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{{Short description|Mammalian protein found in Homo sapiens}}
{{PBB|geneid=3976}}
{{Infobox_gene}}
'''Leukemia inhibitory factor''', or '''LIF''', is an [[interleukin 6]] class [[cytokine]] that affects [[cell (biology)|cell]] growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.
'''Leukemia inhibitory factor''', or '''LIF''', is an [[interleukin 6]] class [[cytokine]] that affects [[cell (biology)|cell]] growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.


== Function ==
== Function ==
LIF derives its name from its ability to induce the terminal [[cellular differentiation|differentiation]] of [[myeloid leukemia|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 (human embryo)|implantation]] in the mouse model and possibly in humans.<ref>{{cite journal | vauthors = Hu W, Feng Z, Teresky AK, Levine AJ | title = p53 regulates maternal reproduction through LIF | journal = Nature | volume = 450 | issue = 7170 | pages = 721–4 | date = November 2007 | pmid = 18046411 | doi = 10.1038/nature05993 | url = http://www.nature.com/nature/journal/v450/n7170/abs/nature05993.html }}</ref> It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.<ref>{{cite journal | vauthors = Aghajanova L | title = Leukemia inhibitory factor and human embryo implantation | journal = Annals of the New York Academy of Sciences | volume = 1034 | issue = 1 | pages = 176–83 | date = December 2004 | pmid = 15731310 | doi = 10.1196/annals.1335.020 }}</ref>
LIF derives its name from its ability to induce the terminal [[cellular differentiation|differentiation]] of [[myeloid leukemia|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 (human embryo)|implantation]] in the mouse model and possibly in humans.<ref>{{cite journal | vauthors = Hu W, Feng Z, Teresky AK, Levine AJ | title = p53 regulates maternal reproduction through LIF | journal = Nature | volume = 450 | issue = 7170 | pages = 721–4 | date = November 2007 | pmid = 18046411 | doi = 10.1038/nature05993 | bibcode = 2007Natur.450..721H | s2cid = 4357527 }}</ref> It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.<ref>{{cite journal | vauthors = Aghajanova L | title = Leukemia inhibitory factor and human embryo implantation | journal = Annals of the New York Academy of Sciences | volume = 1034 | issue = 1 | pages = 176–83 | date = December 2004 | pmid = 15731310 | doi = 10.1196/annals.1335.020 | bibcode = 2004NYASA1034..176A | s2cid = 22083037 }}</ref>


==Binding/activation==
==Binding/activation==
LIF binds to the specific LIF [[receptor (biochemistry)|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 [[Janus kinase|JAK]]/[[STAT protein|STAT]] (Janus kinase/[[Signal transduction|signal transducer]] and activator of [[Transcription (genetics)|transcription]]) and [[MAPK]] ([[mitogen]] activated [[protein]] [[kinase]]) [[biochemical cascade|cascades]].<ref>{{cite journal | vauthors = Suman P, Malhotra SS, Gupta SK | title = LIF-STAT signaling and trophoblast biology | journal = Jak-Stat | volume = 2 | issue = 4 | pages = e25155 | date = October 2013 | pmid = 24416645 | doi = 10.4161/jkst.25155 }}</ref>
LIF binds to the specific LIF [[receptor (biochemistry)|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 [[Janus kinase|JAK]]/[[STAT protein|STAT]] (Janus kinase/[[Signal transduction|signal transducer]] and activator of [[Transcription (genetics)|transcription]]) and [[MAPK]] ([[mitogen]] activated [[protein]] [[kinase]]) [[biochemical cascade|cascades]].{{citation needed|date=December 2012}}


==Expression==
==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.
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.

== Pregnancy ==
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.<ref name=":0">{{cite journal | vauthors = Norwitz ER, Schust DJ, Fisher SJ | title = Implantation and the survival of early pregnancy | journal = The New England Journal of Medicine | volume = 345 | issue = 19 | pages = 1400–8 | date = November 2001 | pmid = 11794174 | doi = 10.1056/NEJMra000763 | url = http://dx.doi.org/10.1056/NEJMra000763 | first2 = Danny J. | first3 = Susan J. }}</ref> Specifically, LIF is expressed in uterine endometrial glands and is under maternal control.<ref name=":1">{{cite journal | vauthors = Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ | title = Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor | language = en | journal = Nature | volume = 359 | issue = 6390 | pages = 76–9 | date = September 1992 | pmid = 1522892 | doi = 10.1038/359076a0 | url = http://www.nature.com/nature/journal/v359/n6390/abs/359076a0.html | first2 = Petr | first3 = Lisa J. }}</ref> 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.<ref name=":0" />

