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Gene Review

LCN2  -  lipocalin 2

Homo sapiens

Synonyms: 24p3, 25 kDa alpha-2-microglobulin-related subunit of MMP-9, HNL, Lipocalin-2, MSFI, ...
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Disease relevance of LCN2

  • Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia [1].
  • Lipocalin 2 diminishes invasiveness and metastasis of Ras-transformed cells [2].
  • CONCLUSIONS: These findings suggest, for the first time, that NGAL may play an important role in breast cancer in vivo by protecting MMP-9 from degradation thereby enhancing its enzymatic activity and facilitating angiogenesis and tumor growth [3].
  • Human neutrophil lipocalin (HNL) cDNA was amplified by PCR technology in combination with deoxyinosine containing oligonucleotides for cloning, sequencing and production of the recombinant protein in E. coli [4].
  • The increased expression of lipocalin 2, which activates matrix metalloproteinases (MMP), is consistent with our previous findings that MMP-9 and other MMPs are highly expressed in pterygium basal epithelium [5].
  • Among SLE patients, urinary lipocalin-2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3-45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1-20.3; n = 38) (P = 0.023) [6].
  • Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards) [7].

High impact information on LCN2

  • The major core proteins (p25) of the isolates were antigenically identical and all three isolates were identical to prototype lymphadenopathy associated virus isolated in France [8].
  • This virus is a typical type-C RNA tumor virus, buds from the cell membrane, prefers magnesium for reverse transcriptase activity, and has an internal antigen (p25) similar to HTLV p24 [9].
  • We further provide evidence that p17 is synthesized by N-terminal proteolytic processing of p25 by a serine protease [10].
  • The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition [11].
  • Here we report that NGAL tightly binds bacterial catecholate-type ferric siderophores through a cyclically permuted, hybrid electrostatic/cation-pi interaction and is a potent bacteriostatic agent in iron-limiting conditions [11].

Chemical compound and disease context of LCN2

  • In contrast, a significant correlation between NGAL expression in breast cancer was found with several other markers of poor prognosis, including estrogen and progesterone receptor-negative status and high proliferation (S-phase fraction) [12].
  • Antibody to LAV p25 was found in the serum of 51 of 125 AIDS patients, 81 of 113 patients with lymphadenopathy syndrome, 0 of 70 workers at the Centers for Disease Control (some of whom had handled specimens from AIDS patients), and 0 of 189 random blood donors [13].
  • Secreted lipocalin 2 (Lcn2) sequesters the Escherichia coli siderophore enterobactin (Ent), preventing E. coli from acquiring iron and protecting mammals from infection by E. coli [14].
  • NGAL levels of >0.6 ng/mg urinary creatinine were 90% sensitive and 100% specific for identifying childhood-onset SLE patients with biopsy-proven nephritis [15].
  • Examining the transcriptional profile of human breast cancer cell lines, MCF7 and T47D, treated with 4-HPR, we identified the lipocalin member LCN2 (NGAL or 24p3) as a gene, markedly induced by the retinoid [16].

Biological context of LCN2

  • We found that lipocalin 2 could also convert 4T1-Ras-transformed mesenchymal tumor cells to an epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and tumor growth and lung metastases in vivo [2].
  • EXPERIMENTAL DESIGN: Clones of MCF-7 human breast cancer cells differentially expressing NGAL were generated by stable transfection with human NGAL expression constructs [3].
  • Here, we characterize the putative human homolog of NRL, neutrophil gelatinase-associated lipocalin (NGAL). ngal gene expression was found at moderate levels in only 2 of 17 human tissues examined, breast and lung [12].
  • To characterize the regulation of NGAL further, we have cloned and sequenced a 5869-bp region of the NGAL gene including 1695 bp of the 5' nontranscribed region and a 3696-bp coding region encompassing seven exons and six introns [17].
  • To gain insight into its potential role in other epithelia we have investigated the expression of NGAL in human skin embryonic development, in normal adult skin, and in skin associated with inflammation and neoplastic transformation [18].

Anatomical context of LCN2

  • Here, both gelatinase B and NGAL were purified from human peripheral blood neutrophils, and the entire contents of the released N- and O-glycan pools were analyzed simultaneously using recently developed high-performance liquid chromatography-based technology [19].
  • Lipocalin 2, an iron-siderophore-binding protein, converts embryonic kidney mesenchyme to epithelia [2].
  • Immuno-histochemical analysis confirmed the presence of NGAL within breast carcinoma cells but detected only low levels of this protein in normal ductal epithelium [12].
  • Also, NGAL may be important in delivering iron to cells during formation of the tubular epithelial cells of the primordial kidney [20].
  • Furthermore, a rat yolk sac cell line known to express high levels of megalin, endocytosed NGAL by a mechanism completely blocked by an antibody against megalin [20].

