Mir-1 microRNA precursor family
Encyclopedia
The miR-1 microRNA precursor is a small micro RNA
that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide
precursors and subsequently processed by the Dicer
enzyme to give a ~22 nucleotide products. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, these are called miR-1-1 and miR-1-2.
These micro RNAs have pivotal roles in development and physiology of muscle tissues including the heart. MiR-1 is known to be involved in important role in heart diseases such as hypertrophy, myocardial infarction, and arrhythmias . Studies have shown that MiR-1 is an important regulator of heart adaption after ischemia
or ischaemic stress and it is upregulated in the remote myocardium of patients with myocardial infarction
. Also MiR-1 is downregulated in myocardial infarcted tissue compared to healthy heart tissue . Plasma levels of MiR-1 can be used as a sensitive biomarker for myocardial infarction .
is also known to be a target for post-transcriptional regulation by miR-1 and miR-206. HSP60 is a component of the defence mechanism against diabetic myocardial injury and its level is reduced in the diabetic myocardium. In both in vivo and in vitro experiments increased levels of glucose in myocardiomyctes led to significant upregulation of miR-1 and miR-206 with resulting modulation of HSP60 leading to accelerated glucose-mediated apoptosis in cardiomyocetes. The level of HSP70
is also a target for post-transcriptional repression by MiR-1.
MiR-1 has key roles in the development and differentiation of smooth and skeletal muscles . For example in the lineage-specific differention of smooth muscle cells from embroyonic stem cell derived cultures, MiR-1 is required; as its loss of function resulted in a reduction in smooth muscle cell biomarkers and a reduction in the derived smooth muscle cell population. There is evidence that the control of smooth muscle cell differentiation by MiR-1 may be mediated by the down regulation of Kruppel-like factor 4 (KLF4
), since a MiR-1 recognition site is predicted in the 3' UTR of KLF4 and inhibition of MiR-1 results in reversed down-regulation of KLF4 and an inhibition of smooth muscle cell differentiation. A mutation in the 3' UTR
of the myostatin
gene in Texel sheep
creates a miR-1 and miR-206 target site. This is likely to cause the muscular phenotype of this breed of sheep.
is the most common soft tissue sarcoma
in children. Since the tumor results from undifferentiated cells, agents that promote differentiation hold promise as possible therapies. A study showed that levels of mir-1 and mir-133a were drastically reduced in tumourous cell lines whilst their targets were up-regulated .
Introduction of miR-1 and miR-133a into an embryonal rhabdomyosarcoma-derived cell line is cytostatic, which suggested a strong tumour-suppressive role for these microRNAs. Expression of miR-1 but not miR-133a gave transcriptional profiles that were consistent with a strong promyogenic influence on the cells, again demonstrating the role of miR-1 in muscle differentiation from precursor stem cells. The authors propose that miR-1 and miR-133a act to repress isoforms of genes that are not normally expressed in muscle cells. All of these observations suggest that mis-regulation of miR-1 and miR-133a can result in tumorogeneis via abolition of the supressive effect they have on certain gene targets and of the removal of the promotion of differentiation of the cells exerted my miR-1 .
The involvement of miR-1 in cancer is not limited to cancers of muscle and muscle tissues. MiR-1 may have a tumour-suppressive effect in bladder cancer by regulation of LIM and SH3 protein 1 (LASP1
)
. In lung cancer there is evidence for the down-regulation of miR-1 .
There is evidence for the role of miR-1-2 as a modulator in acute myeloid leukemia
via its transcription by the zinc-finger transcription factor, EVI1
, ectopic virus expression site 1. ChIP assays have shown that EVI1 binds strongly to the promoters of miR-1-2 and miR-133-a-1, and expression of EVI1 is significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines .
Micro RNA
A microRNA is a short ribonucleic acid molecule found in eukaryotic cells. A microRNA molecule has very few nucleotides compared with other RNAs....
that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
precursors and subsequently processed by the 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...
enzyme to give a ~22 nucleotide products. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, these are called miR-1-1 and miR-1-2.
These micro RNAs have pivotal roles in development and physiology of muscle tissues including the heart. MiR-1 is known to be involved in important role in heart diseases such as hypertrophy, myocardial infarction, and arrhythmias . Studies have shown that MiR-1 is an important regulator of heart adaption after ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
or ischaemic stress and it is upregulated in the remote myocardium of patients with myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. Also MiR-1 is downregulated in myocardial infarcted tissue compared to healthy heart tissue . Plasma levels of MiR-1 can be used as a sensitive biomarker for myocardial infarction .