During pregnancy leukemia inhibitory growth factor is involved in decidualization of the maternal endometrium and implantation of the blastocyst to the endometrium.<ref name=":0" /> LIF levels are highest on the fourth day of pregnancy indicating its involvement in implantation.<ref name=":1" /> 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.<ref>{{cite journal | vauthors = Sharkey AM, King A, Clark DE, Burrows TD, Jokhi PP, Charnock-Jones DS, Loke YW, Smith SK | title = Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy | journal = Biology of Reproduction | volume = 60 | issue = 2 | pages = 355–64 | date = February 1999 | pmid = 9916002 | doi = 10.1095/biolreprod60.2.355 }}</ref> 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.<ref>{{cite journal | vauthors = Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M | title = Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis) | journal = Development | volume = 118 | issue = 4 | pages = 1089–94 | date = August 1993 | pmid = 7505738 | doi = | access-date = | first2 = MG | first3 = M }}</ref>

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.<ref name=":1" /><ref>{{cite journal | vauthors = Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S | title = Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions | journal = Nature Medicine | volume = 4 | issue = 9 | pages = 1020–4 | date = September 1998 | pmid = 9734394 | doi = 10.1038/2006 | url = http://www.nature.com/doifinder/10.1038/2006 | first2 = Lucio | first3 = Claudia }}</ref>


==Use in stem cell culture==
==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.<ref>{{cite journal | vauthors = Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ | title = Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor | journal = Nature | volume = 359 | issue = 6390 | pages = 76–9 | date = September 1992 | pmid = 1522892 | doi = 10.1038/359076a0 | bibcode = 1992Natur.359...76S | s2cid = 4319278 }}</ref> 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.<ref>{{cite journal | vauthors = Martello G, Smith A | title = The nature of embryonic stem cells | journal = Annual Review of Cell and Developmental Biology | volume = 30 | pages = 647–75 | year = 2014 | pmid = 25288119 | doi = 10.1146/annurev-cellbio-100913-013116 | doi-access = free }}</ref>
Removal of LIF pushes stem cells toward [[cellular differentiation|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]].
Removal of LIF pushes stem cells toward [[cellular differentiation|differentiation]], however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene [[Homeobox protein NANOG|Nanog]].


LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.<ref>{{cite journal | vauthors = Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L | title = LIF-free embryonic stem cell culture in simulated microgravity | journal = PloS One | volume = 4 | issue = 7 | pages = e6343 | year = 2009 | pmid = 19626124 | pmc = 2710515 | doi = 10.1371/journal.pone.0006343 | url = http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006343 | editor1-last = Zwaka | editor1-first = Thomas }}</ref><ref>{{cite web |url=http://www.geneticsandsociety.org/article.php?id=5197 |title=CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts' |work= |accessdate=}}</ref>
LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.<ref>{{cite journal | vauthors = Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L | title = LIF-free embryonic stem cell culture in simulated microgravity | journal = PLOS ONE | volume = 4 | issue = 7 | pages = e6343 | date = July 2009 | pmid = 19626124 | pmc = 2710515 | doi = 10.1371/journal.pone.0006343 | veditors = Zwaka T | bibcode = 2009PLoSO...4.6343K | doi-access = free }}</ref><ref>{{cite web |url=http://www.geneticsandsociety.org/article.php?id=5197 |title=CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts' |archive-url=https://web.archive.org/web/20111004055228/http://www.geneticsandsociety.org/article.php?id=5197 |archive-date=2011-10-04 |url-status=dead }}</ref>
{{-}}


