Mir-126
Encyclopedia
In molecular biology mir-126 is a short non-coding RNA
molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms. mir-126 is a human microRNA that is expressed only in endothelial cells, throughout capillaries as well as larger blood vessels, and acts upon various transcripts to control angiogenesis
.
of the EGFL7
gene which resides on human chromosome 9.
through the silencing of both mir-126* and EGFL7.
and ETS2
. Binding of these factors induce the transcription of the mir-126 pre-miRNA resulting in the formation of the hairpin pri-miRNA. Hairpin miRNA is targeted to Dicer
for cleavage, producing mature mir-126 and mir-126* transcripts.
Epigenetic regulation of the host gene by accumulation of methylation
and gene silencing nucleosomes reduces expression of intronic miRNA affecting. This has been observed in cancers which benefit from the silencing of both EGFL7 and mir-126, resulting in neither being expressed.
Only one Single-nucleotide polymorphism within mir-126 has been identified. A change to the 24th base prevents the processing of the pri-miRNA into the mature miRNA, reducing the suppression of the various targets of mir-126. The frequency of the SNP varies between different ethnic backgrounds and potentially is related to the differential acquisition of human disease.
or to transcribed mRNA preventing translation
and directing the mRNA for degradation. One of the main targets of mir-126 is the host gene EGFL7. Transcription of both occur, however mature mir-126 binds to a complementary sequence within EGFL7 preventing translation of the mRNA resulting in a decrease of EGFL7 protein levels. EGFL7 is known to be involved in cell migration and blood vessel formation, making EGFL7 and mir-126 opportune targets for disease, such as cancers, which require the continual formation of blood vessels to supply the tumour with nutrients and cell migration pathways to mediate tissue invasion.
to ensure survival. This includes controlled cell death and responses to wounds. During apoptosis
cell death, cells release apoptotic bodies containing paracrine signals to neighbouring cells. In endothelial cells, mir-126 is also released with in these bodies are upon absorption in a neighbouring cell induce the CXCL12 dependant vascular protection. CXCL12 binds the receptor CXCR4
actively counteracting apoptosis and recruiting progenitor cells to the site of injury.
depending on the type of cancer. Inhibition of cancer progression occurs through mir-126s negative control of proliferation, migration, invasion and cell survival, while mir-126 also may support cancer progression through the promotion of blood vessel formation and inflammation at the site of activation.
Recently, mir-126 has been used as a tumour marker in a non-invasive diagnostic testing method. Urine samples have been able to identify bladder cancer
sufferers apart from those non-effected, as small RNAs are readily excreted through urine.
including: mir-15a, mir-20b, mir-21, mir-124, mir-126, mir-191, mir-197, mir-223
, mir-320
and mir-486. Increased expression of mir-28-3p has also been observed. The consequence of misregulation of these miRNAs has not been fully elucidated, however mir-126 has been shown to decrease in expression in response to high glucose levels. Interestingly the decrease of mir-15a, mir-29b, mir-126 and mir-223 proceedes the manifestation of the disease, making these transcripts a possible target for diagnostic testing for type 2 diabetes.
against non-cystic fibrosis airway epithelial cells shows that various miRNAs are differentially regulated in response to the disease. mir-126 is suspected to play a role in regulating the innate immune responses within Cystic Fibrosis affected lungs.
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms. mir-126 is a human microRNA that is expressed only in endothelial cells, throughout capillaries as well as larger blood vessels, and acts upon various transcripts to control angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
.
Genomic Location
miR-126 is located within the 7th intronIntron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
of the EGFL7
EGFL7
EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene. Intron 7 of EGFL7 hosts the Mir-126 microRNA gene.-Further reading:...
gene which resides on human chromosome 9.
mir-126*
mir-126* is the complementary strand to mir-126 which forms once the double stranded pri-miRNA is cleaved and the two strands denature, separating. mir-126* is less abundantly found in organisms than mir-126 and fewer roles in regulating gene expression have been identified. However, mir-126* has recently been implicated in the silencing of prostien in non-endothelial cells. Prostein is able to be produced specifically in the prostateProstate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
through the silencing of both mir-126* and EGFL7.
Regulation of expression
mir-126 is regulated by the binding of two transcription factors: ETS1ETS1
Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.-Interactions:ETS1 has been shown to interact with TTRAP, UBE2I and Death associated protein 6....
and ETS2
ETS2
Protein C-ets-2 is a protein that in humans is encoded by the ETS2 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.-Interactions:...
. Binding of these factors induce the transcription of the mir-126 pre-miRNA resulting in the formation of the hairpin pri-miRNA. Hairpin miRNA is targeted to Dicer
Dicer
Dicer is an endoribonuclease in the RNase III family that cleaves double-stranded RNA and pre-microRNA into short double-stranded RNA fragments called small interfering RNA about 20-25 nucleotides long, usually with a two-base overhang on the 3' end...
for cleavage, producing mature mir-126 and mir-126* transcripts.
Epigenetic regulation of the host gene by accumulation of methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
and gene silencing nucleosomes reduces expression of intronic miRNA affecting. This has been observed in cancers which benefit from the silencing of both EGFL7 and mir-126, resulting in neither being expressed.
