Leukemia inhibitory factor

Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.

LIF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1EMR, 1PVH, 2Q7N
Identifiers
Aliases	LIF, CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor, interleukin 6 family cytokine, LIF interleukin 6 family cytokine
External IDs	OMIM: 159540 MGI: 96787 HomoloGene: 1734 GeneCards: LIF
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q12.2 Start 30,240,453 bp[1] End 30,246,759 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 A1|11 2.94 cM Start 4,257,557 bp[2] End 4,272,514 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • receptor binding • growth factor activity • cytokine activity • GO:0001948 protein binding • leukemia inhibitory factor receptor binding Cellular component • extracellular region • extracellular • cytosol Biological process • negative regulation of cell proliferation • stem cell differentiation • positive regulation of peptidyl-serine phosphorylation of STAT protein • positive regulation of MAPK cascade • positive regulation of peptidyl-serine phosphorylation • spongiotrophoblast differentiation • lung development • positive regulation of histone H3-K27 acetylation • multicellular organism development • lung lobe morphogenesis • muscle organ morphogenesis • maternal process involved in female pregnancy • negative regulation of hormone secretion • leukemia inhibitory factor signaling pathway • regulation of metanephric nephron tubule epithelial cell differentiation • regulation of cell differentiation • positive regulation of gene expression • stem cell population maintenance • positive regulation of peptidyl-tyrosine phosphorylation • regulation of RNA polymerase II regulatory region sequence-specific DNA binding • positive regulation of astrocyte differentiation • negative regulation of ERK1 and ERK2 cascade • neuron development • decidualization • positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis • lung alveolus development • positive regulation of macrophage differentiation • blood vessel remodeling • trophoblast giant cell differentiation • lung vasculature development • positive regulation of transcription from RNA polymerase II promoter • positive regulation of protein localization to nucleus • embryo implantation • negative regulation of meiotic nuclear division • immune response • positive regulation of cell proliferation • positive regulation of tyrosine phosphorylation of STAT protein • tyrosine phosphorylation of STAT protein • regulation of receptor activity • cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3976	16878
Ensembl	ENSG00000128342	ENSMUSG00000034394
UniProt	P15018	P09056
RefSeq (mRNA)	NM_001257135 NM_002309	NM_001039537 NM_008501
RefSeq (protein)	NP_001244064 NP_002300	NP_001034626 NP_032527
Location (UCSC)	Chr 22: 30.24 – 30.25 Mb	Chr 11: 4.26 – 4.27 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells, thus preventing their continued growth. 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.[5] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.[6]

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. Recombinant LIF has been produced in plants by InVitria.

Use in stem cell culture

LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the LIF gene do not effectively support stem cells.[7] LIF promotes self-renewal by recruiting signal transducer and activator of transcription 3 (Stat3). Stat3 is recruited to the activated LIF receptor and phosphorylated by Janus kinase. It bears noting that LIF and Stat3 are not sufficient to inhibit stem cell differentiation, as cells will differentiate upon removal of serum. During the reversibility phase of differentiation from naive pluripotency, it is possible to revert cells back to naive pluripotency through the addition of LIF.[8] Removal of LIF pushes stem cells toward differentiation, however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene Nanog.

LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.[9][10]

References

1. GRCh38: Ensembl release 89: ENSG00000128342 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000034394 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hu W, Feng Z, Teresky AK, Levine AJ (November 2007). "p53 regulates maternal reproduction through LIF". Nature. 450 (7170): 721–4. Bibcode:2007Natur.450..721H. doi:10.1038/nature05993. PMID 18046411.
6. Aghajanova L (December 2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences. 1034 (1): 176–83. Bibcode:2004NYASA1034..176A. doi:10.1196/annals.1335.020. PMID 15731310.
7. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ (September 1992). "Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor". Nature. 359 (6390): 76–9. Bibcode:1992Natur.359...76S. doi:10.1038/359076a0. PMID 1522892.
8. Martello G, Smith A (2014). "The nature of embryonic stem cells". Annual Review of Cell and Developmental Biology. 30: 647–75. doi:10.1146/annurev-cellbio-100913-013116. PMID 25288119.
9. Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L (July 2009). Zwaka T (ed.). "LIF-free embryonic stem cell culture in simulated microgravity". PLOS ONE. 4 (7): e6343. Bibcode:2009PLoSO...4.6343K. doi:10.1371/journal.pone.0006343. PMC 2710515. PMID 19626124.
10. "CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts'". Archived from the original on 2011-10-04.

Further reading

• Patterson PH (August 1994). "Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology". Proceedings of the National Academy of Sciences of the United States of America. 91 (17): 7833–5. Bibcode:1994PNAS...91.7833P. doi:10.1073/pnas.91.17.7833. PMC 44497. PMID 8058719.
• Aghajanova L (December 2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences. 1034: 176–83. Bibcode:2004NYASA1034..176A. 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 Microbiologica. 50 (3): 179–86. doi:10.1007/BF02931563. PMID 16295654.
• Stahl J, Gearing DP, Willson TA, Brown MA, King JA, Gough NM (May 1990). "Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions". The Journal of Biological Chemistry. 265 (15): 8833–41. PMID 1692837.
• Bazan JF (August 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, McCabe S, Ranges GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Goeddel DV (June 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, Callen DF, Stahl J, Gough NM (January 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 (May 1989). "Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia". Biochemical and Biophysical Research Communications. 160 (3): 1085–92. doi:10.1016/S0006-291X(89)80114-7. PMID 2730639.
• Gough NM, Gearing DP, King JA, Willson TA, Hilton DJ, Nicola NA, Metcalf D (April 1988). "Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor". Proceedings of the National Academy of Sciences of the United States of America. 85 (8): 2623–7. Bibcode:1988PNAS...85.2623G. doi:10.1073/pnas.85.8.2623. PMC 280050. PMID 3128791.
• Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM (December 1988). "Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells". Nature. 336 (6200): 684–7. Bibcode:1988Natur.336..684W. doi:10.1038/336684a0. PMID 3143916.
• Moreau JF, Donaldson DD, Bennett F, Witek-Giannotti J, Clark SC, Wong GG (December 1988). "Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells". Nature. 336 (6200): 690–2. Bibcode:1988Natur.336..690M. doi:10.1038/336690a0. PMID 3143918.
• Yamaguchi M, Miki N, Ono M, Ohtsuka C, Demura H, Kurachi H, Inoue M, Endo H, Taga T, Kishimoto T (March 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, Yedinak CM, Wagner KL, Burton LE (May 1993). "Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor". Archives of Biochemistry and Biophysics. 302 (2): 484–9. doi:10.1006/abbi.1993.1243. PMID 8489250.
• Aikawa J, Ikeda-Naiki S, Ohgane J, Min KS, Imamura T, Sasai K, Shiota K, Ogawa T (September 1997). "Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1353 (3): 266–76. doi:10.1016/s0167-4781(97)00079-1. PMID 9349722.
• Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS (May 1998). "Solution structure of leukemia inhibitory factor". The Journal of Biological Chemistry. 273 (22): 13738–45. doi:10.1074/jbc.273.22.13738. PMID 9593715.
• Sanger Centre, The; Washington University Genome Sequencing Cente, The (November 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–108. doi:10.1101/gr.8.11.1097. PMID 9847074.
• Tanaka M, Hara T, Copeland NG, Gilbert DJ, Jenkins NA, Miyajima A (February 1999). "Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit". Blood. 93 (3): 804–15. doi:10.1182/blood.V93.3.804. PMID 9920829.
• Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (April 1999). "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science. 284 (5413): 479–82. Bibcode:1999Sci...284..479N. doi:10.1126/science.284.5413.479. PMID 10205054.
• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP (December 1999). "The DNA sequence of human chromosome 22". Nature. 402 (6761): 489–95. Bibcode:1999Natur.402..489D. doi:10.1038/990031. PMID 10591208.

External links

• Leukemia+Inhibitory+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Source of Recombiant Leukemia Inhibitory Factor (http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html )
• Overview of all the structural information available in the PDB for UniProt: P15018 (Leukemia inhibitory factor) at the PDBe-KB.