Leukemia inhibitory factor

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LIF
LIF Crystal Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LIF, CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor
External IDs OMIM: 159540 MGI: 96787 HomoloGene: 1734 GeneCards: 3976
RNA expression pattern
PBB GE LIF 205266 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001257135
NM_002309

NM_001039537
NM_008501

RefSeq (protein)

NP_001244064.1
NP_002300.1

NP_001034626.1
NP_032527.1

Location (UCSC) Chr 22: 30.24 – 30.25 Mb Chr 11: 4.26 – 4.27 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

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[edit]

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.[1] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.[2]

Binding/activation[edit]

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.[3]

Expression[edit]

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.

Pregnancy[edit]

Leukemia inhibitory factor is a cytokine expressed in the uterus during the secretory phase of the menstrual cycle, as well as expressed during a normal pregnancy.[4] Specifically, LIF is expressed in uterine endometrial glands and is under maternal control.[5] When the fertilized zygote has reached the blastocyst stage, the stromal cells surrounding the blastocyst produce leukemia inhibitory factor, which needed for the blastocyst to implant into the uterine endometrium.[4]

During pregnancy leukemia inhibitory growth factor is involved in decidualization of the maternal endometrium and implantation of the blastocyst to the endometrium.[4] LIF levels are highest on the fourth day of pregnancy indicating its involvement in implantation.[5] Implantation is critical in pregnancy in order to establish the placenta and maternal-fetal interface. Fetal endothelial cells also express the receptor for leukemia inhibitory factor, indicating it may be involved in placental angiogenesis.[6] There is also evidence leukemia inhibitory factor is involved in the survival and proliferation of primordial germ cells, which are the cellular origins of spermatozoa and oocytes.[7]

Decreased secretion of leukemia inhibitory factor is associated with poor or no implantation and, thus, pregnancy loss. Women with decreased production of LIF and other cytokines are fertile and able to become pregnant, but there is an increased risk for unexplained, recurrent miscarriages.[5][8]

Use in stem cell culture[edit]

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

References[edit]

  1. ^ Hu W, Feng Z, Teresky AK, Levine AJ (November 2007). "p53 regulates maternal reproduction through LIF". Nature 450 (7170): 721–4. doi:10.1038/nature05993. PMID 18046411. 
  2. ^ Aghajanova L (December 2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences 1034 (1): 176–83. doi:10.1196/annals.1335.020. PMID 15731310. 
  3. ^ Suman P, Malhotra SS, Gupta SK (October 2013). "LIF-STAT signaling and trophoblast biology". Jak-Stat 2 (4): e25155. doi:10.4161/jkst.25155. PMID 24416645. 
  4. ^ a b c Norwitz ER, Schust DJ, Fisher SJ (November 2001). "Implantation and the survival of early pregnancy". The New England Journal of Medicine 345 (19): 1400–8. doi:10.1056/NEJMra000763. PMID 11794174. 
  5. ^ a b c 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. doi:10.1038/359076a0. PMID 1522892. 
  6. ^ Sharkey AM, King A, Clark DE, Burrows TD, Jokhi PP, Charnock-Jones DS, Loke YW, Smith SK (February 1999). "Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy". Biology of Reproduction 60 (2): 355–64. doi:10.1095/biolreprod60.2.355. PMID 9916002. 
  7. ^ Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M (August 1993). "Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis)". Development 118 (4): 1089–94. PMID 7505738. 
  8. ^ Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S (September 1998). "Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions". Nature Medicine 4 (9): 1020–4. doi:10.1038/2006. PMID 9734394. 
  9. ^ Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L (2009). Zwaka T, 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. 
  10. ^ "CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts'". 

Further reading[edit]

  • Youngblood BA, Alfano R, Pettit SC, Zhang D, Dallmann HG, Huang N, Macdonald CC (February 2014). "Application of recombinant human leukemia inhibitory factor (LIF) produced in rice (Oryza sativa L.) for maintenance of mouse embryonic stem cells". Journal of Biotechnology 172: 67–72. doi:10.1016/j.jbiotec.2013.12.012. PMID 24380819. 
  • 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. 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. 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. 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. 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. 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 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. 
  • "Toward a complete human genome sequence". Genome Research 8 (11): 1097–108. November 1998. 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. 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. 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. doi:10.1038/990031. PMID 10591208. 

External links[edit]