Alternative titles; symbols
HGNC Approved Gene Symbol: LIF
Cytogenetic location: 22q12.2 Genomic coordinates (GRCh38): 22:30,240,453-30,246,759 (from NCBI)
By use of the murine cDNA of the recently cloned murine leukemia-inhibitory factor (LIF) gene as a hybridization probe, Gough et al. (1988) isolated the human homolog from a genomic library. The nucleotide sequence of the human gene indicated 78% sequence identity with murine LIF, with no insertions or deletions.
Williams et al. (1988) proposed that LIF is identical to a differentiation inhibitory activity (DIA) in embryonic stem (ES) cells.
Using flow cytometry, immunohistochemical analysis, and in situ hybridization, Kubota et al. (2008) demonstrated that mouse retinal endothelial cells expressed Lif, whereas Lif receptor (LIFR; 151443) was expressed in surrounding cells, such as astrocytes.
Gough et al. (1988) determined that the region of the LIF gene encoding the mature protein contains a single intervening sequence (intron).
Sutherland et al. (1989) mapped the LIF gene to 22q11-q12.2 by Southern analysis of a series of mouse/human somatic cell hybrids and by in situ hybridization to the chromosomes of 2 normal males and some individuals with chromosomal rearrangements. The gene maps between the Philadelphia translocation BCR1 (151410) and the breakpoint of the translocation in cell line GM2324 at 22q12.2. From the grain distribution over high resolution chromosome preparations, the most likely location was thought to be 22q12.1-q12.2. Sutherland et al. (1989) concluded that the location of the LIF gene makes it unlikely that it plays a role in myeloid leukemia or in myeloproliferative disorders.
Budarf et al. (1989) likewise mapped the LIF gene to chromosome 22 by Southern blot analysis and further sublocalized the gene to 22q11.2-q13.1, distal to a Ewing sarcoma (ES; 133450) breakpoint. Analysis by pulsed field gel electrophoresis suggested that LIF is not near the ES breakpoint.
Selleri et al. (1991) demonstrated that the LIF gene is translocated to the ES and peripheral neuroepithelioma (PNE) derivative chromosome 11 in the immediate vicinity of the most centromeric marker flanking the breakpoint on chromosome 11. The physical distance between flanking cosmid markers on chromosome 11 was determined to be approximately 1 Mb. Chromosomal in situ suppression hybridization was used to localize the ES and PNE breakpoints between 2 closely spaced DNA markers. The observations confirmed the localization of the breakpoint and of the LIF gene to 22q12. Since LIF had been shown to suppress in vitro proliferation of myeloid leukemia cell lines and to prevent differentiation of embryonic cells in culture, a chromosomal translocation in the vicinity of this gene might induce oncogenesis. However, pulsed field gel electrophoresis demonstrated no abnormalities in a 650-kb region surrounding the LIF locus.
By isolation of a YAC and a cosmid clone containing both LIF and oncostatin M (OSM; 165095), Giovannini et al. (1993) demonstrated that the 2 genes lie in tandem on 22q12, separated by 16 kb of genomic DNA and transcribed in the same head-to-tail orientation. The close physical linkage is further evidence of their evolutionary relationship suggested by their conserved synteny between mouse and the human.
Bucan et al. (1993) mapped the homologous murine Lif gene to chromosome 11. (Strictly speaking, 'murine' refers to the rodent family Muridae, which includes both rats and mice. By common practice, however, the term is used almost exclusively for mice.)
Patterson (1994) reviewed information on leukemia inhibitory factor with particular emphasis on its functional role at the interface between the immune system and the nervous system. Cell surface molecules and transducing mechanisms are shared between the 2 systems and intercellular messengers mediate active signaling between them. Neurotransmitters and neuropeptides, well known for their role in the communication between neurons, are also capable of activating monocytes and macrophages and inducing chemotaxis in immune cells.
The cytokines LIF and BMP2 (112261) signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 (102582) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors.
Barasch et al. (1999) found that ureteric bud cells secrete factors that convert kidney mesenchyme to epithelia that, remarkably, then forms nephrons. Purification and sequencing of 1 such factor identified it as LIF. In situ, the ureteric bud expressed LIF, and metanephric mesenchyme expressed its receptors. The data suggested that LIF is a candidate regulator of mesenchymal-to-epithelial conversion during kidney development.
