Mir-155
Encyclopedia
MicroRNAs are non-coding RNAs (ncRNAs
) that regulate the expression levels of other genes through several mechanisms at a post transcriptional stage, they work by inactivating translation of gene or gene clusters or by degrading genes. About 30 percent of the eukaryotic genome is controlled by miRNAs, the estimated total number of miR genes is ~1000.
They exert influences on cellular processes of proliferation, differentiation, apoptosis and metabolism.
One such showcase of this multi-activity is displayed by the microRNA mir-155, a short RNA molecule that plays a crucial role in various physiological and pathological processes. Potentially, exogenous molecular control in vivo of miR-155 expression could uncover new frontiers to restrain malignant growth and viral infections, or to attenuate the progression of cardiovascular diseases for instance.
With regard to miR-155, its distribution across the animal kingdom
shows very well conservation throughout, it was identified in a wide range of species controlling many key processes by having a target on many genes that are implicated in various levels of cell regulation
and proliferation
. In fact, its overexpression
or underexression has been found to guide many processes that involve immunity
, inflammation
, cancer
...etc.miR-155 is also expressed in mammalian reproductive tissues, fibroblasts
, epithelial tissues, and the central nervous system.
Searching MiRBase
for 'Mir-155' -as of October, 2011- has retrieved records for 17 organisms that contain miR-155 in various genomic locations; in the mouse, the miR-155 on Chromosome
16 B-cell Integration Cluster (BiC) region shares very close homology to that in humans, with the mature region of the miRNA that is responsible for its gene-silencing effect being of high conservation.
band q21.3. Transcription in this areas releases a non-coding RNA product that upon processing finalization becomes miR-155. This particular chromosomal location shows strong sequence conservation in humans, mouse, chicken and explains the distinct expression profiles for miR-155 seen across many species. In the UCSC browser
the entry name for this gene is MIR155HG. The NCBI
nucleotide database saves pertinent information on this gene under record number NR_001458.
Manufacturing miR-155 starts in the nucleus
and ends in the cytoplasm
navigating through many post-transcriptional processing that transforms its nascent initial hairpin-fold-like double-stranded structure into the single-stranded silencer that it is . The sequence of events that culminate into building an active silencing machinery based on miR-155 is summarized as follows:
This complex process involves orchestrated interplay of proteins and cofactors, it begins in transcription by polymerases, export to the cytoplasm by exportin, endonuclease splicing by Dicer where the originally double-stranded miR-155 precursor is spliced into smaller (21-23 nucleotides) single stranded RNAs, and finally, processing and complexing with RISC . The sequence of the RNA latched onto the RISC complex guides it to its target gene-transcript mRNA by virtue of complementarity, upon reaching there; RISC attaches to, cleaves and neutralizes that target. This silencing
effect is brought about by either repressing the translation of that gene or degrading the target mRNA depending on whether the complementarity is partial or perfect.
The pathways that involve biogenesis and Dicer splicing are conserved in animals, plants and fungi; however, silencing mechanisms may differ between plants and animals. In plants, miRNAs action mimics the exogenously introduced siRNAs
, they flag their target mRNAs for silencing by endonucleolytic cleavage whereas in animals, silencing is brought about by translational repression. In addition, complementarity between animals miRNAs and their targets is not a must for miRNAs activity since partial complementarity is enough to bring about silencing; a scenario contrary to what happens in plants miRNAs. On the other hand, Yeast
have a silencing complex similar to RISC called (RNA-induced initiation of transcriptional gene silencing) RITS
.
and hypertension, and was also found to be implicated in immunity, genomic instability
, cell differentiation
, inflammation, virus associated infections and cancer.
in miR-155 target site deny it the optimal access necessary to bring about gene silencing, leading to over abundance of delinquent activities that may go malignant
, for example, miR-155 role as a protective agent against predisposition to B Cell associated malignancies is emphasized by maintaining the balance of Activation-Induced Cytidine Deaminase (AID
) enzyme. MiR-155 mediates regulation of AID abundance and expression time upon immunological cues however, mutations in the target on AID mRNA result in its unresponsiveness to miR-155 silencing and lead to unbridled expression of its protein causing wild immature B-lymphocyte surges and AID-mediated chromosomal translocations
.
receptor AT1R
protein. Furthermore, AT1R is involved in cardiovascular and blood pressure ailments by controlling angiotension II. Defective miR-155 function could be implicated in hypertension
and cardiovascular diseases if the cis-regulatory site on 3` UTR of AT1R (miR-155 target site) was affected due to a SNP polymorphism in AT1R itself. This mutation is disruptive of miR-155 targeting and thus preventive of AT1R expression down-regulation . In low blood pressure over-expression of miR-155 correlates with the impairment of AT1R activity.
