LIN28

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Lin-28 homolog A (C. elegans)
Protein LIN28 PDB 2cqf.png
PDB rendering based on 2cqf.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LIN28A ; CSDD1; LIN-28; LIN28; ZCCHC1; lin-28A
External IDs OMIM611043 MGI1890546 HomoloGene32592 GeneCards: LIN28A Gene
RNA expression pattern
PBB GE LIN28 219823 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 79727 83557
Ensembl ENSG00000213120 ENSMUSG00000050966
UniProt Q9H9Z2 Q8K3Y3
RefSeq (mRNA) NM_024674 NM_145833
RefSeq (protein) NP_078950 NP_665832
Location (UCSC) Chr 1:
26.74 – 26.76 Mb
Chr 4:
134 – 134.02 Mb
PubMed search [1] [2]

Lin-28 homolog A is a protein that in humans is encoded by the LIN28 gene.[1][2]

LIN28 encodes a microRNA-binding protein[3] that binds to and enhances the translation of the IGF-2 (insulin-like growth factor 2) mRNA.[4] Lin28 binds to the let-7 pre-microRNA and blocks production of the mature let-7 microRNA in mouse embryonic stem cells.[5] [6] In pluripotent embryonal carcinoma cells, LIN28 is localized in the ribosomes, P-bodies and stress granules.[7]

Function[edit]

Stem cell expression[edit]

LIN28 is thought to regulate the self-renewal of stem cells. In nematodes, the LIN28 homolog lin-28 is a heterochronic gene that determines the onset of early larval stages of developmental events in Caenorhabditis elegans, by regulating the self-renewal of nematode stem cells in the skin (called seam cells) and vulva (called VPCs) during development.[8] In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early embryogenesis.[9]

LIN28 is highly expressed in human embryonic stem cells[3] and can enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts.[10]

Puberty[edit]

LIN28 overexpression in mice can cause gigantism and a delay in puberty onset, consistent with human genome-wide association studies suggesting that polymorphisms in the human LIN28B gene are associated with human height and puberty timing.[11] Mutations in LIN28B are associated with precocious puberty.[12]

LIN28 can regulate glucose homeostasis in mammals by increasing insulin-PI3K-mTOR signaling and insulin sensitivity, thereby promoting resistance to high fat diet-induced obesity and type 2 diabetes.[13]

Tissue regeneration[edit]

Mice genetically altered to produce LIN28 during their lifespan showed improved hair growth.[14] and healthy tissue regeneration on added puncture wounds[14] in later life stages.[14] While the mice could regenerate limbs, they could not repair damaged heart tissue. Appropriate drugs replicated the regeneration in unaltered mice, using the same metabolic paths. The drugs increased the subjects' metabolic rates, evidently causing the body to heal at higher rates. The effects of Lin28a activation faded with age.[14][15]

Structure[edit]

Crystallographic structures of Lin28/let-7 complexes reveal that two folded domains of Lin28 recognize two distinct RNA regions. The domains are sufficient for inhibition of let-7 in vivo.[16][6]

Applications[edit]

LIN28 is a marker of undifferentiated human embryonic stem cells[3] and has been used to enhance the efficiency of the formation of iPS cells from human fibroblasts.[7]

References[edit]

  1. ^ Moss EG, Tang L (Jun 2003). "Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites". Developmental Biology 258 (2): 432–42. doi:10.1016/S0012-1606(03)00126-X. PMID 12798299. 
  2. ^ "Entrez Gene: LIN28 lin-28 homolog (C. elegans)". 
  3. ^ a b c Richards M, Tan SP, Tan JH, Chan WK, Bongso A (2004). "The transcriptome profile of human embryonic stem cells as defined by SAGE". Stem Cells 22 (1): 51–64. doi:10.1634/stemcells.22-1-51. PMID 14688391. 
  4. ^ Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss EG, Harel-Bellan A (May 2007). "Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency". Genes & Development 21 (9): 1125–38. doi:10.1101/gad.415007. PMC 1855237. PMID 17473174. 
  5. ^ Viswanathan SR, Daley GQ, Gregory RI (Apr 2008). "Selective blockade of microRNA processing by Lin28". Science 320 (5872): 97–100. doi:10.1126/science.1154040. PMC 3368499. PMID 18292307. 
  6. ^ a b Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S (Nov 2012). "Recognition of the let-7g miRNA precursor by human Lin28B". FEBS Letters 586 (22): 3986–90. doi:10.1016/j.febslet.2012.09.034. PMID 23063642. 
  7. ^ a b Balzer E, Moss EG (2007). "Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules". RNA Biology 4 (1): 16–25. doi:10.4161/rna.4.1.4364. PMID 17617744. 
  8. ^ Moss EG, Lee RC, Ambros V (Mar 1997). "The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA". Cell 88 (5): 637–46. doi:10.1016/s0092-8674(00)81906-6. PMID 9054503. 
  9. ^ Yang DH, Moss EG (Dec 2003). "Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse". Gene Expression Patterns 3 (6): 719–26. doi:10.1016/s1567-133x(03)00140-6. PMID 14643679. 
  10. ^ Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S et al. (Dec 2007). "Induced pluripotent stem cell lines derived from human somatic cells". Science 318 (5858): 1917–20. doi:10.1126/science.1151526. PMID 18029452. 
  11. ^ Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR et al. (Jul 2010). "Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies". Nature Genetics 42 (7): 626–30. doi:10.1038/ng.593. PMC 3069638. PMID 20512147. 
  12. ^ Park SW, Lee ST, Sohn YB, Cho SY, Kim SH, Kim SJ et al. (Oct 2012). "LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls". Korean Journal of Pediatrics 55 (10): 388–92. doi:10.3345/kjp.2012.55.10.388. PMC 3488615. PMID 23133486. 
  13. ^ Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS et al. (Sep 2011). "The Lin28/let-7 axis regulates glucose metabolism". Cell 147 (1): 81–94. doi:10.1016/j.cell.2011.08.033. PMC 3353524. PMID 21962509. 
  14. ^ a b c d Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson MT, Tsanov KM et al. (Nov 2013). "Lin28 enhances tissue repair by reprogramming cellular metabolism". Cell 155 (4). doi:10.1016/j.cell.2013.09.059. PMID 24209617. Lay summaryScientific American. 
  15. ^ Shyh-Chang N, Daley GQ (Apr 2013). "Lin28: primal regulator of growth and metabolism in stem cells". Cell Stem Cell 12 (4). doi:10.1016/j.stem.2013.03.005. PMID 23561442. 
  16. ^ PDB: 3TS2 ; Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P (Nov 2011). "Molecular basis for interaction of let-7 microRNAs with Lin28". Cell 147 (5): 1080–91. doi:10.1016/j.cell.2011.10.020. PMC 3277843. PMID 22078496. 

Further reading[edit]