| mir-184 | |
| Width: | 220px |
| Symbol: | mir-184 |
| Rfam: | RF00657 |
| Mirbase Family: | MIPF0000059 |
| Rna Type: | microRNA |
| Tax Domain: | Eukaryota
|
| Entrezgene: | 406960 |
| Hgncid: | 31555 |
| Omim: | 613146 |
In molecular biology, miR-184 microRNA is a short non-coding RNA molecule. MicroRNAs (miRNAs) function as posttranscriptional regulators of expression levels of other genes by several mechanisms.[1] Several targets for miR-184 have been described, including that of mediators of neurological development, apoptosis and it has been suggested that miR-184 plays an essential role in development.[2]
MicroRNAs can bind to the three prime untranslated region (3'UTR) of the target messenger RNA (mRNA).[3] Binding of the miRNA can hinder translation of mRNA by promoting degradation or inducing deadenylation.[4]
miR-184 is a single copy gene and evolutionarily conserved at the nucleotide level from flies to humans.[5] In humans, miR-184 is located within region 25.1 on the q-arm of chromosome 15, and its corresponding transcript is comparatively small (84bp) which is not encoded near other clustered miRNAs.[6] In the mouse genome, miR-184 is located in an imprinted locus on mouse chromosome 9, and it is 55 kb away from the nearest coding gene.[7]
The genomic region immediately surrounding miR-184 does not contain a classic CpG island, but does contain several CpG-rich sequences that are suitable for MBD1 binding.[8]
miR-184 displays a tissue- and developmental-specific expression pattern. In mammals, mature miR-184 is particularly enriched in the brain and testis,[7] along with the corneal epithelium.[9] Depolarization of cortical neurons results in pri-miR-184 expression in an allele specific manner.[7] High expression is observed in suprabasal cells of the corneal epithelium in the mouse model, along with expression in mouse testis and brain tissue.[7] [9] In Zebrafish, it is expressed in lens, hatching gland and epidermis (shown by Northern blot).[10] miR-184 is expressed ubiquitously in Drosophila embryos, larvae and adults, and its expression pattern displays dynamic changes during the development of embryo, especially in the central nervous system.[2] [5] However, the temporal and spatial expression pattern of miR-184 is still being debated.
C. Liu et al. showed that Methyl-CpG binding protein 1 (MBD1) regulates the expression of several miRNAs in adult neural stem/progenitor cells (aNSCs) and, specifically, that miR-184 is directly repressed by MBD1. High levels of miR-184 promotes cell proliferation but inhibits differentiation of aNSCs, whereas inhibition of miR-184 rescued phenotypes associated with MBD1 deficiency.[11]
Numblike (Numbl) is known to be important in embryonic neural stem cell function and cortical brain development and has been identified as a downstream target of miR-184.[12] [13] It has been found that exogenously expressed Numbl could rescue aNSC proliferation and differentiation deficits resulting from either elevated miR-184 or MBD1 deficiency.[11]
An analysis of the primary transcript of miR-184 (pri-mir-184) in several mouse tissues revealed specific expression in the brain and testis. Its expression is repressed by the binding of methyl-CpG binding protein 2 (MeCP2) to its promoter, but is upregulated by the release of MeCP2 after depolarization, suggesting a link between miRNAs and DNA methylation pathways .[7] J. Yu et al. demonstrated that the lipid phosphatase SH2-containing phosphoinositide 5'phosphatase 2 (SHIP2) is a target of miRNA-205 (miR-205) in epithelial cells, and that the corneal epithelial-specific miR-184 can interfere with the ability of miR-205 to suppress SHIP2 levels. The mechanism by which miR-184 negatively regulates miR-205 appears to be unique, and is the first example of a miRNA negatively regulating another to maintain levels of a target protein. miR-184 does not directly affect SHIP2 translation, but instead prevents miR-205 from interacting with SHIP2 mRNA. Interfering with miR-205 function by using a synthetic antagomir, or by the ectopic expression of miR-184, is thought to lead to a coordinated damping of the Akt signaling pathway via SHIP2 induction.[14]
R. Weitzel et al. showed that miR-184 mediates NFAT1 translational regulation in umbilical cord blood (UCB) graft CD4+ T-cells leading to blunted allogenic responses.[15]
J. Roberts et al. found that miR-184 repressed the expression of Argonaute 2 in epidermal keratinocytes.[16] Similarly, Tattikota et al. showed miR-184 reduced Argonaute 2 levels in the MIN6 mouse pancreatic beta islet cell line.[17]
Furthermore, miR-184 has multiple roles in Drosophila female germline development.[18]
Finally, a recent study identified miR-184 as essential for embryonic corneal commitment of pluripotent stem cells.[19]
• A single base mutation in the seed region of miR-184 causes EDICT syndrome, a hereditary eye disease.
• A mutation altering the miR-184 seed region causes familial keratoconus with cataract.[20]
• Several forms of cancer (see below) including elevation of miR-184 levels in squamous cell carcinoma of the tongue.[21] All-trans-retinoic acid induces miR-184 expression in neuroblastoma cell line and ectopic miR-184 causes apoptosis.[22]
• miR-184 has been implicated in ischemia-induced retinal neovascularization.[23]
Dysregulation of miRNA expression is thought to play a part in abnormal gene expression in cancer cells, and miR-184 has been implicated in several forms of cancer.[21] [24] MYCN has been found to contribute to tumorigenesis, in part, by repressing miR-184, leading to increased levels of the serine/threonine kinase, AKT2. AKT2 is a major effector of the phosphatidylinositol 3-kinase (PI3K) pathways, one of the most potent survival pathways in cancer, and is a direct target of miR-184. It has been suggested that MYCN provides a tumourigenic effect, in part, by protecting AKT2 mRNA from degradation by miR-184, permitting the PI3K pathway to remain functional.[25]
miR-184 has been found to be significantly increased in the tumor cells in comparison with the normal epithelial cells of the tongue. High miR-184 levels were not only detected in the tumor tissues, but also in the plasma of patients with tongue squamous cell carcinoma (SCC). Decreased plasma levels of miR-184 were observed in patients after surgical removal of the primary tumor, suggesting that it is a potential oncogenic miRNA in tongue SCC. Inhibiting miR-184 promotes apoptosis as well as hindering cell proliferation in cultured tongue SCC cells.[26] Furthermore, over expression of miR-184 in neuroblastoma cell lines results in apoptosis.[22] SND1 expression is regulated by miR-184 in gliomas.[27]