.
Activated B and T cells show increased miR-155 expression, the same goes for macrophages
and dendritic cells
of the immune system
. MiR-155 is crucial for proper lymphocyte development and maturation. Details of various manifestations of miR-155 levels and involvement in activities that ascertain optimal immune responses have been the subject of many researches:
responses were observed in miR-155-deficient mice, IgG1 is reduced whereas the expression of the IgM
immunoglobulin remains normal in these mice. The abnormality in IgG1 levels maybe explained by an important target for miR-155 in B cells, the protein-encoding mRNA for the transcriptional regulator Pu.1-protein
, elevation of Pu.1 protein predisposes defective IgG1 production. In addition to Pu.1, there are nearly 60 other differentially elevated genes in miR-155 deficient B cells, further inspection revealed possible miR-155 target sites in the 3' UTR regions in these genes .
By Understanding how the process of B cell development takes place we can clearly see the significance of miR-155 in this regard; selection of competent B cells takes place in the germinal center
where they are trained to differentiate body cells vs. foreign antigens, they compete for antigen recognition and for T cell help, in this fashion of selective pressure those B Cells that demonstrated high-affinity receptors and cooperation with T cells (affinity maturation
) are recruited and deployed to the bone marrow or become memory B cells,apoptotic termination
takes place for those B Cells failing the competition. Immature B cells which are miR-155 deficient evade apoptosis as a result of elevated Bcl-2 protein
levels; a protein that was found to be involved in B Cell malignancies and to be controlled by miR-155.
such as Rheumatoid Arthritis miR-155 showed higher expression in patients' tissues and synovial fibroblasts.
, miRNAs were experimentally verified, miRNAs in viruses are encoded by dsDNAs , examples of such viruses include herpesviruses
such as Humans-Epstein-Barr Virus (EBV
) and adenoviruses
, another virus expressing miR-155-like miRNA in chickens is the oncogenic MDV-1 whose non-oncogenic relative MDV-2 does not, this suggests implication of miR-155 in lymphomagenesis.
Viruses can exploit host miRNAs to the degree that they use host miRNAs to encode for viral clones for example:
MiR-k12-11 in Kaposi's-sarcoma-associated Herpesvirus
has a target specificity region orthologous to that of miR-155's; mimicking the action of miR-155 and, sharing targets with it, thus it can be thought to suppress miR-155 accessibility to its targets by competition and this in effect downregulates expression of genes playing roles in cellular growth and apoptosis in a manner that defies regulations by miR-155.
EBV modulates host miR-155. EBV-infected cells have increased expression of miR-155 thereby disturbing equilibrium of expression for genes regulating transcription in those cells.
) is silenced by miR-155, over-expression of miR-155 leads to decreased levels of TP53INP1 in pancreatic ductal adenocarcinomas
and possibly in other epithelial cancers where TP53INP1 activity is lost thereby resulting in apoptosis evasion and uncontrolled bouts of growth.
Inactivation of DNA Mismatch Repair (MMR
) as identified by elevation of mutation rates is the cause of Lynch Syndrome
((LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), down-regulation of MMR controlling protein is carried out by over-expression of miR-155, MMR is controlled by a group of highly conserved proteins, reduced activity of these proteins results in elevated levels of mutations in the phenotype triggering a march towards developing this type of cancer .
Other types of tumors in which miR-155 over-expression was reported include: thyroid carcinoma, breast cancer, colon cancer, cervical cancer, and lung cancer, where distinct miR-155 expression profiles quantification can potentially serve as signals for tumor detection and evaluation of prognosis outcome.
and cis-regulatory
sites of these transcripts. These control elements are typically located in the untranslated regions UTRs on either ends of the transcript and their interactions with microRNAs regulate the activity of their gene expression. However, the target sequences for miRNAs in animals are mainly present in the 3' UTR end of the mRNAs.
