Biology:GATA3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3]

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.[4][5] GATA3 haploinsufficiency (i.e. loss of one or the two inherited GATA3 genes) results in a congenital disorder termed the Barakat syndrome.[6][7][8]

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.[6] 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.[9]

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.[10] 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.[11] 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).[12] 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.[8][13] 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.[14]

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.[15] 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.[16]

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.[8][6]

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).[7] Studies in humans implicate GATA3 in the following:

  • 1) GATA3 is required for the development of the parathyroid gland, sensory components of the auditory system, and the kidney in animals and humans.[8] It may also contribute to the development of the vagina and uterus in humans.[17]
  • 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.[18][17]
  • 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,[19]
  • 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.[20][21]
  • 5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the thymus, and the nervous system.[22][17]

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.[7][8][13]

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.[23] 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.[6][24] For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.[23]

Tumors

Breast tumors

Development

GATA3 is one of the three genes mutated in >10% of breast cancers (Cancer Genome Atlas).[25] 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.[14][26] 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.[27][28][29] 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.[14]

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.[30][31]

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.[32][9]

Interactions

GATA3 has been shown to interact with the following transcription factor regulators: ZFPM1 and ZFPM2;[16] LMO1;[33][34] and FOXA1.[35] These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.

See also

References

  1. ↑ "A T-cell specific TCR delta DNA binding protein is a member of the human GATA family". The EMBO Journal 10 (7): 1809–16. Jul 1991. doi:10.1002/j.1460-2075.1991.tb07706.x. PMID 2050118. 
  2. ↑ "Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci". The Journal of Biological Chemistry 279 (26): 26983–90. Jun 2004. doi:10.1074/jbc.M403688200. PMID 15087456. 
  3. ↑ "Entrez Gene: GATA3 GATA binding protein 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2625. 
  4. ↑ Zheng, Wei-ping; Flavell, Richard A (May 1997). "The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells". Cell 89 (4): 587–596. doi:10.1016/s0092-8674(00)80240-8. PMID 9160750. 
  5. ↑ Zheng, WP; Flavell, RA (1 June 2016). "Pillars Article: The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells. Cell. 1997. 89: 587-596". Journal of Immunology 196 (11): 4426–35. PMID 27207805. 
  6. ↑ 6.0 6.1 6.2 6.3 "Targeting cytokines to treat asthma and chronic obstructive pulmonary disease". Nature Reviews. Immunology 18 (7): 454–466. April 2018. doi:10.1038/s41577-018-0006-6. PMID 29626211. 
  7. ↑ 7.0 7.1 7.2 "OMIM Entry - * 131320 - GATA-BINDING PROTEIN 3; GATA3". http://omim.org/entry/131320. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome". Nephrology, Dialysis, Transplantation 32 (5): 830–837. May 2017. doi:10.1093/ndt/gfw271. PMID 27387476. 
  9. ↑ 9.0 9.1 "Value of GATA3 immunostaining in tumor diagnosis: a review". Advances in Anatomic Pathology 20 (5): 352–60. September 2013. doi:10.1097/PAP.0b013e3182a28a68. PMID 23939152. 
  10. ↑ Homo sapiens GATA binding protein 3 (GATA3), RefSeqGene on chromosome - Nucleotide - NCBI. 2019-05-21. https://www.ncbi.nlm.nih.gov/nuccore/NG_015859.1?&feature=any. 
