GATA3 (GATA binding protein 3)

2011-12-01   Mathieu Tremblay  , Maxime Bouchard  

Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, Canada

Identity

HGNC
LOCATION
10p14
LOCUSID
ALIAS
HDR,HDRS
FUSION GENES

DNA/RNA

Description

The GATA3 locus spans 20,51 kb and contains 6 exons.

Transcription

Two alternative exons 1 (1a and 1b) of the Gata3 locus are spliced to a common second exon, which contains the translation start site. All transcripts share exons 2 to 5 but transcript 1a and 1b splice to two variant exons 6 (6a and 6b respectively) giving rise to isoform a (1a-2-5-6a) and isoform b (1b-2-5-6b) (see figure 1) (Asnagli et al., 2002). The functional significance of these isoforms is unclear.

Proteins

Atlas Image
Figure 1. White boxes indicate a non-coding exonic sequence, and black boxes indicate coding sequences. Gata3 encodes a protein containing 2 transactivation domains (TA1 and TA2) and 2 Zn Finger domains (Zn1 and Zn2).

Description

The full length GATA3 protein contain either 443 AA (isoform a) or 444 AA (isoform b), corresponding to molecular weights of 47,9 kDa and 48,0 kDa respectively. The GATA3 protein contains two zinc finger motifs of a distinctive form CXNCX (17) and CNXC as well as two transactivation domains (TA1 and TA2). The N-terminal Zn finger (Zn1) is known to stabilize DNA binding and interact with other zinc finger proteins, whereas the C-terminal Zn finger (Zn2) binds DNA.

Expression

Hematopoietic system (blood, bone marrow, thymus, B, T, erythroid and myeloid lineages), blood vessels (endothelial cells), adipocytes, adrenal gland, ear, eye, bladder, mammary gland, prostate, seminal vesicle, kidney, CNS, hair follicle.

Localisation

Mostly nuclear.

Function

GATA3 acts as a transcription factor which binds to the consensus DNA sequence 5-(A/T)GATA(A/G)-3.

Gata3 gene inactivation in the mouse is embryonic lethal at mid-gestation (between embryonic days E11 and E12) (Tsai et al., 1994; Pandolfi et al., 1995). These mice display massive internal bleeding, marked growth retardation, severe deformities of the brain and spinal cord, and gross aberrations in fetal liver hematopoiesis. Lethality of Gata3 mutant embryos can be rescued by administration of catechol intermediates during pregnancy as it corrects the reduction in noradrenalin synthesis in the sympathetic nervous system (SNS) caused by reduced expression of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Pharmacologically rescued mutant embryos present developmental defects in structures derived from cephalic neural crest cells (Lim et al., 2000).
In the kidney, Gata3 is important for nephric (Wolffian) duct elongation and metanephric kidney induction (Grote et al., 2006; Grote et al., 2008). Conditional inactivation of Gata3 in the nephric duct leads to hydronephrosis and defective ureter maturation, partly due to the downregulation of the receptor tyrosine kinase gene Ret (Song et al., 2009; Chia et al., 2011).

Gata3 plays an important role in mammary gland maturation and cancer. The conditional deletion of Gata3 in the mouse mammary epithelium is associated with a failure in terminal end bud formation at puberty causing severe defects in mammary development. Moreover, Gata3 loss in adult mice leads to an expansion of undifferentiated luminal cells and basement-membrane detachment, which promotes tumor dissemination (Kouros-Mehr et al., 2006; Asselin-Labat et al., 2007; Kouros-Mehr et al., 2008; Kouros-Mehr et al., 2008; Dydensborg et al., 2009).
Reexpression of Gata3 drives invasive breast cancer cells to undergo the reversal of epithelial-mesenchymal transition, reducing both the tumorigenicity and metastatic potential through reduction of lysyl oxidase (LOX) expression, a metastasis-promoting, matrix-remodeling protein (Chu et al., 2011; Yan et al., 2010). Moreover, Gata3 interact with BRCA1 to repress the expression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including Foxc1, Foxc2, Cxcl1 and P-cadherin. Loss of GATA3 expression also contributes to drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs (Tkocz et al., 2011).

In T cells, Gata3 acts at multiple stages of thymocyte differentiation. It is indispensable for early thymic progenitor differentiation (Hosoya et al., 2009) and for thymocytes to pass through beta selection and T cell commitment. Gata3 is also necessary for single-positive CD4 thymocyte development as well as for Th1-Th2 lineage commitment (Ting et al., 1996; Zhang et al., 1997; Zheng and Flavell, 1997; Zhang et al., 1998; Pai et al., 2003). As master regulator of Th2 lineage commitment, GATA3 acts either as a transcriptional activator or repressor through direct action at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation (Jenner et al., 2009). For example, it regulates the expression of Th2 lineage specific cytokine gene such as IL5 and repress the Th1 lineage specific genes IL-12 receptor β2 and STAT4 as well as neutralizing RUNX3 function through protein-protein interaction. Mice lacking Gata3 produce IFN-gamma rather than Th2 cytokines (IL5 and IL13) in response to infection (Zhu et al., 2004). It acts in mutual opposition to the transcription factor T-bet, as T-bet promotes whereas GATA3 represses Fut7 transcription (Hwang et al., 2005). It also acts with Tbx21 to regulate cell lineage-specific expression of lymphocyte homing receptors and cytokine in both Th1 and Th2 lymphocyte subsets (Chen et al., 2006). Enforced expression of Gata3 during T cell development induced CD4(+)CD8(+) double-positive (DP) T cell lymphoma (Nawijn et al., 2001a; Nawijn et al., 2001b).