== References ==
== References ==
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== Further reading ==
== Further reading ==
{{refbegin |33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Youngblood BA, Alfano R, Pettit SC, Zhang D, Dallmann HG, Huang N, Macdonald CC | title = Application of recombinant human leukemia inhibitory factor (LIF) produced in rice (Oryza sativa L.) for maintenance of mouse embryonic stem cells | journal = Journal of Biotechnology | volume = 172 | issue = | pages = 67–72 | date = February 2014 | pmid = 24380819 | doi = 10.1016/j.jbiotec.2013.12.012 }}
* {{cite journal | vauthors = Patterson PH | title = Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 17 | pages = 7833–5 | date = August 1994 | pmid = 8058719 | pmc = 44497 | doi = 10.1073/pnas.91.17.7833 | bibcode = 1994PNAS...91.7833P | doi-access = free }}
* {{cite journal | vauthors = Patterson PH | title = Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 17 | pages = 7833–5 | date = August 1994 | pmid = 8058719 | pmc = 44497 | doi = 10.1073/pnas.91.17.7833 }}
* {{cite journal | vauthors = Aghajanova L | title = Leukemia inhibitory factor and human embryo implantation | journal = Annals of the New York Academy of Sciences | volume = 1034 | pages = 176–83 | date = December 2004 | issue = 1 | pmid = 15731310 | doi = 10.1196/annals.1335.020 | bibcode = 2004NYASA1034..176A | s2cid = 22083037 }}
* {{cite journal | vauthors = Aghajanova L | title = Leukemia inhibitory factor and human embryo implantation | journal = Annals of the New York Academy of Sciences | volume = 1034 | issue = 1 | pages = 176–83 | date = December 2004 | pmid = 15731310 | doi = 10.1196/annals.1335.020 }}
* {{cite journal | vauthors = Králícková M, Síma P, Rokyta Z | title = Role of the leukemia-inhibitory factor gene mutations in infertile women: the embryo-endometrial cytokine cross talk during implantation--a delicate homeostatic equilibrium | journal = Folia Microbiologica | volume = 50 | issue = 3 | pages = 179–86 | year = 2005 | pmid = 16295654 | doi = 10.1007/BF02931563 | s2cid = 22515632 }}
* {{cite journal | vauthors = Králícková M, Síma P, Rokyta Z | title = Role of the leukemia-inhibitory factor gene mutations in infertile women: the embryo-endometrial cytokine cross talk during implantation--a delicate homeostatic equilibrium | journal = Folia Microbiologica | volume = 50 | issue = 3 | pages = 179–86 | year = 2005 | pmid = 16295654 | doi = 10.1007/BF02931563 }}
* {{cite journal | vauthors = Stahl J, Gearing DP, Willson TA, Brown MA, King JA, Gough NM | title = Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions | journal = The Journal of Biological Chemistry | volume = 265 | issue = 15 | pages = 8833–41 | date = May 1990 | doi = 10.1016/S0021-9258(19)38963-X | pmid = 1692837 | doi-access = free }}
* {{cite journal | vauthors = Stahl J, Gearing DP, Willson TA, Brown MA, King JA, Gough NM | title = Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions | journal = The Journal of Biological Chemistry | volume = 265 | issue = 15 | pages = 8833–41 | date = May 1990 | pmid = 1692837 | doi = }}
* {{cite journal | vauthors = Bazan JF | title = Neuropoietic cytokines in the hematopoietic fold | journal = Neuron | volume = 7 | issue = 2 | pages = 197–208 | date = August 1991 | pmid = 1714745 | doi = 10.1016/0896-6273(91)90258-2 | s2cid = 24161982 }}
* {{cite journal | vauthors = Bazan JF | title = Neuropoietic cytokines in the hematopoietic fold | journal = Neuron | volume = 7 | issue = 2 | pages = 197–208 | date = August 1991 | pmid = 1714745 | doi = 10.1016/0896-6273(91)90258-2 }}
* {{cite journal | vauthors = Lowe DG, Nunes W, Bombara M, McCabe S, Ranges GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Goeddel DV | title = Genomic cloning and heterologous expression of human differentiation-stimulating factor | journal = DNA | volume = 8 | issue = 5 | pages = 351–9 | date = June 1989 | pmid = 2475312 | doi = 10.1089/dna.1.1989.8.351 }}
* {{cite journal | vauthors = Lowe DG, Nunes W, Bombara M, McCabe S, Ranges GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Goeddel DV | title = Genomic cloning and heterologous expression of human differentiation-stimulating factor | journal = Dna | volume = 8 | issue = 5 | pages = 351–9 | date = June 1989 | pmid = 2475312 | doi = 10.1089/dna.1.1989.8.351 }}
* {{cite journal | vauthors = Sutherland GR, Baker E, Hyland VJ, Callen DF, Stahl J, Gough NM | authorlink1=Grant Robert Sutherland | title = The gene for human leukemia inhibitory factor (LIF) maps to 22q12 | journal = Leukemia | volume = 3 | issue = 1 | pages = 9–13 | date = January 1989 | pmid = 2491897 }}
