GATA3
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GATA3 is a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that in humans is encoded by the ''GATA3''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes. 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 The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
of
blood vessels Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...
. GATA3 plays central role in allergy and immunity against worm infections. ''GATA3''
haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
(i.e. loss of one or the two inherited ''GATA3'' genes) results in a
congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
disorder termed the Barakat syndrome. 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. 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.


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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...
, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2. Expression of ''GATA3'' may be regulated in part or at times by the
antisense RNA Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
, GATA3-AS1, whose gene is located close to the ''GATA3'' gene on the short arm of chromosome 10 at position p14. Various types of
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
including
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
s as well as small- and large-scale deletional mutations cause an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
, 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). 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. 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.


Protein

GATA3 variant 1 is a
linear In mathematics, the term ''linear'' is used in two distinct senses for two different properties: * linearity of a '' function'' (or '' mapping''); * linearity of a '' polynomial''. An example of a linear function is the function defined by f(x) ...
protein consisting of 444
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
. GATA3 variant 2 protein is an identically structured
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported. With respect to the best studied variant, variant 1, but presumably also variant 2, one of the
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...
s, ZNF2, is located at the protein's
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
and binds to specific
gene promoter In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription (genetics), transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can hav ...
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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
and interacts with various nuclear factors, including Zinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1 .e. FOG-1 and ZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.


Pathophysiology

The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in
physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
as well as
pathological Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
humoral inflammatory and allergic responses.


Function

GATA3 belongs to the GATA family of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s. 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 Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...
,
neural crest cell The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, an ...
s,
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland). Studies in humans implicate GATA3 in the following: *1) GATA3 is required for the development of the
parathyroid gland Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...
, sensory components of the auditory system, and the kidney in animals and humans. It may also contribute to the development of the vagina and uterus in humans. *2) In humans, GATA3 is required for the development and/or function of
innate lymphoid cell Innate lymphoid cells (ILCs) are the most recently discovered family of Innate immune system, innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secreti ...
s (ILCs), particularly Group 2 ILCs as well as for the development of
T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s,(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. *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, *4) GATA3 induces the maturation of precursor cells into
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
and maintains these cells in their mature state in mice and possibly humans. *5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the
thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...
, and the nervous system.


Clinical significance


Mutations

Inactivating mutations in one of the two parental GATA3 genes cause the
congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
disorder of
hypoparathyroidism Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary m ...
with
sensorineural deafness Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...
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 A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
because of 1) individual differences in the
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
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 Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues during
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
.


Allergy

Mouse studies indicate that inhibiting the expression of GATA3 using
antisense RNA Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
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. In a phase IIA clinical study of individuals suffering allergen-induced asthma, inhalation of
Deoxyribozyme Deoxyribozymes, also called DNA enzymes, DNAzymes, or catalytic DNA, are DNA oligonucleotides that are capable of performing a specific chemical reaction, often but not always catalytic. This is similar to the action of other biological enzymes, s ...
ST010, which specifically inactivates GATA3
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
, 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 Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses. For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.


Tumors


Breast tumors


= Development

= ''GATA3'' is one of the three genes mutated in >10% of
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
s (Cancer Genome Atlas). 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. 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 Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...
, and (in estrogen receptor negative/androgen receptor positive cancers)
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
signaling. 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.


= 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 cancer Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...
s. This analysis is widely used as a clinically valuable marker for breast cancer.


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 The bladder () is a hollow organ in humans and other vertebrates that stores urine from the Kidney (vertebrates), kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the ...
and
urethral cancer Urethral cancer is a rare cancer originating from the urethra. The disease has been classified by the TNM staging system and the World Health Organization. Symptoms include blood in the urine, lump at end of penis, or bloody penile discharge. ...
s as well as for
parathyroid gland Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...
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
paraganglioma A paraganglioma is a rare neuroendocrine tumour, neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a p ...
s.


Interactions

GATA3 has been shown to interact with the following transcription factor regulators: ZFPM1 and ZFPM2;
LMO1 Rhombotin-1 is a protein that in humans is encoded by the ''LMO1'' gene. LMO1 encodes a cysteine-rich, two LIM domain transcriptional regulator. It is mapped to an area of consistent chromosomal translocation in chromosome 11, disrupting it in T ...
; and FOXA1. These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.


See also

*
GATA transcription factor The GATA transcription factor family consists of six DNA-binding proteins (GATA1-6) that regulates transcription of DNA due to their ability to bind to the DNA sequence "GATA" which can therefore affect different diseases. These six proteins a ...
s


References

; Attribution


Further reading

* * * * * * * * * * * * * * * * * * *


External links

* * {{Transcription factors, g2 Transcription factors