S2CID 8874053.
- ^ "Homo sapiens GATA binding protein 3 (GATA3), RefSeqGene on chromosome - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. 2019-05-21.
- ^ "GATA3-AS1 GATA3 antisense RNA 1 [Homo sapiens (human)] - Gene - NCBI".
- ^ "DiGeorge syndrome/velocardiofacial syndrome complex 2 - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov.
- ^ S2CID 22213304.
- ^ S2CID 11668034.
- ^ "Homo sapiens GATA binding protein 3 (GATA3), transcript variant 2, mRN - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. 2019-05-19.
- ^ a b "trans-acting T-cell-specific transcription factor GATA-3 isoform 1 [Ho - Protein - NCBI". www.ncbi.nlm.nih.gov.
- ^ a b c "OMIM Entry - * 131320 - GATA-BINDING PROTEIN 3; GATA3".
- PMID 29184556.
- PMID 21632975.
- PMID 17129787.
- PMID 26772397.
- PMID 17349208.
- ^ PMID 26654192.
- PMID 27910098.
- PMID 23000897.
- PMID 18242514.
- PMID 18533032.
- S2CID 2923763.
- PMID 19747394.
- PMID 22706858.
- PMID 28574279.
- PMID 29614760.
- PMID 9819382.
- PMID 9020185.
- PMID 19549328.
- Attribution
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Further reading
- Naylor MJ, Ormandy CJ (2007). "Gata-3 and mammary cell fate". Breast Cancer Research. 9 (2): 302. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. S2CID 4327212.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. 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. 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. 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. 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. 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. 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. 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. PMID 12217316.
External links
- GATA3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook GATA3