Mir-15 microRNA precursor family

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mir-15 microRNA precursor family
RF00455.jpg
Predicted secondary structure and sequence conservation of mir-15
Identifiers
Symbolmir-15
Rfam RF00455
miRBase MI0000069
miRBase family MIPF0000006
Other data
RNA type Gene; miRNA
Domain(s) Eukaryota
GO GO:0035195 GO:0035068
SO SO:0001244
PDB structures PDBe

The miR-15 microRNA precursor family is made up of small non-coding RNA genes that regulate gene expression. The family includes the related mir-15a and mir-15b sequences, as well as miR-16-1, miR-16-2, miR-195 and miR-497. These six highly conserved miRNAs are clustered on three separate chromosomes. [1] In humans miR-15a and miR-16 are clustered within 0.5 kilobases at chromosome position 13q14. [2] This region has been found to be the most commonly affected in chronic lymphocytic leukaemia (CLL), with deletions of the entire region in more than half of cases. Both miR-15a and miR-16 are thus frequently deleted or down-regulated in CLL samples with 13q14 deletions; occurring in more than two thirds of CLL cases. [3] The expression of miR-15a is associated with survival in triple negative breast cancer. [4]

Contents

miR-15a/16-1 deletion has been shown to accelerate the proliferation of both human and mouse B-cells through modulation of the expression of genes controlling cell cycle progression. [5] Studies have found the miR-15a/16-1 microRNA cluster to function as a tumour suppressor, with the oncogene BCL2 as its target. [6] Specifically, miR-15a/16-1 downregulates BCL2 expression and is itself deleted or downregulated in tumour cells. [7] There is a marked increase in BCL2 levels observed in advanced prostate tumour cases, which is inversely correlated with miR-15a/16-1 expression (and so corresponds to a decrease in miR-15a/16-1 levels). Inhibition of cell proliferation by the miR-15a/16-1 cluster occurs in both lymphoid and non-lymphoid tissue. [6]

The miR-15a/16-1 cluster has further been found to be highly expressed in CD5+ cells, therefore hinting at an important role of miR-15/16 in normal CD5+ B-cell homeostasis. [3]

CHEK1

The CHEK1 (checkpoint kinase 1) gene, located at chromosome position 11q24.2, is responsible for encoding the protein kinase Chk1. [8] Chk1 in turn phosphorylates a phosphatase involved in cell cycle control. It mediates the cellular response to DNA replication errors, whilst also playing an important role in the prevention of genetic instability. Elevated CHEK1 levels have been found to be consistent with a lack of miR-15a/16-1 in mice. [1] Postnatal induction of the miR-15 family has been shown to mediate the developmental inactivation of CHEK1 after birth. This inactivation has been identified as a possible contributing factor to the onset of cardiomyocyte binucleation during the neonatal period. [1]

Neonatal cardiomyocyte arrest

Postnatal heart development sees the upregulation of multiple miR-15 family members. In particular, miR-195, when found at higher levels than normal in the developing heart, has been identified as a factor that may cause heart abnormalities in newborns. [1] This has been linked to premature cell cycle arrest, through impaired proliferation of heart muscle fibres and through repressed mitotic gene expression. [9] An accumulation of cardiac muscle fibres sees a consequent block in the transition between the pre-mitotic/G2 phase and mitotic phase of the cell cycle, with postnatal inhibition of the miR-15 family inducing cardiac muscle fibres to enter mitosis. miR-195 overexpression is further associated with cellular hypertrophy. [10]

Related Research Articles

Non-coding RNA Class of ribonucleic acid that is not translated into proteins

A non-coding RNA (ncRNA) is an RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-coding RNAs include transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as small RNAs such as microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs and the long ncRNAs such as Xist and HOTAIR.