Human leukocyte antigen type G (HLA-G; 142871) is a nonclassic class I MHC molecule specifically expressed by human invasive cytotrophoblast cells, which has been suggested to play a role in facilitating the immune tolerance of the conceptus. Bamberger et al. (2000) investigated the regulation of the human HLA-G promoter. LIF administration resulted in induction of the HLA-G promoter. LIF treatment also resulted in induction of HLA-G mRNA. JEG-3 cells were shown to possess LIF receptors. LIF is a pleiotropic cytokine produced at the maternal-fetal interface that has been shown to play an essential role in implantation in mice. LIF is produced in high amounts by the human endometrium and the trophoblast itself, and LIF receptors are present on cytotrophoblast cells. The authors concluded that LIF could play a role in modulating HLA-G production and immune tolerance at the maternal-fetal interface.
Niwa et al. (2009) showed that 2 LIF signaling pathways are each connected to the core circuitry required to maintain pluripotency via different transcription factors. In mouse embryonic stem cells, Klf4 (602253) is mainly activated by the Jak-Stat3 pathway and preferentially activates Sox2 (184429), whereas Tbx3 (601621) is preferentially regulated by the phosphatidylinositol-3-OH kinase-Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog (607937). In the absence of Lif, artificial expression of Klf4 or Tbx3 was sufficient to maintain pluripotency while maintaining the expression of Oct3/4 (164177). Notably, overexpression of Nanog supported Lif-independent self-renewal of mouse embryonic stem cells in the absence of Klf4 and Tbx3 activity. Therefore, Niwa et al. (2009) concluded that KLF4 and TBX3 are involved in mediating LIF signaling to the core circuitry but are not directly associated with the maintenance of pluripotency, because embryonic stem cells keep pluripotency without their expression in the particular context.
Bozec et al. (2008) demonstrated that the FOS-related protein FRA2 (601575) controls osteoclast survival and size. They observed that bones of Fra2-deficient newborn mice had giant osteoclasts, and signaling through Lif and its receptor Lifr was impaired. Similarly, newborn animals lacking Lif had giant osteoclasts, and Bozec et al. (2008) demonstrated that Lif is a direct transcriptional target of Fra2 and c-Jun (604641). Moreover, bones deficient in Fra2 and Lif were hypoxic and expressed increased levels of hypoxia-induced factor 1-alpha (HIF1A; 603348) and Bcl2 (151430). Overexpression of Bcl2 was sufficient to induce giant osteoclasts in vivo, whereas Fra2 and Lif affected Hif1a through transcriptional modulation of the Hif prolyl hydroxylase Phd2 (606425). This pathway is operative in the placenta, because specific inactivation of Fra2 in the embryo alone did not cause hypoxia or the giant osteoclast phenotype. Bozec et al. (2008) concluded that thus, placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups.
Starting with a systematic proteomic investigation of secreted pancreatic cancer disease mediators and underlying molecular mechanisms, Shi et al. (2019) revealed that LIF is a key paracrine factor from activated pancreatic stellate cells acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slowed tumor progression and augmented the efficacy of chemotherapy to prolong survival of pancreatic ductal adenocarcinoma mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human pancreatic ductal adenocarcinoma, aberrant production of LIF in the pancreas was restricted to pathologic conditions and correlated with pancreatic ductal adenocarcinoma pathogenesis, and changes in the levels of circulating LIF correlated well with tumor response to therapy.
Zou et al. (2003) injected LIF plasmid DNA into the thigh muscle of mice immediately after inducing myocardial infarction, and noted a marked increase in circulating LIF protein concentrations. At 2 weeks, infarct size and myocardial fibrosis were markedly attenuated in the LIF cDNA-treated mice compared to vehicle-injected mice, and myocardial preservation and cardiac function were better in the former than in the latter. Injection of LIF cDNA not only prevented the death of cardiomyocytes in the ischemic area but also induced neovascularization in the myocardium. In addition, LIF cDNA injection increased the number of cardiomyocytes in cell cycle and enhanced mobilization of bone marrow cells to the heart and their differentiation into cardiomyocytes. Zou et al. (2003) suggested that LIF cDNA may induce regeneration of the myocardium and may represent gene therapy for myocardial infarction.