So far, MiR-155 targets are estimated to number into 991, however, it is worth noting that not all in silico predicted targets have been found to be responsive to the miRNA control upon experimental validation., the existence for many targets per miRNA on mRNA transcripts can also be explained by the various levels of complementarity between the target sequences and the miRNA sequence itself thereby explaining different degrees of silencing efficiency exerted by miRNA influence on each one of its targets. MiR-155 targets involve members falling into many categories:
This underscores the variety of roles miR-155 plays in transcripts control and cellular processes by interacting with the 3'UTR regions in these genes.
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...
) that regulate the expression levels of other genes through several mechanisms at a post transcriptional stage, they work by inactivating translation of gene or gene clusters or by degrading genes. About 30 percent of the eukaryotic genome is controlled by miRNAs, the estimated total number of miR genes is ~1000.
They exert influences on cellular processes of proliferation, differentiation, apoptosis and metabolism.
One such showcase of this multi-activity is displayed by the microRNA mir-155, a short RNA molecule that plays a crucial role in various physiological and pathological processes. Potentially, exogenous molecular control in vivo of miR-155 expression could uncover new frontiers to restrain malignant growth and viral infections, or to attenuate the progression of cardiovascular diseases for instance.
Phylogenetic Characteristics:
MiRNAs are phylogentically diverse, some miRNAs are more restricted to single species, some are present throughout different cell types, some have isoforms and others have only single forms.With regard to miR-155, its distribution across the animal kingdom
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
shows very well conservation throughout, it was identified in a wide range of species controlling many key processes by having a target on many genes that are implicated in various levels of cell regulation
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
and proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
. In fact, its overexpression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
or underexression has been found to guide many processes that involve immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
...etc.miR-155 is also expressed in mammalian reproductive tissues, fibroblasts
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
, epithelial tissues, and the central nervous system.
Searching MiRBase
MiRBase
The miRBase database is an archive of microRNA sequences. As of September 2010 it contained information about 15,172 microRNAs. The miRBase registry provides a centralised system for assigning new names to microRNA genes....
for 'Mir-155' -as of October, 2011- has retrieved records for 17 organisms that contain miR-155 in various genomic locations; in the mouse, the miR-155 on Chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
16 B-cell Integration Cluster (BiC) region shares very close homology to that in humans, with the mature region of the miRNA that is responsible for its gene-silencing effect being of high conservation.
MiR-155 Biogenesis:
On the human genome, miR-155 gene is about 1500 bases long located on the BiC area on chromosome 21Chromosome 21 (human)
Chromosome 21 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. The trisomy of the 21st chromosome causes Down Syndrome...
band q21.3. Transcription in this areas releases a non-coding RNA product that upon processing finalization becomes miR-155. This particular chromosomal location shows strong sequence conservation in humans, mouse, chicken and explains the distinct expression profiles for miR-155 seen across many species. In the UCSC browser
UCSC Genome Browser
The University of California, Santa Cruz is an up-to-date source for genome sequence data from a variety of vertebrate and invertebrate species and major model organisms, integrated with a large collection of aligned annotations...
the entry name for this gene is MIR155HG. The NCBI
National Center for Biotechnology Information
The National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
nucleotide database saves pertinent information on this gene under record number NR_001458.
Manufacturing miR-155 starts in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and ends in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
navigating through many post-transcriptional processing that transforms its nascent initial hairpin-fold-like double-stranded structure into the single-stranded silencer that it is . The sequence of events that culminate into building an active silencing machinery based on miR-155 is summarized as follows:
- MiR genes are transcribed into pri-miRNAs via RNA polymerase II in the nucleus.
- Pri-miRNAs are processed into pre-miRNAs via DroshaDroshaDrosha is a Class 2 RNase III enzyme responsible for initiating the processing of microRNA , or short RNA molecules naturally expressed by the cell that regulate a wide variety of other genes by interacting with the RNA-induced silencing complex to induce cleavage of complementary messenger RNA ...
and DGCR8Pasha (protein)Pasha , also known as DGCR8 in vertebrates organisms, is a protein localized to the cell nucleus that is required for microRNA processing. It binds to Drosha, an RNase III enzyme, to form the Microprocessor complex that cleaves a primary transcript known as pri-miRNA to a characteristic stem-loop...
