Leukemia inhibitory factor

Leukemia inhibitory factor (cholinergic differentiation factor)
PDB rendering based on 1LKI.
Available structures PDB 1A7M, 1EMR, 1PVH, 2Q7N
Identifiers
Symbols	LIF; CDF; DIA; HILDA
External IDs	OMIM: 159540 MGI: 96787 HomoloGene: 1734 GeneCards: LIF Gene
Gene Ontology Molecular function • receptor binding • cytokine activity • leukemia inhibitory factor receptor binding • leukemia inhibitory factor receptor binding • growth factor activity Cellular component • extracellular region • extracellular space Biological process • blood vessel remodeling • immune response • multicellular organismal development • embryo implantation • positive regulation of cell proliferation • negative regulation of cell proliferation • positive regulation of neuron projection development • negative regulation of angiogenesis • stem cell maintenance • organ regeneration • positive regulation of peptidyl-serine phosphorylation • positive regulation of peptidyl-serine phosphorylation of STAT protein • positive regulation of tyrosine phosphorylation of Stat1 protein • positive regulation of tyrosine phosphorylation of Stat3 protein • positive regulation of MAPKKK cascade • regulation of cell differentiation • positive regulation of macrophage differentiation • negative regulation of meiosis • positive regulation of transcription from RNA polymerase II promoter • decidualization • negative regulation of hormone secretion • lung alveolus development • muscle organ morphogenesis • neuron development • positive regulation of astrocyte differentiation • leukemia inhibitory factor signaling pathway • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of corticotropin secretion • retina development in camera-type eye • maternal process involved in female pregnancy • transdifferentiation • lung vasculature development • lung lobe morphogenesis • trophoblast giant cell differentiation • spongiotrophoblast differentiation • negative regulation of ERK1 and ERK2 cascade • positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis • regulation of metanephric nephron tubule epithelial cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3976	16878
Ensembl	ENSG00000128342	ENSMUSG00000034394
UniProt	P15018	Q3U1H5
RefSeq (mRNA)	NM_002309.3	NM_001039537
RefSeq (protein)	NP_002300.1	NP_001034626
Location (UCSC)	Chr 22: 30.64 – 30.64 Mb	Chr 11: 4.16 – 4.17 Mb
PubMed search	[1]	[2]

Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.

Function

LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on bone metabolism, cachexia, neural development, embryogenesis and inflammation. p53 regulated LIF has been shown to facilitate implantation in the mouse model and possibly in humans.^[1] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.^[2]

Binding/activation

LIF binds to the specific LIF receptor (LIFR-α) which forms a heterodimer with a specific subunit common to all members of that family of receptors, the GP130 signal transducing subunit. This leads to activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen activated protein kinase) cascades.

Expression

LIF is normally expressed in the trophectoderm of the developing embryo, with its receptor LIFR expressed throughout the inner cell mass. As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF.

Use in stem cell culture

Removal of LIF pushes stem cells toward differentiation, but they retain their proliferative potential or pluripotency. Therefore LIF is used in mouse embryonic stem cell culture. It is necessary to maintain the stem cells in an undifferentiated state, however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene Nanog.

LIF is not required for culture of human embryonic stem cells.^[3][4]

References

1. ^ Wenwei Hu, Zhaohui Feng, Angelika K. Teresky1, Arnold J. Levine (November 29, 2007). "p53 regulates maternal reproduction through LIF". Nature 450 (7170): 721–724. doi:10.1038/nature05993. PMID 18046411. http://www.nature.com/nature/journal/v450/n7170/abs/nature05993.html. 
2. ^ Aghajanova, L (2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences 1034: 176–83. doi:10.1196/annals.1335.020. PMID 15731310. 
3. ^ Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L (2009). Zwaka, Thomas. ed. "LIF-Free Embryonic Stem Cell Culture in Simulated Microgravity". PLoS ONE 4 (7): e6343. doi:10.1371/journal.pone.0006343. PMC 2710515. PMID 19626124. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006343. 
4. ^ "CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts'". http://www.geneticsandsociety.org/article.php?id=5197. 