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans, and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs. miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002). miRNAs are initially transcribed in long transcripts called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

mir-10 microRNA precursor family

The miR-10 microRNA precursor is a short non-coding RNA gene involved in gene regulation. It is part of an RNA gene family which contains miR-10, miR-51, miR-57, miR-99 and miR-100. miR-10, miR-99 and miR-100 have now been predicted or experimentally confirmed in a wide range of species. mir-51 and mir-57 have currently only been identified in the nematode Caenorhabditis elegans.

mir-129 microRNA precursor family

The miR-129 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. This microRNA was first experimentally characterised in mouse and homologues have since been discovered in several other species, such as humans, rats and zebrafish. The mature sequence is excised by the Dicer enzyme from the 5' arm of the hairpin. It was elucidated by Calin et al. that miR-129-1 is located in a fragile site region of the human genome near a specific site, FRA7H in chromosome 7q32, which is a site commonly deleted in many cancers. miR-129-2 is located in 11p11.2.

mir-16 microRNA precursor family

The miR-16 microRNA precursor family is a group of related small non-coding RNA genes that regulates gene expression. miR-16, miR-15, mir-195 and miR-497 are related microRNA precursor sequences from the mir-15 gene family. This microRNA family appears to be vertebrate specific and its members have been predicted or experimentally validated in a wide range of vertebrate species.

mir-17 microRNA precursor family

The miR-17 microRNA precursor family are a group of related small non-coding RNA genes called microRNAs that regulate gene expression. The microRNA precursor miR-17 family, includes miR-20a/b, miR-93, and miR-106a/b. With the exception of miR-93, these microRNAs are produced from several microRNA gene clusters, which apparently arose from a series of ancient evolutionary genetic duplication events, and also include members of the miR-19, and miR-25 families. These clusters are transcribed as long non-coding RNA transcripts that are processed to form ~70 nucleotide microRNA precursors, that are subsequently processed by the Dicer enzyme to give a ~22 nucleotide products. The mature microRNA products are thought to regulate expression levels of other genes through complementarity to the 3' UTR of specific target messenger RNA.

mir-181 microRNA precursor

In molecular biology miR-181 microRNA precursor is a small non-coding RNA molecule. MicroRNAs (miRNAs) are transcribed as ~70 nucleotide precursors and subsequently processed by the RNase-III type enzyme Dicer to give a ~22 nucleotide mature product. In this case the mature sequence comes from the 5' arm of the precursor. They target and modulate protein expression by inhibiting translation and / or inducing degradation of target messenger RNAs. This new class of genes has recently been shown to play a central role in malignant transformation. miRNA are downregulated in many tumors and thus appear to function as tumor suppressor genes. The mature products miR-181a, miR-181b, miR-181c or miR-181d are thought to have regulatory roles at posttranscriptional level, through complementarity to target mRNAs. miR-181 which has been predicted or experimentally confirmed in a wide number of vertebrate species as rat, zebrafish, and in the pufferfish.

mir-199 microRNA precursor

The miR-199 microRNA precursor is a short non-coding RNA gene involved in gene regulation. miR-199 genes have now been predicted or experimentally confirmed in mouse, human and a further 21 other species. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The mature products are thought to have regulatory roles through complementarity to mRNA.

mir-19 microRNA precursor family

There are 89 known sequences today in the microRNA 19 (miR-19) family but it will change quickly. They are found in a large number of vertebrate species. The miR-19 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. Within the human and mouse genome there are three copies of this microRNA that are processed from multiple predicted precursor hairpins:

mir-1 microRNA precursor family

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 products at ~22 nucleotides. 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.

mIRN21

microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.

An oncomir is a microRNA (miRNA) that is associated with cancer. MicroRNAs are short RNA molecules about 22 nucleotides in length. Essentially, miRNAs specifically target certain messenger RNAs (mRNAs) to prevent them from coding for a specific protein. The dysregulation of certain microRNAs (oncomirs) has been associated with specific cancer forming (oncogenic) events. Many different oncomirs have been identified in numerous types of human cancers.

mir-127

mir-127 microRNA is a short non-coding RNA molecule with interesting overlapping gene structure. miR-127 functions to regulate the expression levels of genes involved in lung development, placental formation and apoptosis. Aberrant expression of miR-127 has been linked to different cancers.

mir-145

In molecular biology, mir-145 microRNA is a short RNA molecule that in humans is encoded by the MIR145 gene. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

mir-184

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. 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.

mir-200

In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429. There is growing evidence to suggest that miR-200 microRNAs are involved in cancer metastasis.

miR-214

miR-214 is a vertebrate-specific family of microRNA precursors. The ~22 nucleotide mature miRNA sequence is excised from the precursor hairpin by the enzyme Dicer. This sequence then associates with RISC which effects RNA interference.