. - Pre-miRNA leaves the nucleus into the cytoplasm carried by the enzyme exportinKaryopherinKaryopherins are a group of proteins involved in transporting molecules from the cytoplasm into the nucleus of eukaryotic cells. The inside of the nucleus is called the karyoplasm . Generally, karyopherin-mediated transport occurs through the nuclear pore, which acts as a gateway into and out of...
. - In the cytoplasm, pre-miRNA is cleaved by the endonuclease DicerDicerDicer 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...
resulting in a duplex RNA that has a guide strand and a passenger strand (the later usually degraded). - The mature guide strand is loaded into the RNA-Induced Silencing Complex RISCRNA-induced silencing complexRNA-Induced Silencing Complex, or RISC, is a multiprotein complex that incorporates one strand of a small interfering RNA or micro RNA . RISC uses the siRNA or miRNA as a template for recognizing complementary mRNA. When it finds a complementary strand, it activates RNase and cleaves the RNA...
. - Upon this integration RISC becomes activated.
This complex process involves orchestrated interplay of proteins and cofactors, it begins in transcription by polymerases, export to the cytoplasm by exportin, endonuclease splicing by Dicer where the originally double-stranded miR-155 precursor is spliced into smaller (21-23 nucleotides) single stranded RNAs, and finally, processing and complexing with RISC . The sequence of the RNA latched onto the RISC complex guides it to its target gene-transcript mRNA by virtue of complementarity, upon reaching there; RISC attaches to, cleaves and neutralizes that target. This silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
effect is brought about by either repressing the translation of that gene or degrading the target mRNA depending on whether the complementarity is partial or perfect.
The pathways that involve biogenesis and Dicer splicing are conserved in animals, plants and fungi; however, silencing mechanisms may differ between plants and animals. In plants, miRNAs action mimics the exogenously introduced siRNAs
Small interfering RNA
Small interfering RNA , sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules, 20-25 nucleotides in length, that play a variety of roles in biology. The most notable role of siRNA is its involvement in the RNA interference pathway, where it...
, they flag their target mRNAs for silencing by endonucleolytic cleavage whereas in animals, silencing is brought about by translational repression. In addition, complementarity between animals miRNAs and their targets is not a must for miRNAs activity since partial complementarity is enough to bring about silencing; a scenario contrary to what happens in plants miRNAs. On the other hand, Yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
have a silencing complex similar to RISC called (RNA-induced initiation of transcriptional gene silencing) RITS
RNA-induced transcriptional silencing
RNA-induced transcriptional silencing is a form of RNA interference by which short RNA molecules - such as small interfering RNA - trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails...
.
MiR-155 Activity and Phenotypes:
The hallmark of miR-155 activities is that they transcend to and fro within protective roles to normal physiological functions to disease associated manifestations. It is estimated to participate in cascades associated with cardiovascular diseasesCardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
and hypertension, and was also found to be implicated in immunity, genomic instability
Genome instability
Usually, all cells in an individual in a given species show a constant number of chromosomes, which constitute what is known as the karyotype defining this species , although some species present a very high karyotypic variability.Sometimes, in a species with a stable karyotype, random variations...
, cell differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, inflammation, virus associated infections and cancer.
Mode of Action:
Protective roles of miR-155 may arise in response to its action on silencing genes thereby regulating their expression time, mutationsMutation
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...
in miR-155 target site deny it the optimal access necessary to bring about gene silencing, leading to over abundance of delinquent activities that may go malignant
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
, for example, miR-155 role as a protective agent against predisposition to B Cell associated malignancies is emphasized by maintaining the balance of Activation-Induced Cytidine Deaminase (AID
Activation-Induced (Cytidine) Deaminase
Activation-induced deaminase is a 24 kDa enzyme that creates deliberate mutations in DNA.AID removes the amino group from a cytidine base, turning it into a uridine...