Only one Single-nucleotide polymorphism within mir-126 has been identified. A change to the 24th base prevents the processing of the pri-miRNA into the mature miRNA, reducing the suppression of the various targets of mir-126. The frequency of the SNP varies between different ethnic backgrounds and potentially is related to the differential acquisition of human disease.
Targets of mir-126
miRNA binds to target sequences reducing the expression of the target gene. miRNA can bind either directly to DNA preventing transcriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
or to transcribed mRNA preventing translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
and directing the mRNA for degradation. One of the main targets of mir-126 is the host gene EGFL7. Transcription of both occur, however mature mir-126 binds to a complementary sequence within EGFL7 preventing translation of the mRNA resulting in a decrease of EGFL7 protein levels. EGFL7 is known to be involved in cell migration and blood vessel formation, making EGFL7 and mir-126 opportune targets for disease, such as cancers, which require the continual formation of blood vessels to supply the tumour with nutrients and cell migration pathways to mediate tissue invasion.
- CRKCRK (gene)Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
, a protein involved in intracellular signal pathways involved in regulating cellular adhesion, proliferation, migration and invasion. - TOM1TOM1Target of Myb protein 1 is a protein that in humans is encoded by the TOM1 gene.-Interactions:TOM1 has been shown to interact with TOLLIP and ZFYVE16.-Further reading:...
a negative regulator of the IL-1beta and TNF-alpha signalling pathways. - Production of CXCL12, a chemokineChemokineChemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
, is regulated by mir-126. - POU3F1POU3F1POU domain, class 3, transcription factor 1 is a protein that in humans is encoded by the POU3F1 gene....
, a factor required for the activation of the transcription factor PU.1. PU.1 negatively regulates GATA3GATA3Trans-acting T-cell-specific transcription factor GATA-3 is a protein that in humans is encoded by the GATA3 gene.GATA-3 belongs to the GATA family of transcription factors. The protein contains two GATA-type zinc fingers and is an important regulator of T cell development and plays an important...
expression, altering the response of the T helper 2 cellsT helper cellT helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
. - VEGF-A protein production is reduced as mir-126 binds to the 3' untranslated region of the VEGF-A mRNA.
- IRS-1 inhibiting the cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
from progressing from G0G0 phaseThe G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...
/G1G1 phaseThe G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
into S phaseS phaseS-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
. - HOXA9HOXA9Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.-Interactions:HOXA9 has been shown to interact with PBX2, TRIP6 and MEIS1.-Further reading:...
, mir-126 modulates HOXA9 expression in haematopoietic cellsHaematopoiesisHaematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
. HOX genes are important developmental regulatory genes.
Involvement in homeostasis
Tissue repair and maintenance are important parts of the life cycle of an organism, cells and tissues must remain in homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
to ensure survival. This includes controlled cell death and responses to wounds. During apoptosis
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...
cell death, cells release apoptotic bodies containing paracrine signals to neighbouring cells. In endothelial cells, mir-126 is also released with in these bodies are upon absorption in a neighbouring cell induce the CXCL12 dependant vascular protection. CXCL12 binds the receptor CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
actively counteracting apoptosis and recruiting progenitor cells to the site of injury.
Cancer
mir-126 has been shown to be both a tumour suppressor and an oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
depending on the type of cancer. Inhibition of cancer progression occurs through mir-126s negative control of proliferation, migration, invasion and cell survival, while mir-126 also may support cancer progression through the promotion of blood vessel formation and inflammation at the site of activation.
- mir-126 and mir126* are overexpressed in acute myeloid leukemiaAcute myeloid leukemiaAcute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
. - mir-126 expression is reduced in colorectal cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. - mir-126 expression is reduced in gastric cancer.
- mir-126 expression is reduced in lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
cell lines. - mir-126 expression is reduced in prostate cancerProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
and bladder cancerBladder cancerBladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
. - mir-126 expression is reduced in breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. - Increased expression of mir-126 inhibits cell proliferation of non-small cell lung carcinoma cells in vitro and prevents tomour growth through the targeting of EGFL7.
Recently, mir-126 has been used as a tumour marker in a non-invasive diagnostic testing method. Urine samples have been able to identify bladder cancer
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
sufferers apart from those non-effected, as small RNAs are readily excreted through urine.
Diabetes
Low expression levels of many types of miRNA have been observed in type 2 diabetesDiabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
including: mir-15a, mir-20b, mir-21, mir-124, mir-126, mir-191, mir-197, mir-223
Mir-223
In molecular biology MicroRNA-223 is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-223 is a hematopoietic specific microRNA with crucial functions in myeloid lineage development...
, mir-320
Mir-320
In molecular biology mir-320 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms....
and mir-486. Increased expression of mir-28-3p has also been observed. The consequence of misregulation of these miRNAs has not been fully elucidated, however mir-126 has been shown to decrease in expression in response to high glucose levels. Interestingly the decrease of mir-15a, mir-29b, mir-126 and mir-223 proceedes the manifestation of the disease, making these transcripts a possible target for diagnostic testing for type 2 diabetes.
Cystic fibrosis
Comparisons of cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
against non-cystic fibrosis airway epithelial cells shows that various miRNAs are differentially regulated in response to the disease. mir-126 is suspected to play a role in regulating the innate immune responses within Cystic Fibrosis affected lungs.