In molecular biology mir-365 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

Anti-miRNA Oligonucleotides have many uses in cellular mechanics. These synthetically designed molecules are used to neutralize microRNA (miRNA) function in cells for desired responses. miRNA are complementary sequences to mRNA that are involved in the cleavage of RNA or the suppression of the translation. By controlling the miRNA that regulate mRNAs in cells, AMOs can be used as further regulation as well as for therapeutic treatment for certain cellular disorders. This regulation can occur through a steric blocking mechanism as well as hybridization to miRNA. These interactions, within the body between miRNA and AMOs, can be for therapeutics in disorders in which over/under expression occurs or aberrations in miRNA lead to coding issues. Some of the miRNA linked disorders that are encountered in the humans include cancers, muscular diseases, autoimmune disorders, and viruses. In order to determine the functionality of certain AMOs, the AMO/miRNA binding expression must be measured against the expressions of the isolated miRNA. The direct detection of differing levels of genetic expression allow the relationship between AMOs and miRNAs to be shown. This can be detected through luciferase activity. Understanding the miRNA sequences involved in these diseases can allow us to use anti miRNA Oligonucleotides to disrupt pathways that lead to the under/over expression of proteins of cells that can cause symptoms for these diseases.

References

  1. 1 2 3 4 Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, et al. (2011). "MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes". Circ Res. 109 (6): 670–9. doi:10.1161/CIRCRESAHA.111.248880. PMC   3167208 . PMID   21778430.
  2. ↑ Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001). "Identification of novel genes coding for small expressed RNAs". Science. 294 (5543): 853–8. doi:10.1126/science.1064921. hdl: 11858/00-001M-0000-0012-F65F-2 . PMID   11679670. S2CID   18101169.
  3. 1 2 Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. (2002). "Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia". Proc Natl Acad Sci U S A. 99 (24): 15524–9. doi: 10.1073/pnas.242606799 . PMC   137750 . PMID   12434020.
  4. ↑ Lánczky, András; Nagy, Ádám; Bottai, Giulia; Munkácsy, Gyöngyi; Szabó, András; Santarpia, Libero; Győrffy, Balázs (2016-12-01). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment. 160 (3): 439–446. doi:10.1007/s10549-016-4013-7. ISSN   1573-7217. PMID   27744485. S2CID   11165696.
  5. ↑ Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, et al. (2010). "The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia". Cancer Cell. 17 (1): 28–40. doi: 10.1016/j.ccr.2009.11.019 . PMID   20060366.
  6. 1 2 Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, et al. (2008). "The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities". Nat Med. 14 (11): 1271–7. doi:10.1038/nm.1880. PMID   18931683. S2CID   1452987.
  7. ↑ Aqeilan RI, Calin GA, Croce CM (2010). "miR-15a and miR-16-1 in cancer: discovery, function and future perspectives". Cell Death Differ. 17 (2): 215–20. doi: 10.1038/cdd.2009.69 . PMID   19498445.
  8. ↑ Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, et al. (1997). "Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25". Science. 277 (5331): 1497–501. doi:10.1126/science.277.5331.1497. PMID   9278511.
  9. ↑ Botting KJ, Wang KC, Padhee M, McMillen IC, Summers-Pearce B, Rattanatray L, et al. (2011). "Early origins of heart disease: Low birth weight and determinants of cardiomyocyte endowment". Clin Exp Pharmacol Physiol. 39 (9): 814–823. doi:10.1111/j.1440-1681.2011.05649.x. PMID   22126336. S2CID   31294307.
  10. ↑ Chen H, Untiveros GM, McKee LA, Perez J, Li J, Antin PB, et al. (2012). "Micro-RNA-195 and -451 Regulate the LKB1/AMPK Signaling Axis by Targeting MO25". PLOS ONE. 7 (7): e41574. doi: 10.1371/journal.pone.0041574 . PMC   3402395 . PMID   22844503.

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