Associations of LCN2 with chemical compounds

  • Although both proteins were isolated from neutrophils and contained O-linked glycans mainly with type 2 cores, the glycans attached to individual serine/threonine residue(s) in NGAL were significantly smaller than those on gelatinase B [19].
  • More than 95% of the N-linked glycans attached to both gelatinase B and NGAL were partially sialylated, core-fucosylated biantennary structures with and without outer arm fucose [19].
  • Following intravenous injection of 125-iodine labelled NGAL there was a more rapid initial clearance of the monomeric than of the dimeric form; t1/2 10 min vs. 20 min [21].
  • All-trans retinoic acid also induced LCN2 protein, particularly in T47D cells [16].
  • Analysis of the crystal structure of NGAL expressed in E.coli showed that NGAL has the ability to bind catecholate type siderophores and in this way prevent bacteria from acquisition of siderophore-bound iron [22].

Physical interactions of LCN2

  • In addition, MMP-9/NGAL complex was detected in 86.36% of the urine samples from breast cancer patients but not in those from healthy age and sex-matched controls [3].

Co-localisations of LCN2


Regulatory relationships of LCN2


Other interactions of LCN2


Analytical, diagnostic and therapeutic context of LCN2


  1. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. Mori, K., Lee, H.T., Rapoport, D., Drexler, I.R., Foster, K., Yang, J., Schmidt-Ott, K.M., Chen, X., Li, J.Y., Weiss, S., Mishra, J., Cheema, F.H., Markowitz, G., Suganami, T., Sawai, K., Mukoyama, M., Kunis, C., D'Agati, V., Devarajan, P., Barasch, J. J. Clin. Invest. (2005) [Pubmed]
  2. Lipocalin 2 diminishes invasiveness and metastasis of Ras-transformed cells. Hanai, J., Mammoto, T., Seth, P., Mori, K., Karumanchi, S.A., Barasch, J., Sukhatme, V.P. J. Biol. Chem. (2005) [Pubmed]
  3. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Fernández, C.A., Yan, L., Louis, G., Yang, J., Kutok, J.L., Moses, M.A. Clin. Cancer Res. (2005) [Pubmed]
  4. Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. Bartsch, S., Tschesche, H. FEBS Lett. (1995) [Pubmed]
  5. Microarray and protein analysis of human pterygium. John-Aryankalayil, M., Dushku, N., Jaworski, C.J., Cox, C.A., Schultz, G., Smith, J.A., Ramsey, K.E., Stephan, D.A., Freedman, K.A., Reid, T.W., Carper, D.A. Mol. Vis. (2006) [Pubmed]
  6. Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Pitashny, M., Schwartz, N., Qing, X., Hojaili, B., Aranow, C., Mackay, M., Putterman, C. Arthritis Rheum. (2007) [Pubmed]
  7. Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Hinze, C.H., Suzuki, M., Klein-Gitelman, M., Passo, M.H., Olson, J., Singer, N.G., Haines, K.A., Onel, K., O'Neil, K., Silverman, E.D., Tucker, L., Ying, J., Devarajan, P., Brunner, H.I. Arthritis Rheum. (2009) [Pubmed]
  8. Lymphadenopathy associated virus infection of a blood donor--recipient pair with acquired immunodeficiency syndrome. Feorino, P.M., Kalyanaraman, V.S., Haverkos, H.W., Cabradilla, C.D., Warfield, D.T., Jaffe, H.W., Harrison, A.K., Gottlieb, M.S., Goldfinger, D., Chermann, J.C. Science (1984) [Pubmed]
  9. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Barré-Sinoussi, F., Chermann, J.C., Rey, F., Nugeyre, M.T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vézinet-Brun, F., Rouzioux, C., Rozenbaum, W., Montagnier, L. Science (1983) [Pubmed]
  10. Identification of the C-signal, a contact-dependent morphogen coordinating multiple developmental responses in Myxococcus xanthus. Lobedanz, S., Søgaard-Andersen, L. Genes Dev. (2003) [Pubmed]
  11. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Goetz, D.H., Holmes, M.A., Borregaard, N., Bluhm, M.E., Raymond, K.N., Strong, R.K. Mol. Cell (2002) [Pubmed]