  11. ↑ "GATA3-AS1 GATA3 antisense RNA 1 [Homo sapiens (human)] - Gene - NCBI". https://www.ncbi.nlm.nih.gov/gene/399717#summary. 
  12. ↑ "DiGeorge syndrome/velocardiofacial syndrome complex 2 - Conditions - GTR - NCBI". https://www.ncbi.nlm.nih.gov/gtr/conditions/C1832431/. 
  13. ↑ 13.0 13.1 "Molecular and clinical characterization of patients with overlapping 10p deletions". American Journal of Medical Genetics. Part A 152A (5): 1233–43. May 2010. doi:10.1002/ajmg.a.33366. PMID 20425828. 
  14. ↑ 14.0 14.1 14.2 "The Significance and Therapeutic Potential of GATA3 Expression and Mutation in Breast Cancer: A Systematic Review". Medicinal Research Reviews 35 (6): 1300–15. November 2015. doi:10.1002/med.21362. PMID 26313026. 
  15. ↑ Homo sapiens GATA binding protein 3 (GATA3), transcript variant 2, mRN - Nucleotide - NCBI. 2019-05-19. https://www.ncbi.nlm.nih.gov/nuccore/NM_002051.2. 
  16. ↑ 16.0 16.1 "trans-acting T-cell-specific transcription factor GATA-3 isoform 1 [Ho - Protein - NCBI". https://www.ncbi.nlm.nih.gov/protein/50541959. 
  17. ↑ 17.0 17.1 17.2 "OMIM Entry - * 131320 - GATA-BINDING PROTEIN 3; GATA3". https://www.omim.org/entry/131320. 
  18. ↑ "GATA3 Regulates the Development and Functions of Innate Lymphoid Cell Subsets at Multiple Stages". Frontiers in Immunology 8: 1571. 2017. doi:10.3389/fimmu.2017.01571. PMID 29184556. 
  19. ↑ "An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation Z". International Immunology 23 (7): 415–20. Jul 2011. doi:10.1093/intimm/dxr029. PMID 21632975. 
  20. ↑ "GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland". Cell 127 (5): 1041–55. Dec 2006. doi:10.1016/j.cell.2006.09.048. PMID 17129787. 
  21. ↑ "The role of GATA3 in breast carcinomas: a review". Human Pathology 48: 37–47. February 2016. doi:10.1016/j.humpath.2015.09.035. PMID 26772397. 
  22. ↑ "GATA-3 - not just for Th2 cells anymore". Cellular & Molecular Immunology 4 (1): 15–29. February 2007. PMID 17349208. 
  23. ↑ 23.0 23.1 "Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis". The Journal of Allergy and Clinical Immunology 136 (6): 1431–1440. December 2015. doi:10.1016/j.jaci.2015.10.010. PMID 26654192. 
  24. ↑ "GATA-3-specific DNAzyme - A novel approach for stratified asthma therapy". European Journal of Immunology 47 (1): 22–30. January 2017. doi:10.1002/eji.201646450. PMID 27910098. 
  25. ↑ "Comprehensive molecular portraits of human breast tumours". Nature 490 (7418): 61–70. Oct 2012. doi:10.1038/nature11412. PMID 23000897. Bibcode: 2012Natur.490...61T. 
  26. ↑ "GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model". Cancer Cell 13 (2): 141–52. Feb 2008. doi:10.1016/j.ccr.2008.01.011. PMID 18242514. 
  27. ↑ "Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway". Molecular Cancer 7: 49. 2008. doi:10.1186/1476-4598-7-49. PMID 18533032. 
  28. ↑ "GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis". Oncogene 28 (29): 2634–42. Jul 2009. doi:10.1038/onc.2009.126. PMID 19483726. 
  29. ↑ "Gene expression meta-analysis supports existence of molecular apocrine breast cancer with a role for androgen receptor and implies interactions with ErbB family". BMC Medical Genomics 2: 59. 2009. doi:10.1186/1755-8794-2-59. PMID 19747394. 
  30. ↑ "Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas". American Journal of Clinical Pathology 138 (1): 57–64. July 2012. doi:10.1309/AJCP5UAFMSA9ZQBZ. PMID 22706858. 
  31. ↑ "Update on Immunohistochemical Analysis in Breast Lesions". Archives of Pathology & Laboratory Medicine 141 (8): 1033–1051. August 2017. doi:10.5858/arpa.2016-0482-RA. PMID 28574279. 
  32. ↑ "Bladder Cancer: New Insights into Its Molecular Pathology". Cancers 10 (4): 100. April 2018. doi:10.3390/cancers10040100. PMID 29614760. 
  33. ↑ "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. Dec 1998. doi:10.1128/MCB.18.12.6939. PMID 9819382. 
  34. ↑ "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. Feb 1997. doi:10.1074/jbc.272.7.4576. PMID 9020185. 
  35. ↑ "Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours". Breast Cancer Research 11 (3): R40. 2009. doi:10.1186/bcr2327. PMID 19549328. 
Attribution

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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