* {{cite journal | vauthors = Sutherland GR, Baker E, Hyland VJ, Callen DF, Stahl J, Gough NM | title = The gene for human leukemia inhibitory factor (LIF) maps to 22q12 | journal = Leukemia | volume = 3 | issue = 1 | pages = 9–13 | date = January 1989 | pmid = 2491897 | doi = }}
* {{cite journal | vauthors = Mori M, Yamaguchi K, Abe K | title = Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia | journal = Biochemical and Biophysical Research Communications | volume = 160 | issue = 3 | pages = 1085–92 | date = May 1989 | pmid = 2730639 | doi = 10.1016/S0006-291X(89)80114-7 }}
* {{cite journal | vauthors = Mori M, Yamaguchi K, Abe K | title = Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia | journal = Biochemical and Biophysical Research Communications | volume = 160 | issue = 3 | pages = 1085–92 | date = May 1989 | pmid = 2730639 | doi = 10.1016/S0006-291X(89)80114-7 }}
* {{cite journal | vauthors = Gough NM, Gearing DP, King JA, Willson TA, Hilton DJ, Nicola NA, Metcalf D | title = Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 8 | pages = 2623–7 | date = April 1988 | pmid = 3128791 | pmc = 280050 | doi = 10.1073/pnas.85.8.2623 }}
* {{cite journal | vauthors = Gough NM, Gearing DP, King JA, Willson TA, Hilton DJ, Nicola NA, Metcalf D | title = Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 8 | pages = 2623–7 | date = April 1988 | pmid = 3128791 | pmc = 280050 | doi = 10.1073/pnas.85.8.2623 | bibcode = 1988PNAS...85.2623G | doi-access = free }}
* {{cite journal | vauthors = Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM | title = Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells | journal = Nature | volume = 336 | issue = 6200 | pages = 684–7 | date = December 1988 | pmid = 3143916 | doi = 10.1038/336684a0 }}
* {{cite journal | vauthors = Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM | title = Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells | journal = Nature | volume = 336 | issue = 6200 | pages = 684–7 | date = December 1988 | pmid = 3143916 | doi = 10.1038/336684a0 | bibcode = 1988Natur.336..684W | s2cid = 4346252 }}
* {{cite journal | vauthors = Moreau JF, Donaldson DD, Bennett F, Witek-Giannotti J, Clark SC, Wong GG | title = Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells | journal = Nature | volume = 336 | issue = 6200 | pages = 690–2 | date = December 1988 | pmid = 3143918 | doi = 10.1038/336690a0 }}
* {{cite journal | vauthors = Moreau JF, Donaldson DD, Bennett F, Witek-Giannotti J, Clark SC, Wong GG | title = Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells | journal = Nature | volume = 336 | issue = 6200 | pages = 690–2 | date = December 1988 | pmid = 3143918 | doi = 10.1038/336690a0 | bibcode = 1988Natur.336..690M | s2cid = 4259150 }}
* {{cite journal | vauthors = Yamaguchi M, Miki N, Ono M, Ohtsuka C, Demura H, Kurachi H, Inoue M, Endo H, Taga T, Kishimoto T | title = Inhibition of growth hormone-releasing factor production in mouse placenta by cytokines using gp130 as a signal transducer | journal = Endocrinology | volume = 136 | issue = 3 | pages = 1072–8 | date = March 1995 | pmid = 7867561 | doi = 10.1210/en.136.3.1072 }}
* {{cite journal | vauthors = Yamaguchi M, Miki N, Ono M, Ohtsuka C, Demura H, Kurachi H, Inoue M, Endo H, Taga T, Kishimoto T | title = Inhibition of growth hormone-releasing factor production in mouse placenta by cytokines using gp130 as a signal transducer | journal = Endocrinology | volume = 136 | issue = 3 | pages = 1072–8 | date = March 1995 | pmid = 7867561 | doi = 10.1210/endo.136.3.7867561 }}
* {{cite journal | vauthors = Schmelzer CH, Harris RJ, Butler D, Yedinak CM, Wagner KL, Burton LE | title = Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor | journal = Archives of Biochemistry and Biophysics | volume = 302 | issue = 2 | pages = 484–9 | date = May 1993 | pmid = 8489250 | doi = 10.1006/abbi.1993.1243 }}
* {{cite journal | vauthors = Schmelzer CH, Harris RJ, Butler D, Yedinak CM, Wagner KL, Burton LE | title = Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor | journal = Archives of Biochemistry and Biophysics | volume = 302 | issue = 2 | pages = 484–9 | date = May 1993 | pmid = 8489250 | doi = 10.1006/abbi.1993.1243 }}
* {{cite journal | vauthors = Aikawa J, Ikeda-Naiki S, Ohgane J, Min KS, Imamura T, Sasai K, Shiota K, Ogawa T | title = Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy | journal = Biochimica et Biophysica Acta | volume = 1353 | issue = 3 | pages = 266–76 | date = September 1997 | pmid = 9349722 | doi = 10.1016/s0167-4781(97)00079-1 }}
* {{cite journal | vauthors = Aikawa J, Ikeda-Naiki S, Ohgane J, Min KS, Imamura T, Sasai K, Shiota K, Ogawa T | title = Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1353 | issue = 3 | pages = 266–76 | date = September 1997 | pmid = 9349722 | doi = 10.1016/s0167-4781(97)00079-1 }}