  12. Heterogeneous expression of the lipocalin NGAL in primary breast cancers. Stoesz, S.P., Friedl, A., Haag, J.D., Lindstrom, M.J., Clark, G.M., Gould, M.N. Int. J. Cancer (1998) [Pubmed]
  13. Antibodies to the core protein of lymphadenopathy-associated virus (LAV) in patients with AIDS. Kalyanaraman, V.S., Cabradilla, C.D., Getchell, J.P., Narayanan, R., Braff, E.H., Chermann, J.C., Barré-Sinoussi, F., Montagnier, L., Spira, T.J., Kaplan, J. Science (1984) [Pubmed]
  14. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Fischbach, M.A., Lin, H., Zhou, L., Yu, Y., Abergel, R.J., Liu, D.R., Raymond, K.N., Wanner, B.L., Strong, R.K., Walsh, C.T., Aderem, A., Smith, K.D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  15. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Brunner, H.I., Mueller, M., Rutherford, C., Passo, M.H., Witte, D., Grom, A., Mishra, J., Devarajan, P. Arthritis Rheum. (2006) [Pubmed]
  16. Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Caramuta, S., De Cecco, L., Reid, J.F., Zannini, L., Gariboldi, M., Kjeldsen, L., Pierotti, M.A., Delia, D. Int. J. Cancer (2006) [Pubmed]
  17. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Cowland, J.B., Borregaard, N. Genomics (1997) [Pubmed]
  18. Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin. Mallbris, L., O'Brien, K.P., Hulthén, A., Sandstedt, B., Cowland, J.B., Borregaard, N., Ståhle-Bäckdahl, M. Exp. Dermatol. (2002) [Pubmed]
  19. Glycosylation of natural human neutrophil gelatinase B and neutrophil gelatinase B-associated lipocalin. Rudd, P.M., Mattu, T.S., Masure, S., Bratt, T., Van den Steen, P.E., Wormald, M.R., Küster, B., Harvey, D.J., Borregaard, N., Van Damme, J., Dwek, R.A., Opdenakker, G. Biochemistry (1999) [Pubmed]
  20. The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. Hvidberg, V., Jacobsen, C., Strong, R.K., Cowland, J.B., Moestrup, S.K., Borregaard, N. FEBS Lett. (2005) [Pubmed]
  21. Studies of the release and turnover of a human neutrophil lipocalin. Axelsson, L., Bergenfeldt, M., Ohlsson, K. Scand. J. Clin. Lab. Invest. (1995) [Pubmed]
  22. Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Borregaard, N., Cowland, J.B. Biometals (2006) [Pubmed]
  23. Sorting of the specific granule protein, NGAL, during granulocytic maturation of HL-60 cells. Le Cabec, V., Calafat, J., Borregaard, N. Blood (1997) [Pubmed]
  24. Lipocalin 2 antagonizes the proangiogenic action of ras in transformed cells. Venkatesha, S., Hanai, J., Seth, P., Karumanchi, S.A., Sukhatme, V.P. Mol. Cancer Res. (2006) [Pubmed]
  25. Human neutrophil lipocalin (HNL) and myeloperoxidase (MPO). Studies of lung lavage fluid and lung tissue. Schmekel, B., Seveus, L., Xu, S.Y., Venge, P. Respiratory medicine. (2000) [Pubmed]
  26. Neutrophil gelatinase-associated lipocalin as a survival factor. Tong, Z., Wu, X., Ovcharenko, D., Zhu, J., Chen, C.S., Kehrer, J.P. Biochem. J. (2005) [Pubmed]
  27. Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24p3, and progestagen-associated endometrial protein map to HSA9 and MMU2. Chan, P., Simon-Chazottes, D., Mattei, M.G., Guenet, J.L., Salier, J.P. Genomics (1994) [Pubmed]
  28. The development of an assay for human neutrophil lipocalin (HNL)--to be used as a specific marker of neutrophil activity in vivo and vitro. Xu, S.Y., Petersson, C.G., Carlson, M., Venge, P. J. Immunol. Methods (1994) [Pubmed]
  29. Molecular cloning and expression of a cDNA encoding NGAL: a lipocalin expressed in human neutrophils. Bundgaard, J.R., Sengeløv, H., Borregaard, N., Kjeldsen, L. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
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