) enzyme. MiR-155 mediates regulation of AID abundance and expression time upon immunological cues however, mutations in the target on AID mRNA result in its unresponsiveness to miR-155 silencing and lead to unbridled expression of its protein causing wild immature B-lymphocyte surges and AID-mediated chromosomal translocations
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
.
Cardiopulmonary Disease and Hypertension:
Transfection of miR-155 into human primary lung fibroblasts reduces the endogenous expression of the angiotensin IIAngiotensin
Angiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...
receptor AT1R
Angiotensin II receptor type 1
Angiotensin II receptor, type 1 or AT1 receptor is an angiotensin receptor. It has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system...
protein. Furthermore, AT1R is involved in cardiovascular and blood pressure ailments by controlling angiotension II. Defective miR-155 function could be implicated in hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and cardiovascular diseases if the cis-regulatory site on 3` UTR of AT1R (miR-155 target site) was affected due to a SNP polymorphism in AT1R itself. This mutation is disruptive of miR-155 targeting and thus preventive of AT1R expression down-regulation . In low blood pressure over-expression of miR-155 correlates with the impairment of AT1R activity.
Immunity:
miR-155 is highly involved in immunity by playing key roles in modulating humoral and innate cell-mediated immune responses, for example, In miR-155 deficient mice, immunological-memory is impaired; making it fall prey to repetitive bouts of invasions by the same pathogen (Rodriguez et al. 2007),maturation and specificity of miR-155-deficient B-lymphocytes are impaired since the process relies on AID enzyme which has a miR-155 target in its 3' UTR end . The phenotypic consequences involving deficiency of miR-155 in mice show later in life where the animals develop lung and intestinal lesionsLesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
.
Activated B and T cells show increased miR-155 expression, the same goes for macrophages
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
and dendritic cells
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. MiR-155 is crucial for proper lymphocyte development and maturation. Details of various manifestations of miR-155 levels and involvement in activities that ascertain optimal immune responses have been the subject of many researches:
Reduction of IgG1:
Defective T and B cells as well as markedly decreased IgG1Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
responses were observed in miR-155-deficient mice, IgG1 is reduced whereas the expression of the IgM
Immunoglobulin M
Immunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
immunoglobulin remains normal in these mice. The abnormality in IgG1 levels maybe explained by an important target for miR-155 in B cells, the protein-encoding mRNA for the transcriptional regulator Pu.1-protein
SPI1
Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene.-Interactions:SPI1 has been shown to interact with NONO, GATA2, FUS and IRF4.-See also:*Invasion gene associated RNA , a ncRNA located in the SPI-1 region...
, elevation of Pu.1 protein predisposes defective IgG1 production. In addition to Pu.1, there are nearly 60 other differentially elevated genes in miR-155 deficient B cells, further inspection revealed possible miR-155 target sites in the 3' UTR regions in these genes .
Predisposition to Lymphocyte Malignancies:
Mature receptors affinity and specificity of lymphocytes to pathogenic agents underlie proper immune responses, optimal miR-155 coordination is required for manufacturing of normal B lymphocytes and production of high-affinity antibodies and memory cells, this has been evidenced by comparisons of miR-155 expression patterns in normal and abnormal B cells revealing a miR-155 role in differentiation. Were miR-155 expression abnormally elevated; pre-B cell lymphomas formed .By Understanding how the process of B cell development takes place we can clearly see the significance of miR-155 in this regard; selection of competent B cells takes place in the germinal center
Germinal center
Germinal centers are sites within lymph nodes where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies , and class switch their antibodies during a normal immune response to an infection...
where they are trained to differentiate body cells vs. foreign antigens, they compete for antigen recognition and for T cell help, in this fashion of selective pressure those B Cells that demonstrated high-affinity receptors and cooperation with T cells (affinity maturation
Affinity maturation
In immunology, affinity maturation is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response...
) are recruited and deployed to the bone marrow or become memory B cells,apoptotic termination
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...
takes place for those B Cells failing the competition. Immature B cells which are miR-155 deficient evade apoptosis as a result of elevated Bcl-2 protein
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
levels; a protein that was found to be involved in B Cell malignancies and to be controlled by miR-155.
