Disease relevance of Lcn2

• However, we found that Lcn2-/- mice exhibited an increased susceptibility to bacterial infections, in keeping with the proposed function of lipocalin 2 in iron sequestration [1].
• We analyzed Lcn2-/- mice using a mouse model for severe renal failure and could not detect any significant differences compared with their WT littermates [1].
• Furthermore, we show that mice rapidly succumb to infection by an iroA-harboring strain of E. coli but not its wild-type counterpart, and that this increased virulence depends on evasion of host Lcn2 [2].
• Here, we show that the iroA gene cluster, found in many pathogenic strains of Gram-negative enteric bacteria, including E. coli, Salmonella spp., and Klebsiella pneumoniae, allows bacteria to evade sequestration of Ent by Lcn2 [2].
• Lcn2 is a member of the acute phase response family of proteins and its mRNA levels in the brain increase in response to inflammation [3].

High impact information on Lcn2

• A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake [4].
• 24p3 also induced apoptosis in a wide variety of leukocytes but not other cell types [5].
• Neutrophils isolated from Lcn2-/- mice showed significantly less bacteriostatic activity compared with WT controls [1].
• Analysis of Lcn2-/- mice showed normal cell death upon IL-3 withdrawal and normal kidney development [1].
• We demonstrate that C-glucosylated derivatives of Ent produced by iroA-encoded enzymes do not bind purified Lcn2, and an iroA-harboring strain of E. coli is insensitive to the growth inhibitory effects of Lcn2 in vitro [2].

Chemical compound and disease context of Lcn2

• In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements [6].
• We recently demonstrated that enterochelin, a bacterial catecholate siderophore, binds to the host protein lipocalin 2 (ref. 5). Here, we show that this event is pivotal in the innate immune response to bacterial infection [7].

Biological context of Lcn2

• The lipocalin 24p3 was reported to be secreted by mouse hematopoietic cells deprived of IL-3, resulting in apoptosis induction in a variety of hematopoietic cells including bone marrow cells [8].
• These findings indicate that suppression of normal hematopoiesis in BCR-ABL-induced leukemia is an active process involving secretion of the cell death-inducing factor 24p3 by mouse leukemia cells, raising the possibility that similar factors are involved in BCR-ABL+ CML [8].
• In this study, we assign the Lcn2 gene to rat chromosome band 3q12 by genetic linkage analysis [9].
• In vitro studies have suggested that lipocalin 2 is important for cellular apoptosis induced by IL-3 withdrawal, and for the induction of kidney differentiation during embryogenesis [1].
• These experiments demonstrate that the local expression of Ngal can play a regulatory role in epithelial morphogenesis by promoting the organization of cells into tubular structures while simultaneously negatively modulating the branching effects of HGF [10].

Anatomical context of Lcn2

• In contrast, prostaglandin-D-synthase (Ptgds) and lipocalin 2 (Lcn2) mRNA increase in basal forebrain of both strains after influenza infection [11].
• Results of Northern-blot analysis for various tissues of adult mice revealed that the 24p3 gene was expressed in lung, spleen, uterus, vagina and epididymis [12].
• 24p3 in differentiation of myeloid cells [13].
• Both these growth factors, which cause myeloid cells to differentiate into granulocytes, induced a marked increase in the expression of both 24p3 protein and mRNA [13].
• 24p3 is a secreted lipocalin that has been variously related to apoptosis, proliferation, and the neutrophil lineage of blood cells [13].

Associations of Lcn2 with chemical compounds

• The expression of the Bcr-Abl oncoprotein and its tyrosine kinase were required for induction of 24p3 expression [8].
• Automated Edman degradation was unable to determine the N-terminal residue of the glycoprotein and the partial sequences determined from its trypsin digests were found to be identical with the protein sequence deduced from 24p3 cDNA [12].
• Based on this observation, we examined the effect of a glucocorticoid (dexamethasone, Dex) on 24p3 expression [14].
• We report here that spermatozoa, from the caudal epididymis, demonstrate the ability to bind with 24p3 protein and further internalize it and deliver the ferric ion to the spermatozoa via protein internalization [15].
• Using a fluorometric method, the binding affinities of ferrous ion and ferric ion to 24p3 protein were shown to be (1.5+/-0.2)x10(6) and (3.0+/-0.4)x10(7)M(-1), respectively [15].

Regulatory relationships of Lcn2

• Both of the phosphorylated and dephosphorylated form of 24p3 protein can enhance the cAMP-dependent protein kinase activity in vitro [16].

Other interactions of Lcn2

• We isolated 20 known genes and 4 novel genes, including 2 genes encoding lipocalin family members (prostaglandin D synthetase and 24p3) and 2 tumor suppressors (protein tyrosine phosphatase TD14 and Sui1) [17].
• Moreover, many lipocalins have been implicated in the regulation of cell homeostasis: apolipoprotein D, quiescience specific protein, purpurin, alpha-1-microglobulin, and NGAL [18].
• The expression of rat 24p3, encoded by the Lcn2 gene, has been associated with rat mammary carcinomas initiated by the neu oncogene (Stoesz and Gould, 1995) [9].
• Demonstration of a glycoprotein derived from the 24p3 gene in mouse uterine luminal fluid [12].
• Neither casein kinase II nor cAMP-dependent protein kinase reacted to the 24p3 protein; however, protein kinase C demonstrated phosphorylation to this protein [16].
• The GRE proximal to the Lcn2 promoter apparently functions to regulate both the Lcn2 gene and the distal Ciz1 gene [19].

Analytical, diagnostic and therapeutic context of Lcn2

• By differential screening of the library we have isolated and then sequenced cDNA recombinant 24p3; determined by Northern blotting, 24p3 mRNA steady state levels increased in parallel with polyoma and SV40 T-antigen synthesis [20].
• Siderocalin (Scn, or lipocalin 2 or neutrophil gelatinase-associated lipocalin) expression was increased up to 65-fold during colonization by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) [21].
• NGAL (or 24p3 as the highly homologous murine orthologue is named) knock out mice have a profound defect in defense against E.coli after intraperitoneal injection [22].
• Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography [23].
• Using DNA microarrays to analyze interleukin-3 (IL-3)-dependent murine FL5.12 pro-B cells, we found that the gene undergoing maximal transcriptional induction after cytokine withdrawal is 24p3, which encodes a secreted lipocalin [5].

References