Hu et al. (2007) identified the LIF gene, encoding a cytokine critical for implantation, as a p53 (191170)-regulated gene that functions as the downstream mediator of impaired implantation in female p53-null mice. p53 regulated both basal and inducible transcription of LIF. Loss of p53 decreased both the level and function of LIF in uteri. Lower LIF levels were observed in the uteri of p53-null mice than in those of p53 wildtype mice, particularly at day 4 of pregnancy, when transiently induced high levels of LIF were crucial for embryonic implantation. This observation probably accounted for the impaired transplantation of embryos in p53-null female mice. Administration of LIF to pregnant p53-null mice restored maternal reproduction by improving implantation. Hu et al. (2007) concluded that their results demonstrated a function for p53 in maternal reproduction through the regulation of LIF.
Kubota et al. (2008) found that retinas from Lif -/- mice displayed increased microvessel density, accompanied by sustained tip cell activity, due to increased Vegf (192240) expression by astrocytes in the vascularized area. Lif -/- mice resisted hyperoxygen challenge in the oxygen-induced retinopathy model, but paradoxically they had increased numbers of neovascular tufts. In cultured astrocytes, Lif inhibited hypoxia-induced Vegf expression. Lif -/- mice exhibited increased microvessel density and upregulated Vegf in tissues outside retina. Kubota et al. (2008) concluded that tissues and advancing vasculature communicate to ensure adequate vascularization using LIF as well as oxygen, suggesting a new strategy for antiangiogenic therapy.
Moreau et al. (1988) concluded that the human hemopoietic growth factor HILDA (human interleukin in DA cells) is identical to LIF in cDNA sequence. Justice et al. (1990) showed that the murine homolog, Hilda, maps near the gene for dihydrofolate reductase (126060) on chromosome 13. Doolittle (1992) indicated, however, that LIF and HILDA are not the same. Lif and Hilda map to different chromosomes in the mouse, 11 and 13, respectively.
Bamberger, A.-M., Jenatschke, S., Schulte, H. M., Loning, T., Bamberger, C. M. Leukemia inhibitory factor (LIF) stimulates the human HLA-G promoter in JEG3 choriocarcinoma cells. J. Clin. Endocr. Metab. 85: 3932-3936, 2000. [PubMed: 11061559] [Full Text: https://doi.org/10.1210/jcem.85.10.6849]
Barasch, J., Yang, J., Ware, C. B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., Oliver, J. A. Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell 99: 377-386, 1999. [PubMed: 10571180] [Full Text: https://doi.org/10.1016/s0092-8674(00)81524-x]
Bozec, A., Bakiri, L., Hoebertz, A., Eferl, R., Schilling, A. F., Komnenovic, V., Scheuch, H., Priemel, M., Stewart, C. L., Amling, M., Wagner, E. F. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454: 221-225, 2008. [PubMed: 18548006] [Full Text: https://doi.org/10.1038/nature07019]
Bucan, M., Gatalica, B., Nolan, P., Chung, A., Leroux, A., Grossman, M. H., Nadeau, J. H., Emanuel, B. S., Budarf, M. Comparative mapping of 9 human chromosome 22q loci in the laboratory mouse. Hum. Molec. Genet. 2: 1245-1252, 1993. [PubMed: 8401507] [Full Text: https://doi.org/10.1093/hmg/2.8.1245]
Budarf, M., Emanuel, B. S., Mohandas, T., Goeddel, D. V., Lowe, D. G. Human differentiation-stimulating factor (leukemia inhibitory factor, human interleukin DA) gene maps distal to the Ewing sarcoma breakpoint on 22q. Cytogenet. Cell Genet. 52: 19-22, 1989. [PubMed: 2558855] [Full Text: https://doi.org/10.1159/000132831]
Doolittle, D. Personal Communication. Bar Harbor, Me. 3/10/1992.
