Biology:mir-34 microRNA precursor family

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mir-34 microRNA precursor family
MicroRNA-34 precursor structure.svg
Predicted secondary structure and sequence conservation of mir-34
Identifiers
Symbolmir-34
RfamRF00456
miRBaseMI0000268
miRBase familyMIPF0000039
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GO0035195 0035068
SO0001244
PDB structuresPDBe

The miR-34 microRNA precursor family are non-coding RNA molecules that, in mammals, give rise to three major mature miRNAs. The miR-34 family members were discovered computationally[1] and later verified experimentally.[2][3] The precursor miRNA stem-loop is processed in the cytoplasm of the cell, with the predominant miR-34 mature sequence excised from the 5' arm of the hairpin.[4]

The miR-34 family

In mammals, three miR-34 precursors are produced from two transcriptional units.[5] The human miR-34a precursor is transcribed from chromosome 1. The miR-34b and miR-34c precursors are co-transcribed from a region on chromosome 11, apparently as part of a transcript known as BC021736.

Expression of MIR34A (gene) in mouse is observed in all tissues examined but is highest in brain. miR-34b and -c are relatively less abundant in most tissues, but are the predominant miR-34 species in lung.[5] The presence of miR-34 products has also been confirmed in embryonic stem cells. miR-34 has been shown to be maternally inherited in Drosophila and zebrafish and the loss of miR-34 resulted in defects in hindbrain development in zebrafish embryos. This was the first report of knockdown phenotype of miR-34 in any model organism although the phenotype was observed in only about 30% of zebrafish embryos.[6]

Targets of miR-34

Yamakuchi et al.. showed that miR-34a targets the silent information regulator 1 (SIRT1) gene:[7]

"miR-34 inhibition of SIRT1 leads to an increase in acetylated p53 and expression of p21 and PUMA, transcriptional targets of p53 that regulate the cell cycle and apoptosis, respectively. Furthermore, miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53. Finally, miR-34a itself is a transcriptional target of p53, suggesting a positive feedback loop between p53 and miR-34a. Thus, miR-34a functions as a tumor suppressor, in part, through a SIRT1-p53 pathway."[7]

Recently Quantitative proteomics – SILAC approach was used to identify miR-34a targets at genome level in HEK293T cells.[8]

Mir-34 inhibits human p53-mutant gastric cancer tumorspheres

p53-deficient human gastric cancer cells, restoration of functional miR-34 inhibits cell growth and induces chemosensitization and apoptosis, indicating that miR-34 may restore p53 function. Restoration of miR-34 inhibits tumorsphere formation and growth, which is reported to be correlated to the self-renewal of cancer stem cells. The mechanism of miR-34-mediated suppression of self-renewal appears to be related to the direct modulation of downstream targets Bcl-2, Notch, and HMGA2, indicating that miR-34 may be involved in gastric cancer stem cell self-renewal/differentiation decision-making.[9][10] miR-34c has also been associated to bone development and bone cancer.[11]

References

  1. ↑ "Vertebrate microRNA genes". Science 299 (5612): 1540. Mar 2003. doi:10.1126/science.1080372. PMID 12624257. 
  2. ↑ "Numerous microRNPs in neuronal cells containing novel microRNAs". RNA 9 (2): 180–6. Feb 2003. doi:10.1261/rna.2141503. PMID 12554860. 
  3. ↑ "Embryonic stem cell-specific MicroRNAs". Developmental Cell 5 (2): 351–8. Aug 2003. doi:10.1016/S1534-5807(03)00227-2. PMID 12919684. 
  4. ↑ "A microRNA component of the p53 tumour suppressor network". Nature 447 (7148): 1130–4. Jun 2007. doi:10.1038/nature05939. PMID 17554337. 
  5. ↑ 5.0 5.1 "The miR-34 family in cancer and apoptosis". Cell Death and Differentiation 17 (2): 193–9. Feb 2010. doi:10.1038/cdd.2009.56. PMID 19461653. 
  6. ↑ "miR-34 is maternally inherited in Drosophila melanogaster and Danio rerio". Nucleic Acids Research 41 (8): 4470–80. Apr 2013. doi:10.1093/nar/gkt139. PMID 23470996. 
  7. ↑ 7.0 7.1 "miR-34a repression of SIRT1 regulates apoptosis". Proceedings of the National Academy of Sciences of the United States of America 105 (36): 13421–6. Sep 2008. doi:10.1073/pnas.0801613105. PMID 18755897. 
  8. ↑ "Identification of novel targets for miR-29a using miRNA proteomics". PLOS ONE 7 (8): e43243. 2012. doi:10.1371/journal.pone.0043243. PMID 22952654. 
  9. ↑ "Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres". BMC Cancer 8: 266. 2008. doi:10.1186/1471-2407-8-266. PMID 18803879. 
  10. ↑ Mir-34 and p53 pathway
  11. ↑ "miRNA-34c regulates Notch signaling during bone development". Human Molecular Genetics 21 (13): 2991–3000. Jul 2012. doi:10.1093/hmg/dds129. PMID 22498974. 

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