Targets of miR-1
The heat shock protein, HSP60HSP60
Heat shock proteins are generally responsible for preventing damage to proteins in response to high levels of heat. Heat shock proteins are classified into six major families based on their molecular mass: small HSPs, HSP40, HSP60, HSP70, HSP90, and HSP110...
is also known to be a target for post-transcriptional regulation by miR-1 and miR-206. HSP60 is a component of the defence mechanism against diabetic myocardial injury and its level is reduced in the diabetic myocardium. In both in vivo and in vitro experiments increased levels of glucose in myocardiomyctes led to significant upregulation of miR-1 and miR-206 with resulting modulation of HSP60 leading to accelerated glucose-mediated apoptosis in cardiomyocetes. The level of HSP70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
is also a target for post-transcriptional repression by MiR-1.
MiR-1 has key roles in the development and differentiation of smooth and skeletal muscles . For example in the lineage-specific differention of smooth muscle cells from embroyonic stem cell derived cultures, MiR-1 is required; as its loss of function resulted in a reduction in smooth muscle cell biomarkers and a reduction in the derived smooth muscle cell population. There is evidence that the control of smooth muscle cell differentiation by MiR-1 may be mediated by the down regulation of Kruppel-like factor 4 (KLF4
KLF4
Krueppel-like factor 4 is a protein that in humans is encoded by the KLF4 gene.. In embryonic stem cells , KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells ....
), since a MiR-1 recognition site is predicted in the 3' UTR of KLF4 and inhibition of MiR-1 results in reversed down-regulation of KLF4 and an inhibition of smooth muscle cell differentiation. A mutation in the 3' UTR
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
of the myostatin
Myostatin
Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...
gene in Texel sheep
Texel (sheep)
The Texel is a breed of domestic sheep originally from the island of Texel in the Netherlands. It is now a popular lean meat sheep in the USA, Australia, New Zealand, Uruguay and Europe. The Texel is a heavily muscled sheep. It produces a lean meat carcass and will pass on this quality to crossbred...
creates a miR-1 and miR-206 target site. This is likely to cause the muscular phenotype of this breed of sheep.
Clinical relevance of miR-1
Mir-1 plays an important role in some cancers. RhabdomyosarcomaRhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
is the most common soft tissue sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
in children. Since the tumor results from undifferentiated cells, agents that promote differentiation hold promise as possible therapies. A study showed that levels of mir-1 and mir-133a were drastically reduced in tumourous cell lines whilst their targets were up-regulated .
Introduction of miR-1 and miR-133a into an embryonal rhabdomyosarcoma-derived cell line is cytostatic, which suggested a strong tumour-suppressive role for these microRNAs. Expression of miR-1 but not miR-133a gave transcriptional profiles that were consistent with a strong promyogenic influence on the cells, again demonstrating the role of miR-1 in muscle differentiation from precursor stem cells. The authors propose that miR-1 and miR-133a act to repress isoforms of genes that are not normally expressed in muscle cells. All of these observations suggest that mis-regulation of miR-1 and miR-133a can result in tumorogeneis via abolition of the supressive effect they have on certain gene targets and of the removal of the promotion of differentiation of the cells exerted my miR-1 .
The involvement of miR-1 in cancer is not limited to cancers of muscle and muscle tissues. MiR-1 may have a tumour-suppressive effect in bladder cancer by regulation of LIM and SH3 protein 1 (LASP1
LASP1
LIM and SH3 domain protein 1 is a protein that in humans is encoded by the LASP1 gene.-Further reading:...
)
. In lung cancer there is evidence for the down-regulation of miR-1 .
There is evidence for the role of miR-1-2 as a modulator in acute myeloid leukemia
Acute myeloid leukemia
Acute 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...
via its transcription by the zinc-finger transcription factor, EVI1
EVI1
MDS1 and EVI1 complex locus protein EVI1 also known as ecotropic virus integration site 1 protein homolog or positive regulatory domain zinc finger protein 3 is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine...
, ectopic virus expression site 1. ChIP assays have shown that EVI1 binds strongly to the promoters of miR-1-2 and miR-133-a-1, and expression of EVI1 is significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines .