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.
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. It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.
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. 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. 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.
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 (1): 176–83. Bibcode:2004NYASA1034..176A. doi:10.1196/annals.1335.020. PMID 15731310. S2CID 22083037.
- 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. S2CID 22515632.
- 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. doi:10.1016/S0021-9258(19)38963-X. 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. S2CID 24161982.
- 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. S2CID 4346252.
- 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. S2CID 4259150.
- 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/endo.136.3.7867561. 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. S2CID 39078004.
- 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.
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External links
- Leukemia+Inhibitory+Factor at the U.S. 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.