Gata3 is essential for the expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. Gata3 overexpression causes enhanced allergen-induced airway inflammation and airway remodeling, including subepithelial fibrosis, and smooth muscle cell hyperplasia (Kiwamoto et al., 2006). It additionally has a critical function in regulatory T cells and immune tolerance since deletion of Gata3 specifically in regulatory T cells led to a spontaneous inflammatory disorder in mice (Wang et al., 2011).

Gata3 is critical for the differentiation and survival of parathyroid progenitor cells through regulation of GCM2/B (Grigorieva et al., 2010). Gata3 is essential for the survival but not the differentiation of sympathetic neurons and adrenal chromaffin cells (Tsarovina et al., 2010) and acts with Hand2 to induce noradrenergic genes during development (Pellegrino et al., 2011).

Gata3 drives trophoblast differentiation and has been shown to induce a trophoblast cell fate in embryonic stem cells (Ralston et al., 2010). Gata3 and its close paralog Gata2 are important for trophectoderm lineage specification (Ray et al., 2009).

During adipogenesis, Gata3 is a negative regulator of differentiation which needs to be downregulated to permit expression of the peroxisome proliferator-activated receptor-gamma and preadipocyte to adipocyte transition (Tong et al., 2000).

In keratinocytes, Gata3 is a key regulator of KLK1 expression and is involved in growth control and the maintenance of a differentiated state in epithelial cells (Son do et al., 2009).
In hair follicle morphogenesis Gata3 controls cell fate decision between the inner root sheath and hair shaft cell (Kaufman et al., 2003; Kurek et al., 2007).

Gata3 is essential for lens cells differentiation and proper cell cycle control (Maeda et al., 2009) as well as in the morphogenesis of the mouse inner ear (Karis et al., 2001; Lilleväli et al., 2004).
It plays an essential role during angiogenesis through ANGPT1-TEK and Ang-1-Tie2-mediated signaling in large vessel endothelial cells.
A role for Gata3 in the developing heart was revealed by pharmacological rescue of Gata3-null embryos, which survive until birth and harbor ventricular septal defect (VSD), double-outlet of right ventricle (DORV), anomalies of the aortic arch (AAA) and persistent truncus arteriosus (PTA) (Raid et al., 2009).

Homology

GATA3 is a member of the GATA family of proteins comprising 6 paralogs. GATA1, GATA2 and GATA3 are mainly expressed in hematopoiesis, whereas GATA4, GATA5 and GATA6 are expressed in mesoderm and endoderm-derived tissue. All six GATA family members share a highly conserved double zinc-finger DNA-binding domain. GATA3 Zn fingers are most closely conserved with those of GATA1.

Mutations

Germinal

Deletion of chromosome 10 (del10p) and GATA3 gene mutations leading to haploinsufficiency associated with HDR syndrome (Van Esch et al., 2000; Nesbit et al., 2004; Ali et al., 2007; Lindstrand et al., 2010).

Somatic

Heterozygous frameshift mutations close to the second Zn finger domain of GATA3 are associated with familial and sporadic breast tumors (Ciocca et al., 2009; Arnold et al., 2010).

Implicated in

Entity name
Sporadic breast cancer and familial breast cancer
Cytogenetics
Somatic mutations in GATA3: familial breast tumors harbored heterozygous frameshift somatic mutations close to the second Zn finger domain.
Oncogenesis
GATA3 is mutated in ~5% of sporadic and ~13% of familial breast tumors (Usary et al., 2004; Mehra et al., 2005; Arnold et al., 2010).
GATA3 is an important predictor of disease outcome in breast cancer patients whereby low GATA3 expression was a significant predictor of disease-related death (Yoon et al., 2010).
Entity name
HDR (Barakat) syndrome
Disease
Familial hypoparathyroidism - deafness - renal defects syndrome.
- Hypoparathyroidism.
- Sensorineural deafness, bilateral, symmetric, deficit affecting all frequencies but slightly more marked at the higher end of the frequency range.
- Renal defects such as aplasia, dysplasia and vesicoureteral reflux, associated or not to genital tract malformation.
Prognosis
Depends on the penetrance of renal defects.
Cytogenetics
- Deletion of chromosome 10 (del10p).
- GATA3 gene mutations leading to functional haploinsufficiency.
Atlas Image
Figure 2. Both chromosome deletion and point mutations of the GATA3 locus have been associated with HDR syndrome.

Article Bibliography

Other Information

Locus ID:

NCBI: 2625
MIM: 131320
HGNC: 4172
Ensembl: ENSG00000107485

Variants:

dbSNP: 2625
ClinVar: 2625
TCGA: ENSG00000107485
COSMIC: GATA3

RNA/Proteins

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

References

Citation

Mathieu Tremblay ; Maxime Bouchard

GATA3 (GATA binding protein 3)

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/gene/107/gata3id107ch10p14