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.[1][2][3][4] 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.[5]

mir-199 microRNA precursor
Predicted secondary structure and sequence conservation of mir-199
Identifiers
Symbolmir-199
RfamRF00144
miRBaseMI0000242
miRBase familyMIPF0000040
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GOGO:0035195 GO:0035068
SOSO:0001244
PDB structuresPDBe

Origin and evolution of miR-199

miR-199 has been shown to be a vertebrate specific miR family that emerge at the origin of the vertebrate lineage [6] Three paralogs of miR-199 can usually be found in non-teleost vertebrate species and 4 to 5 copies in the teleost species. All miR-199 genes are located on opposite strand of orthologous intron of Dynamin genes. Within Dynamin3 gene (Dnm3), miR-199 is associated with miR-214 and both miRs are transcribed together as a common primary transcript, demonstrated in mouse, human and zebrafish.[7]

Targets and expression of miR-199

miR-199 has been shown to be implicated in a wide variety of cellular and developmental mechanisms such as various cancer development and progression, cardiomyocytes protection or skeletal formation.[8]

Using microarray and immunoblotting analyses it has been shown that miR-199a* targets the Met proto-oncogene.[9]

MicroRNA hsa-miR-199a is a regulator of IκB kinase-β (IKKβ) expression.[10]

Using TaqMan real-time quantitative PCR array methods, miRNA expression has been profiled. miR-199a, one of the most significantly overexpressed in invasive squamous cell carcinomas (ISCCs), was evaluated by transfecting cervical cancer cells (SiHa and ME-180) with anti-miR-199a oligonucleotides and the cell viability assessed. mirR-199a*, mir199a and mirR-199b were significantly overexpressed in ISCCs.[11]

Implication of miR-199 in skeletogenesis

miR-199, along with its cluster mate MiR-214, has been shown to be implicated in skeleton formation. In mice, miR-199 is expressed in perichondrial cells, periarticular chondrocytes, tracheal cartilage, limb mesenchyme, and most tissues in the upper and lower jaw.[7] In zebrafish, miR-199 is expressed in the developing notochord and in all tissues surrounding developing skeletal elements.[6] Comparative miRNA array led to the isolation of several Bone Morphogenic Protein 2 (BMP2)-responsive miRNAs. Among them, miR-199a* is of particular interest, because it was reported to be specifically expressed in the skeletal system and was shown to inhibit chondrogenesis by down-regulation of Smad1, a major regulator of bone and cartilage formation and development.[12] Also, Twist-1, which is a major actor in skeleton formation, regulates miR-199 and miR-214 cluster expression in mouse.[13] Furthermore, miR199-214 cluster deletion in mouse lead to skeletal development abnormalities including craniofacial defects, neural arch and spinous processes malformations, and osteopenia.[14]

Clinical relevance of miR-199

Alcoholic liver disease is a common medical consequence of long-term excessive alcohol use. Activation of hypoxia-Inducible Factor-1α (HIF-1α) is an indicator of hypoxia. Endothelin-1 (ET-1) is a protein that constricts blood vessels and raises blood pressure. It has been shown that ethanol-induced miR-199 down-regulation may contribute to augmented HIF-1α and ET-1 expression.[15]

References
  1. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T (February 2003). "New microRNAs from mouse and human". RNA. 9 (2): 175–9. doi:10.1261/rna.2146903. PMC 1370382. PMID 12554859.
  2. Houbaviy HB, Murray MF, Sharp PA (August 2003). "Embryonic stem cell-specific MicroRNAs". Developmental Cell. 5 (2): 351–8. doi:10.1016/S1534-5807(03)00227-2. PMID 12919684.
  3. Dostie J, Mourelatos Z, Yang M, Sharma A, Dreyfuss G (February 2003). "Numerous microRNPs in neuronal cells containing novel microRNAs". RNA. 9 (2): 180–6. doi:10.1261/rna.2141503. PMC 1370383. PMID 12554860.
  4. MIPF0000040
  5. Ambros V (December 2001). "microRNAs: tiny regulators with great potential". Cell. 107 (7): 823–6. doi:10.1016/S0092-8674(01)00616-X. PMID 11779458. S2CID 14574186.
  6. Desvignes, T; Postlethwait JH. 2013. Evolution of the miR199-214 cluster and vertebrate skeletal development. Submitted to RNA Biology.
  7. Loebel DA, Tsoi B, Wong N, Tam PP (June 2005). "A conserved noncoding intronic transcript at the mouse Dnm3 locus". Genomics. 85 (6): 782–9. doi:10.1016/j.ygeno.2005.02.001. PMID 15885504.
  8. Gu S, Chan WY (2012). "Flexible and versatile as a chameleon-sophisticated functions of microRNA-199a". International Journal of Molecular Sciences. 13 (7): 8449–66. doi:10.3390/ijms13078449. PMC 3430244. PMID 22942713.
  9. Kim S, Lee UJ, Kim MN, Lee EJ, Kim JY, Lee MY, Choung S, Kim YJ, Choi YC (June 2008). "MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2)". The Journal of Biological Chemistry. 283 (26): 18158–66. doi:10.1074/jbc.M800186200. PMID 18456660.
  10. Chen R, Alvero AB, Silasi DA, Kelly MG, Fest S, Visintin I, Leiser A, Schwartz PE, Rutherford T, Mor G (August 2008). "Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells". Oncogene. 27 (34): 4712–23. doi:10.1038/onc.2008.112. PMC 3041589. PMID 18408758.
  11. Lee JW, Choi CH, Choi JJ, Park YA, Kim SJ, Hwang SY, Kim WY, Kim TJ, Lee JH, Kim BG, Bae DS (May 2008). "Altered MicroRNA expression in cervical carcinomas". Clinical Cancer Research. 14 (9): 2535–42. doi:10.1158/1078-0432.CCR-07-1231. PMID 18451214.
  12. Lin EA, Kong L, Bai XH, Luan Y, Liu CJ (April 2009). "miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1". The Journal of Biological Chemistry. 284 (17): 11326–35. doi:10.1074/jbc.M807709200. PMC 2670138. PMID 19251704.
  13. Lee YB, Bantounas I, Lee DY, Phylactou L, Caldwell MA, Uney JB (January 2009). "Twist-1 regulates the miR-199a/214 cluster during development". Nucleic Acids Research. 37 (1): 123–8. doi:10.1093/nar/gkn920. PMC 2615617. PMID 19029138.
  14. Burkardt DD, Rosenfeld JA, Helgeson ML, Angle B, Banks V, Smith WE, Gripp KW, Moline J, Moran RT, Niyazov DM, Stevens CA, Zackai E, Lebel RR, Ashley DG, Kramer N, Lachman RS, Graham JM (June 2011). "Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25". American Journal of Medical Genetics. Part A. 155A (6): 1336–51. doi:10.1002/ajmg.a.34049. PMC 3109510. PMID 21548129.
  15. Yeligar S, Tsukamoto H, Kalra VK (October 2009). "Ethanol-induced expression of ET-1 and ET-BR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199". Journal of Immunology. 183 (8): 5232–43. doi:10.4049/jimmunol.0901084. PMC 3622549. PMID 19783678.

Further reading
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