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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. In humans miR-15a and miR-16 are clustered within 0.5 kilobases at chromosome position 13q14. 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.
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. Studies have found the miR-15a/16-1 microRNA cluster to function as a tumour suppressor, with the oncogene BCL2 as its target. Specifically, miR-15a/16-1 downregulates BCL2 expression and is itself deleted or downregulated in tumour cells. 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.
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.
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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]
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.[4] Studies have found the miR-15a/16-1 microRNA cluster to function as a tumour suppressor, with the oncogene BCL2 as its target.[5] Specifically, miR-15a/16-1 downregulates BCL2 expression and is itself deleted or downregulated in tumour cells.[6] 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.[5]
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]
The CHEK1 (checkpoint kinase 1) gene, located at chromosome position 11q24.2, is responsible for encoding the protein kinase Chk1.[7] Chk1 in turn phosphorylates a phosphatase involved in cell cycle control. CHEK1 is the only cell-cycle-associated gene possessing an miR-15 family binding site in its 3' UTR. 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]
[edit] 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.[8] 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.[9]
[edit] References
- ^ a b c d 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3167208/.
- ^ 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. PMID 11679670. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11679670.
- ^ a b 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC137750/.
- ^ 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. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20060366.
- ^ a b 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. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18931683.
- ^ 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. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19498445.
- ^ 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. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9278511.
- ^ 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. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22126336.
- ^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3402395/.
[edit] Further reading
- Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G, Nelson PT (August 2010). "The miR-15/107 Group of MicroRNA Genes: Evolutionary Biology, Cellular Functions, and Roles in Human Diseases". J Mol Biol 402 (3): 491–509. doi:10.1016/j.jmb.2010.07.051. PMC 2978331. PMID 20678503. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2978331/.
- Cimmino A, Calin GA, Fabbri M, et al. (September 2005). "miR-15 and miR-16 induce apoptosis by targeting BCL2". Proc. Natl. Acad. Sci. U.S.A. 102 (39): 13944–9. doi:10.1073/pnas.0506654102. PMC 1236577. PMID 16166262. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1236577/.
- Palamarchuk A, Efanov A, Nazaryan N, et al. (May 2010). "13q14 deletions in CLL involve cooperating tumor suppressors". Blood 115 (19): 3916–22. doi:10.1182/blood-2009-10-249367. PMC 2869560. PMID 20071661. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2869560/.
- Aqeilan RI, Calin GA, Croce CM (February 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.
- Guo CJ, Pan Q, Li DG, Sun H, Liu BW (April 2009). "miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis". J. Hepatol. 50 (4): 766–78. doi:10.1016/j.jhep.2008.11.025. PMID 19232449.
- Xia L, Zhang D, Du R, et al. (July 2008). "miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells". Int. J. Cancer 123 (2): 372–9. doi:10.1002/ijc.23501. PMID 18449891.
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