Further reading

• Patterson PH (1994). "Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology". Proc. Natl. Acad. Sci. U.S.A. 91 (17): 7833–5. doi:10.1073/pnas.91.17.7833. PMC 44497. PMID 8058719. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=44497. 
• Aghajanova L (2005). "Leukemia inhibitory factor and human embryo implantation". Ann. N. Y. Acad. Sci. 1034: 176–83. doi:10.1196/annals.1335.020. PMID 15731310. 
• Králícková M, Síma P, Rokyta Z (2005). "Role of the leukemia-inhibitory factor gene mutations in infertile women: the embryo-endometrial cytokine cross talk during implantation--a delicate homeostatic equilibrium". Folia Microbiol. (Praha) 50 (3): 179–86. doi:10.1007/BF02931563. PMID 16295654. 
• Stahl J, Gearing DP, Willson TA, et al. (1990). "Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions". J. Biol. Chem. 265 (15): 8833–41. PMID 1692837. 
• Bazan JF (1991). "Neuropoietic cytokines in the hematopoietic fold". Neuron 7 (2): 197–208. doi:10.1016/0896-6273(91)90258-2. PMID 1714745. 
• Lowe DG, Nunes W, Bombara M, et al. (1989). "Genomic cloning and heterologous expression of human differentiation-stimulating factor". DNA 8 (5): 351–9. doi:10.1089/dna.1.1989.8.351. PMID 2475312. 
• Sutherland GR, Baker E, Hyland VJ, et al. (1989). "The gene for human leukemia inhibitory factor (LIF) maps to 22q12". Leukemia 3 (1): 9–13. PMID 2491897. 
• Mori M, Yamaguchi K, Abe K (1989). "Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia". Biochem. Biophys. Res. Commun. 160 (3): 1085–92. doi:10.1016/S0006-291X(89)80114-7. PMID 2730639. 
• Gough NM, Gearing DP, King JA, et al. (1988). "Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor". Proc. Natl. Acad. Sci. U.S.A. 85 (8): 2623–7. doi:10.1073/pnas.85.8.2623. PMC 280050. PMID 3128791. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=280050. 
• Williams RL, Hilton DJ, Pease S, et al. (1989). "Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells". Nature 336 (6200): 684–7. doi:10.1038/336684a0. PMID 3143916. 
• Moreau JF, Donaldson DD, Bennett F, et al. (1989). "Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells". Nature 336 (6200): 690–2. doi:10.1038/336690a0. PMID 3143918. 
• Yamaguchi M, Miki N, Ono M, et al. (1995). "Inhibition of growth hormone-releasing factor production in mouse placenta by cytokines using gp130 as a signal transducer". Endocrinology 136 (3): 1072–8. doi:10.1210/en.136.3.1072. PMID 7867561. 
• Schmelzer CH, Harris RJ, Butler D, et al. (1993). "Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor". Arch. Biochem. Biophys. 302 (2): 484–9. doi:10.1006/abbi.1993.1243. PMID 8489250. 
• Aikawa J, Ikeda-Naiki S, Ohgane J, et al. (1997). "Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy". Biochim. Biophys. Acta 1353 (3): 266–76. PMID 9349722. 
• Hinds MG, Maurer T, Zhang JG, et al. (1998). "Solution structure of leukemia inhibitory factor". J. Biol. Chem. 273 (22): 13738–45. doi:10.1074/jbc.273.22.13738. PMID 9593715. 
• "Toward a complete human genome sequence". Genome Res. 8 (11): 1097–108. 1999. doi:10.1101/gr.8.11.1097. PMID 9847074. 
• Tanaka M, Hara T, Copeland NG, et al. (1999). "Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit". Blood 93 (3): 804–15. PMID 9920829. 
• Nakashima K, Yanagisawa M, Arakawa H, et al. (1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science 284 (5413): 479–82. doi:10.1126/science.284.5413.479. PMID 10205054. 
• Dunham I, Shimizu N, Roe BA, et al. (1999). "The DNA sequence of human chromosome 22". Nature 402 (6761): 489–95. doi:10.1038/990031. PMID 10591208. 

External links

• MeSH Leukemia+Inhibitory+Factor