* {{cite journal | vauthors = Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS | title = Solution structure of leukemia inhibitory factor | journal = The Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 13738–45 | date = May 1998 | pmid = 9593715 | doi = 10.1074/jbc.273.22.13738 }}
* {{cite journal | vauthors = Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS | title = Solution structure of leukemia inhibitory factor | journal = The Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 13738–45 | date = May 1998 | pmid = 9593715 | doi = 10.1074/jbc.273.22.13738 | doi-access = free }}
* {{cite journal | vauthors = | title = Toward a complete human genome sequence | journal = Genome Research | volume = 8 | issue = 11 | pages = 1097–108 | date = November 1998 | pmid = 9847074 | doi = 10.1101/gr.8.11.1097 }}
* {{cite journal | title = Toward a complete human genome sequence | journal = Genome Research | volume = 8 | issue = 11 | pages = 1097–108 | date = November 1998 | pmid = 9847074 | doi = 10.1101/gr.8.11.1097 | vauthors = ((Sanger Centre)), ((Washington University Genome Sequencing Center)) | doi-access = free }}
* {{cite journal | vauthors = Tanaka M, Hara T, Copeland NG, Gilbert DJ, Jenkins NA, Miyajima A | title = Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit | journal = Blood | volume = 93 | issue = 3 | pages = 804–15 | date = February 1999 | pmid = 9920829 | doi = }}
* {{cite journal | vauthors = Tanaka M, Hara T, Copeland NG, Gilbert DJ, Jenkins NA, Miyajima A | title = Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit | journal = Blood | volume = 93 | issue = 3 | pages = 804–15 | date = February 1999 | pmid = 9920829 | doi = 10.1182/blood.V93.3.804| s2cid = 39078004 }}
* {{cite journal | vauthors = Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T | title = Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300 | journal = Science | volume = 284 | issue = 5413 | pages = 479–82 | date = April 1999 | pmid = 10205054 | doi = 10.1126/science.284.5413.479 }}
* {{cite journal | vauthors = Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T | title = Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300 | journal = Science | volume = 284 | issue = 5413 | pages = 479–82 | date = April 1999 | pmid = 10205054 | doi = 10.1126/science.284.5413.479 | bibcode = 1999Sci...284..479N }}
* {{cite journal | vauthors = 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 | title = The DNA sequence of human chromosome 22 | journal = Nature | volume = 402 | issue = 6761 | pages = 489–95 | date = December 1999 | pmid = 10591208 | doi = 10.1038/990031 }}
* {{cite journal | vauthors = 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 | title = The DNA sequence of human chromosome 22 | journal = Nature | volume = 402 | issue = 6761 | pages = 489–95 | date = December 1999 | pmid = 10591208 | doi = 10.1038/990031 | bibcode = 1999Natur.402..489D | doi-access = free }}
{{refend}}
{{refend}}
{{PDB Gallery|geneid=3976}}
{{PDB Gallery|geneid=3976}}
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== External links ==
== External links ==
* {{MeshName|Leukemia+Inhibitory+Factor}}
* {{MeshName|Leukemia+Inhibitory+Factor}}
* Source of Recombiant Leukemia Inhibitory Factor (http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html )
* Source of Recombiant Leukemia Inhibitory Factor (http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html {{Webarchive|url=https://web.archive.org/web/20140225034322/http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html |date=2014-02-25 }} )
* {{PDBe-KB2|P15018|Leukemia inhibitory factor}}



{{Interleukins}}
{{Interleukins}}


[[Category:Cytokines]]
[[Category:Cytokines]]
[[Category:Drugs]]
[[Category:Oncology]]
[[Category:Oncology]]

Latest revision as of 04:50, 17 August 2024

LIF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLIF, CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor, interleukin 6 family cytokine, LIF interleukin 6 family cytokine
External IDsOMIM: 159540; MGI: 96787; HomoloGene: 1734; GeneCards: LIF; OMA:LIF - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 11: 4.21 – 4.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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

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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.[citation needed]

Expression

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128342 – Ensembl, May 2017
  2. ^ a b c 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. S2CID 4357527.
  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. S2CID 22083037.
  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. S2CID 4319278.
  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

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