Inflammation:
Inflammatory responses to triggers such as TNF-α involve macrophages with components that include miR-155. In Autoimmune disordersAutoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
such as Rheumatoid Arthritis miR-155 showed higher expression in patients' tissues and synovial fibroblasts.
DNA Viruses:
In DNA virusesDNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...
, miRNAs were experimentally verified, miRNAs in viruses are encoded by dsDNAs , examples of such viruses include herpesviruses
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
such as Humans-Epstein-Barr Virus (EBV
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
) and adenoviruses
Adenoviridae
Adenoviruses are medium-sized , nonenveloped icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA genome...
, another virus expressing miR-155-like miRNA in chickens is the oncogenic MDV-1 whose non-oncogenic relative MDV-2 does not, this suggests implication of miR-155 in lymphomagenesis.
Viruses can exploit host miRNAs to the degree that they use host miRNAs to encode for viral clones for example:
MiR-k12-11 in Kaposi's-sarcoma-associated Herpesvirus
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...
has a target specificity region orthologous to that of miR-155's; mimicking the action of miR-155 and, sharing targets with it, thus it can be thought to suppress miR-155 accessibility to its targets by competition and this in effect downregulates expression of genes playing roles in cellular growth and apoptosis in a manner that defies regulations by miR-155.
EBV modulates host miR-155. EBV-infected cells have increased expression of miR-155 thereby disturbing equilibrium of expression for genes regulating transcription in those cells.
Cancer:
Over-silencing by miR-155 may result in triggering oncogenic cascades that begin by apoptotic resistance, The pro-apoptotic Tumour Protein-53-induced-nuclear-protein1 (TP53INP1TP53INP1
Tumor protein p53-inducible nuclear protein 1 is a protein that in humans is encoded by the TP53INP1 gene. In mice this protein is also called TRP53INP1 and is encoded by the Trp53inp1 gene. The protein is also referred to as SIP or "stress inducible protein"-Interactions:TP53INP1 has been shown to...
) is silenced by miR-155, over-expression of miR-155 leads to decreased levels of TP53INP1 in pancreatic ductal adenocarcinomas
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
and possibly in other epithelial cancers where TP53INP1 activity is lost thereby resulting in apoptosis evasion and uncontrolled bouts of growth.
Inactivation of DNA Mismatch Repair (MMR
DNA mismatch repair
DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage....
) as identified by elevation of mutation rates is the cause of Lynch Syndrome
Hereditary nonpolyposis colorectal cancer
Lynch syndrome is an autosomal dominant genetic condition which has a high risk of colon cancer as well as other cancers including endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin...
((LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), down-regulation of MMR controlling protein is carried out by over-expression of miR-155, MMR is controlled by a group of highly conserved proteins, reduced activity of these proteins results in elevated levels of mutations in the phenotype triggering a march towards developing this type of cancer .
Other types of tumors in which miR-155 over-expression was reported include: thyroid carcinoma, breast cancer, colon cancer, cervical cancer, and lung cancer, where distinct miR-155 expression profiles quantification can potentially serve as signals for tumor detection and evaluation of prognosis outcome.
Targets:
On the transcripts level, microRNAs affect replication, translation and stability of genes by interacting with the riboswitchesRiboswitch
In molecular biology, a riboswitch is a part of an mRNA molecule that can directly bind a small target molecule, and whose binding of the target affects the gene's activity. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the...
and cis-regulatory
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
sites of these transcripts. These control elements are typically located in the untranslated regions UTRs on either ends of the transcript and their interactions with microRNAs regulate the activity of their gene expression. However, the target sequences for miRNAs in animals are mainly present in the 3' UTR end of the mRNAs.
So far, MiR-155 targets are estimated to number into 991, however, it is worth noting that not all in silico predicted targets have been found to be responsive to the miRNA control upon experimental validation., the existence for many targets per miRNA on mRNA transcripts can also be explained by the various levels of complementarity between the target sequences and the miRNA sequence itself thereby explaining different degrees of silencing efficiency exerted by miRNA influence on each one of its targets. MiR-155 targets involve members falling into many categories:
- Transcriptional Regulatory Genes
- Protein Receptors
- Nuclear Proteins
- Binding Proteins
This underscores the variety of roles miR-155 plays in transcripts control and cellular processes by interacting with the 3'UTR regions in these genes.