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Gene Review

Lif  -  leukemia inhibitory factor

Mus musculus

Synonyms: D factor, Differentiation-stimulating factor, LIF, Leukemia inhibitory factor
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Disease relevance of Lif


High impact information on Lif


Chemical compound and disease context of Lif


Biological context of Lif


Anatomical context of Lif

  • We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif(-/-) mice, pSTAT3 is absent and the STAT3 target, C/EBPdelta, is not upregulated [13].
  • The haploinsufficiency of the Igf-I gene on a Lif null background caused a marked reduction in body mass index and white adipose tissue only in female mice [17].
  • Here we describe the spatial and temporal regulation of LIF signaling in vivo by using tissues isolated from uteri on different days over the implantation period [18].
  • During this time, LIF receptors are expressed predominantly in the luminal epithelium (LE) of the uterus [18].
  • Our results show that LIF is the only one of these factors expressed at detectable levels in the endometrium of women of proven fertility [19].

Associations of Lif with chemical compounds

  • These results suggest that uterine expression of LIF in humans, like mice, may have a role in regulating embryo implantation, possibly through an autocrine/paracrine interaction between LIF and its receptor at the luminal epithelium [19].
  • We have further demonstrated that a combination of LIF with forskolin or retinoic acid, a potent mitogen for PGC, supported the proliferation of PGC, leading to propagation of the embryonic stem cell-like cells, termed embryonic germ (EG) cells [20].
  • We report here that treatment of 3T3-L1 cells with IL-11, IL-6, LIF, and ONC induces overlapping but distinct patterns of tyrosine phosphorylation and activates indistinguishable primary response genes [21].
  • More importantly, the synergistic effect between LIF and PGF2alpha to promote S phase entry is independent of PKC activation [22].
  • Since estrogen is essential for uterine receptivity, LIF induction, and blastocyst activation, it is possible that the nidatory estrogen effects in the P4-primed uterus for implantation are mediated via LIF signaling [23].

Physical interactions of Lif


Enzymatic interactions of Lif


Regulatory relationships of Lif


Other interactions of Lif

  • Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling [15].
  • These results demonstrate a novel region-specific role for CNTF/LIF/gp130 signaling in the development of the germinal layers of the embryonic telencephalon [24].
  • In contrast to the forebrain, CNTF/LIF/gp130 signaling reduced, rather than enhanced, precursor self-renewal/expansion in the spinal cord [24].
  • OSM was able to fully substitute for LIF; both cytokines promoted the proliferation of migratory PGC (mPGC) and enhanced the viability of postmigratory (colonizing) PGC (cPGC) when cultured on SI/SI4-m220 cells [20].
  • Quantitative analysis of leukemia inhibitory factor (LIF) mRNA expression revealed that the dramatic upregulation seen in wild-type mice after peripheral nerve lesion did not occur in pmn mice [29].

