Gli2
Encyclopedia
Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene
. The protein
encoded by this gene is a transcription factor
.
GLI2 belongs to the C2H2-type zinc finger
protein subclass of the Gli family. Members of this subclass are characterized as transcription factor
s which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog
(Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH
) gene expression. It is also thought to play a role during embryogenesis.
activator
and N-terminal repressor
regions have been identified in both Gli2 and Gli3
. However, the N-terminal part of human
Gli2 is much smaller than its mouse
or frog
homologs
, suggesting that it may lack repressor function.
al development by regulating at least three different gene
s; Wnt gene
s involved in morphogenesis
, Brachyury
genes involved in tissue
specification and Xhox3 genes involved in positional information. The anti-apoptotic
protein
BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1
– but not Gli3, which may lead to carcinogenesis
.
It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus
. This suggests that in mouse embryogenesis
, Gli1 and Gli2 regulate a similar set of target genes. Mutation
s do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent. Gli2 and Gli3 are important in the formation and development of lung
, trachea
and oesophagus tissue during embryo development. Studies have also shown that GLI2 plays a dual role as activator of keratinocyte
proliferation and repressor of
epidermal differentiation. There is a significant level of crosstalk
and functional overlap between the Gli TF
s. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically
normal. However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally
and Gli3 dorsally in transgenic mice. Gli2 null mice embryos develop neural tube
defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system
and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs. Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level. These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumor
s form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous
keratinocyte
s develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma
(BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastoma
s, cylindroma
s and hamartoma
s but rarely developed BCCs. Gli2 is expressed in the
interfollicular epidermis and the outer root sheath of hair follicle
s in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.
, Pallister-Hall syndrome
, preaxial polydactyly
type IV, postaxial polydactyly types A1 and B.
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by this gene is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
.
GLI2 belongs to the C2H2-type zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
protein subclass of the Gli family. Members of this subclass are characterized as transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog
Hedgehog signaling pathway
In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The hedgehog signaling pathway gives cells information that they need to make the embryo develop properly....
(Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH
PTCH1
Protein patched homolog 1 is a protein that is the member of the Patched family and in humans is encoded by the PTCH1 gene.- Function :PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in...
) gene expression. It is also thought to play a role during embryogenesis.
Structure
C-terminalC-terminal end
The C-terminus is the end of an amino acid chain , terminated by a free carboxyl group . When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus...
activator
Activator (genetics)
An activator is a DNA-binding protein that regulates one or more genes by increasing the rate of transcription. The activator may increase transcription by virtue of a connected domain which assists in the formation of the RNA polymerase holoenzyme, or may operate through a coactivator. A...
and N-terminal repressor
Repressor
In molecular genetics, a repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called...
regions have been identified in both Gli2 and Gli3
Gli3
Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog signaling...
. However, the N-terminal part of human
Human
Humans are the only living species in the Homo genus...
Gli2 is much smaller than its mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
or frog
Frog
Frogs are amphibians in the order Anura , formerly referred to as Salientia . Most frogs are characterized by a short body, webbed digits , protruding eyes and the absence of a tail...
homologs
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
, suggesting that it may lack repressor function.
Function
Gli2 affects ventroposterior mesodermMesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
al development by regulating at least three different gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s; Wnt gene
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
s involved in morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
, Brachyury
Brachyury
Brachyury is a protein that in humans is encoded by the T gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.-History:...
genes involved in tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
specification and Xhox3 genes involved in positional information. The anti-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1
Gli1
Gli1 is a protein originally isolated in human glioblastoma.-Overview:The Gli proteins are the effectors of Hedgehog signaling and have been shown to be involved in cell fate determination, proliferation and patterning in many cell types and most organs during embryo development.The Gli...
– but not Gli3, which may lead to carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
.
It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. This suggests that in mouse embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
, Gli1 and Gli2 regulate a similar set of target genes. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent. Gli2 and Gli3 are important in the formation and development of lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, trachea
Vertebrate trachea
In tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...
and oesophagus tissue during embryo development. Studies have also shown that GLI2 plays a dual role as activator of keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
proliferation and repressor of
epidermal differentiation. There is a significant level of crosstalk
Crosstalk (biology)
Biological crosstalk refers to instances in which one or more components of a signal transduction pathway affect a different pathway. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction...
and functional overlap between the Gli TF
TF
TF can refer to:* Task force* Teaching fellow, a member of the teaching fellowship* Transformation -Biology:* Theaflavin, a type ofn antioxidant polyphenols flavan-3-ols that are formed from catechins in tea leaves...
s. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
normal. However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally
Anatomical terms of location
Standard anatomical terms of location are designations employed in science that deal with the anatomy of animals to avoid ambiguities that might otherwise arise. They are not language-specific, and thus require no translation...
and Gli3 dorsally in transgenic mice. Gli2 null mice embryos develop neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs. Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level. These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
s develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
(BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastoma
Trichoblastoma
Trichoblastomas are a cutaneous condition characterized by benign neoplasms of follicular germinative cells. Trichoblastic fibroma is a designation used to characterize small nodular trichoblastomas with conspicuous fibrocytic stroma, sometimes constituting over 50% of the lesion....
s, cylindroma
Cylindroma
In pathology, a cylindroma is a tumour with nests of cells that resemble a cylinder in cross section.Types include:*Dermal eccrine cylindroma, a benign tumour of the skin*Adenoid cystic carcinoma, a malignant tumour of the salivary gland...
s and hamartoma
Hamartoma
A hamartoma is a benign, focal malformation that resembles a neoplasm in the tissue of its origin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues. It is composed of tissue elements normally found at that site, but which are growing in a disorganized mass...
s but rarely developed BCCs. Gli2 is expressed in the
interfollicular epidermis and the outer root sheath of hair follicle
Hair follicle
A hair follicle is a skin organ that produces hair. Hair production occurs in phases, including a growth phase , and cessation phase , and a rest phase . Stem cells are principally responsible for the production of hair....
s in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.
Clinical significance
Mutations of the GLI2 gene are associated with several phenotypes including Greig cephalopolysyndactyly syndromeGreig cephalopolysyndactyly syndrome
Greig cephalopolysyndactyly syndrome is a disorder that affects development of the limbs, head, and face. The features of this syndrome are highly variable, ranging from very mild to severe...
, Pallister-Hall syndrome
Pallister-Hall syndrome
Pallister-Hall syndrome is a disorder that affects the development of many parts of the body.It is named for Judith Hall and Philip Pallister.-Presentation:...
, preaxial polydactyly
Polydactyly
Polydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
type IV, postaxial polydactyly types A1 and B.
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other.