Giovannini, M., Djabali, M., McElligott, D., Selleri, L., Evans, G. A. Tandem linkage of genes coding for leukemia inhibitory factor (LIF) and oncostatin M (OSM) on human chromosome 22. Cytogenet. Cell Genet. 64: 240-244, 1993. [PubMed: 8404048] [Full Text: https://doi.org/10.1159/000133586]
Gough, N. M., Gearing, D. P., King, J. A., Willson, T. A., Hilton, D. J., Nicola, N. A., Metcalf, D. Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor. Proc. Nat. Acad. Sci. 85: 2623-2627, 1988. [PubMed: 3128791] [Full Text: https://doi.org/10.1073/pnas.85.8.2623]
Hu, W., Feng, Z., Teresky, A. K., Levine, A. J. p53 regulates maternal reproduction through LIF. Nature 450: 721-724, 2007. [PubMed: 18046411] [Full Text: https://doi.org/10.1038/nature05993]
Justice, M. J., Silan, C. M., Ceci, J. D., Buchberg, A. M., Copeland, N. G., Jenkins, N. A. A molecular genetic linkage map of mouse chromosome 13 anchored by the beige (bg) and satin (sa) loci. Genomics 6: 341-351, 1990. [PubMed: 2307475] [Full Text: https://doi.org/10.1016/0888-7543(90)90575-f]
Kubota, Y., Hirashima, M., Kishi, K., Stewart, C. L., Suda, T. Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice. J. Clin. Invest. 118: 2393-2403, 2008. [PubMed: 18521186] [Full Text: https://doi.org/10.1172/JCI34882]
Moreau, J.-F., Donaldson, D. D., Bennett, F., Witek-Giannotti, J., Clark, S. C., Wong, G. C. Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells. Nature 336: 690-692, 1988. [PubMed: 3143918] [Full Text: https://doi.org/10.1038/336690a0]
Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., Taga, T. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284: 479-482, 1999. [PubMed: 10205054] [Full Text: https://doi.org/10.1126/science.284.5413.479]
Niwa, H., Ogawa, K., Shimosato, D., Adachi, K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460: 118-122, 2009. [PubMed: 19571885] [Full Text: https://doi.org/10.1038/nature08113]
Patterson, P. H. Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology. Proc. Nat. Acad. Sci. 91: 7833-7835, 1994. [PubMed: 8058719] [Full Text: https://doi.org/10.1073/pnas.91.17.7833]
Selleri, L., Hermanson, G. G., Eubanks, J. H., Lewis, K. A., Evans, G. A. Molecular localization of the t(11;22)(q24;q12) translocation of Ewing sarcoma by chromosomal in situ suppression hybridization. Proc. Nat. Acad. Sci. 88: 887-891, 1991. [PubMed: 1992479] [Full Text: https://doi.org/10.1073/pnas.88.3.887]
Shi, Y., Gao, W., Lytle, N. K., Huang, P., Yuan, X., Dann, A. M., Ridinger-Saison, M., DelGiorno, K. E., Antal, C. E., Liang, G., Atkins, A. R., Erikson, G., and 25 others. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569: 131-135, 2019. Note: Erratum: Nature 600: E18, 2021. [PubMed: 30996350] [Full Text: https://doi.org/10.1038/s41586-019-1130-6]
Sutherland, G. R., Baker, E., Hyland, V. J., Callen, D. F., Stahl, J., Gough, N. M. The gene for human leukemia inhibitory factor (LIF) maps to 22q12. Leukemia 3: 9-13, 1989. [PubMed: 2491897]
Williams, R. L., Hilton, D. J., Pease, S., Willson, T. A., Stewart, C. L., Gearing, D. P., Wagner, E. F., Metcalf, D., Nicola, N. A., Gough, N. M. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336: 684-687, 1988. [PubMed: 3143916] [Full Text: https://doi.org/10.1038/336684a0]
Zou, Y., Takano, H., Mizukami, M., Akazawa, H., Qin, Y., Toko, H., Sakamoto, M., Minamino, T., Nagai, T., Komuro, I. Leukemia inhibitory factor enhances survival of cardiomyocytes and induces regeneration of myocardium after myocardial infarction. Circulation 108: 748-753, 2003. [PubMed: 12860906] [Full Text: https://doi.org/10.1161/01.CIR.0000081773.76337.44]