Analytical, diagnostic and therapeutic context of Lif


  1. Developmental cooperation of leukemia inhibitory factor and insulin-like growth factor I in mice is tissue-specific and essential for lung maturation involving the transcription factors Sp3 and TTF-1. Pichel, J.G., Fernández-Moreno, C., Vicario-Abejón, C., Testillano, P.S., Patterson, P.H., de Pablo, F. Mech. Dev. (2003) [Pubmed]
  2. Members of the family of IL-6-type cytokines activate Stat5a in various cell types. Piekorz, R.P., Nemetz, C., Hocke, G.M. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  3. Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. Akita, S., Webster, J., Ren, S.G., Takino, H., Said, J., Zand, O., Melmed, S. J. Clin. Invest. (1995) [Pubmed]
  4. Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but does not prevent inflammatory disease. Robb, L., Boyle, K., Rakar, S., Hartley, L., Lochland, J., Roberts, A.W., Alexander, W.S., Metcalf, D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. 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. Cell (1999) [Pubmed]
  6. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Neubauer, H., Cumano, A., Müller, M., Wu, H., Huffstadt, U., Pfeffer, K. Cell (1998) [Pubmed]
  7. The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding. Robinson, R.C., Grey, L.M., Staunton, D., Vankelecom, H., Vernallis, A.B., Moreau, J.F., Stuart, D.I., Heath, J.K., Jones, E.Y. Cell (1994) [Pubmed]
  8. Alternative signaling mechanism of leukemia inhibitory factor responsiveness in a differentiating embryonal carcinoma cell. Takeda, T., Kurachi, H., Yamamoto, T., Homma, H., Adachi, K., Morishige, K., Miyake, A., Murata, Y. Endocrinology (1997) [Pubmed]
  9. Endogenous leukemia inhibitory factor attenuates endotoxin response. Weber, M.A., Schnyder-Candrian, S., Schnyder, B., Quesniaux, V., Poli, V., Stewart, C.L., Ryffel, B. Lab. Invest. (2005) [Pubmed]
  10. Leukaemia inhibitory factor and interleukin 6 are expressed at very low levels in the normal adult mouse and are induced by inflammation. Brown, M.A., Metcalf, D., Gough, N.M. Cytokine (1994) [Pubmed]
  11. Interleukin-4 inhibits the differentiation of mouse myeloid leukemia M1 cells induced by dexamethasone, D-factor/leukemia inhibitory factor and interleukin-6, but not by 1 alpha,25-dihydroxyvitamin D3. Kasukabe, T., Okabe-Kado, J., Honma, Y., Hozumi, M. FEBS Lett. (1991) [Pubmed]
  12. The disulfide bond arrangement of leukemia inhibitory factor: homology to oncostatin M and structural implications. Nicola, N.A., Cross, B., Simpson, R.J. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  13. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Kritikou, E.A., Sharkey, A., Abell, K., Came, P.J., Anderson, E., Clarkson, R.W., Watson, C.J. Development (2003) [Pubmed]
  14. The murine leukemia inhibition factor gene (Lif) is located on proximal chromosome 11, not chromosome 13. Bottorff, D., Stone, J.C. Mamm. Genome (1992) [Pubmed]
  15. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. Nicholson, S.E., Willson, T.A., Farley, A., Starr, R., Zhang, J.G., Baca, M., Alexander, W.S., Metcalf, D., Hilton, D.J., Nicola, N.A. EMBO J. (1999) [Pubmed]
  16. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. Gearing, D.P., Thut, C.J., VandeBos, T., Gimpel, S.D., Delaney, P.B., King, J., Price, V., Cosman, D., Beckmann, M.P. EMBO J. (1991) [Pubmed]
  17. Increased leptin and white adipose tissue hypoplasia are sexually dimorphic in Lif null/Igf-I haploinsufficient mice. Fernández-Moreno, C., Pichel, J.G., Chesnokova, V., De Pablo, F. FEBS Lett. (2004) [Pubmed]
  18. Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. Cheng, J.G., Chen, J.R., Hernandez, L., Alvord, W.G., Stewart, C.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  19. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Cullinan, E.B., Abbondanzo, S.J., Anderson, P.S., Pollard, J.W., Lessey, B.A., Stewart, C.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  20. Functional requirement of gp130-mediated signaling for growth and survival of mouse primordial germ cells in vitro and derivation of embryonic germ (EG) cells. Koshimizu, U., Taga, T., Watanabe, M., Saito, M., Shirayoshi, Y., Kishimoto, T., Nakatsuji, N. Development (1996) [Pubmed]
  21. Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells. Yin, T., Yang, Y.C. J. Biol. Chem. (1994) [Pubmed]
  22. Leukemia inhibitory factor induces DNA synthesis in Swiss mouse 3T3 cells independently of cyclin D1 expression through a mechanism involving MEK/ERK1/2 activation. Dekanty, A., Sauane, M., Cadenas, B., Coluccio, F., Barrio, M., Casala, J., Paciencia, M., Rogers, F., Coso, O.A., Piwien-Pilipuk, G., Rudland, P.S., de Asúa, L.J. J. Biol. Chem. (2006) [Pubmed]
  23. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Song, H., Lim, H., Das, S.K., Paria, B.C., Dey, S.K. Mol. Endocrinol. (2000) [Pubmed]
  24. CNTF/LIF/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain. Gregg, C., Weiss, S. Development (2005) [Pubmed]
  25. A secreted and LIF-mediated stromal cell-derived activity that promotes ex vivo expansion of human hematopoietic stem cells. Shih, C.C., Hu, M.C., Hu, J., Weng, Y., Yazaki, P.J., Medeiros, J., Forman, S.J. Blood (2000) [Pubmed]
  26. Inhibition of Stat3 activation in the endometrium prevents implantation: a nonsteroidal approach to contraception. Catalano, R.D., Johnson, M.H., Campbell, E.A., Charnock-Jones, D.S., Smith, S.K., Sharkey, A.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  27. Leukemia inhibitory factor enhances mast cell growth in a mast cell/fibroblast co-culture system through stat3 signaling pathway of fibroblasts. Hiragun, T., Morita, E., Mihara, S., Tanaka, T., Gyotoku, E., Kameyoshi, Y., Yamamoto, S. FEBS Lett. (2000) [Pubmed]
  28. Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade. Aubert, J., Dessolin, S., Belmonte, N., Li, M., McKenzie, F.R., Staccini, L., Villageois, P., Barhanin, B., Vernallis, A., Smith, A.G., Ailhaud, G., Dani, C. J. Biol. Chem. (1999) [Pubmed]
  29. Endogenous ciliary neurotrophic factor is a lesion factor for axotomized motoneurons in adult mice. Sendtner, M., Götz, R., Holtmann, B., Thoenen, H. J. Neurosci. (1997) [Pubmed]
  30. Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination. Emery, B., Cate, H.S., Marriott, M., Merson, T., Binder, M.D., Snell, C., Soo, P.Y., Murray, S., Croker, B., Zhang, J.G., Alexander, W.S., Cooper, H., Butzkueven, H., Kilpatrick, T.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  31. Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation. Daikoku, T., Song, H., Guo, Y., Riesewijk, A., Mosselman, S., Das, S.K., Dey, S.K. Mol. Endocrinol. (2004) [Pubmed]
  32. Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway. Dani, C., Chambers, I., Johnstone, S., Robertson, M., Ebrahimi, B., Saito, M., Taga, T., Li, M., Burdon, T., Nichols, J., Smith, A. Dev. Biol. (1998) [Pubmed]
  33. Leukemia inhibitory factor gene improves skin allograft survival in the mouse model. Akita, S., Ishihara, H., Mohammad Abdur, R., Fujii, T. Transplantation (2000) [Pubmed]
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