Disease relevance of Scgb1a1

• However, exposure to supplemental oxygen, a common therapeutic modality for lung disease, represses the expression of CCSP in the adult mouse lung [1].
• These results define an essential role for UG in preventing mouse IgA nephropathy and warrant further studies to determine if a similar mechanism(s) underlies the human disease [2].
• The generation of UG knockout mice revealed that disruption of this gene causes: (i) severe renal disease due to an abnormal deposition of fibronectin and collagen in the glomeruli; (ii) predisposition to a high incidence of malignancies; and (iii) a lack of polychlorinated biphenyl binding and increased oxygen toxicity in the lungs [3].
• Epithelial cell hypertrophy and mucus cell metaplasia were observed in the lungs of CCSP-IL-4 mice at all ages [4].
• Surprisingly, transgenics most frequently developed T-lymphoblastic lymphomas, a polycystic kidney phenotype and renal cell carcinoma derived from tubular epithelial cells, which are both tissues that had so far not been known to express UG [5].

High impact information on Scgb1a1

• Thus, UG is essential for maintaining normal renal function in mice, which raises the possibility that an analogous pathogenic mechanism may underlie genetic Fn-deposit human glomerular disease [6].
• Despite myriads of biological activities ascribed to uteroglobin (UG), a steroid-inducible secreted protein, its physiological functions are unknown [6].
• We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses [7].
• Furthermore, we identified putative HFH-4 target genes in the bronchiolar epithelium including the clara cell secretory protein gene and the HNF-3alpha gene, a winged helix family member involved in the transcriptional regulation of genes in the bronchiolar epithelium [8].
• In support of these binding studies, cotransfection assays show that HFH-4 potentiates expression of the HNF-3alpha and clara cell secretory protein promoter regions [8].

Chemical compound and disease context of Scgb1a1

• To investigate contributions made by CE and CGRP-expressing cells to epithelial renewal, CE cells were ablated through acute administration of ganciclovir to transgenic mice expressing herpes simplex virus thymidine kinase under the regulatory control of the mouse CCSP promoter [9].
• Strain 129 CCSP-/- mice have normal kidney function, as assessed by urinary glucose, lactate dehydrogenase, and glomerular filtration rate; they show no kidney fibrosis or abnormalities in fibronectin accumulation and no histological abnormalities in proximal convoluted tubules or glomeruli at either light or electron microscopic levels [10].
• The strain-dependent changes in CC10 and SPC gene expression after bleomycin treatment are suggestive of a role for the epithelium in pulmonary fibrosis versus repair [11].
• Our earlier studies have demonstrated that CCSP-deficient mice are more sensitive to either hyperoxia or ozone toxicity and show altered oxidant-induced pulmonary proinflammatory responses [12].
• We have previously used a Clara cell-specific toxicant, naphthalene, to induce airway injury in mice and have demonstrated that naphthalene-resistant Clara cells, characterized by their expression of Clara cell secretory protein (CCSP), and PNE cells contribute to airway repair and associated hyperplasia of NEBs [13].

Biological context of Scgb1a1

• In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene [14].
• Inhibition of cPLA2 in wild-type and CCSP-/- mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype [15].
• 1. Cotransfection of LIP or c-Jun expression plasmids decreased the transcriptional activity of the proximal -166-bp CCSP promoter [1].
• The human UG gene is mapped to chromosome 11q12.2 13.1, a region that is frequently rearranged or deleted in many cancers [3].
• Molecular characterization of the UG receptor and signal transduction via this receptor pathway may show that this protein belongs to a novel cytokine/chemokine family [3].

Anatomical context of Scgb1a1

• However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells [16].
• Lung-specific increase in T-cell proliferative responses to mitogenic stimulation and antibody secretion were detected in CCSP-IL-4 mice [4].
• During development and injury, pulmonary neuroendocrine (NE) cells may transiently express Clara cell 10 kD protein (CC10), a major product of the nonciliated progenitor cells for normal and neoplastic airway epithelia suggesting a close relationship between the cells [17].
• We conclude that CGRP, CC10, and SP-A are co-expressed in most or all cells of the distal lung epithelium at E13-E15 and later become restricted to different cell lineages [18].
• These mice expressed the c-MYC transgene in Clara cells and other UG expressing tissues like uterus and prostate [5].

Associations of Scgb1a1 with chemical compounds

• These observations suggest that hyperoxia-induced repression of the CCSP gene is mediated, at least in part, at the level of transcription and that multiple mechanisms mediate this repression [1].
• In addition, by inhibiting secretory phospholipase A2 (sPLA2) activity and decreasing the level of lysophosphatidic acid (LPA), UG may indirectly prevent the activation of integrins (eg, alpha5beta1) that enhance abnormal tissue deposition of Fn [19].
• We previously reported that the lungs of UG-knock-out (UG-KO) mice express elevated levels of Th2 cytokines (e.g. interleukin (IL)-4 and IL-13), which are augmented by allergen sensitization and challenge leading to exaggerated airway inflammation [20].
• We previously reported that the expression of CC10 is markedly reduced in animals exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK, a potent carcinogen in tobacco smoke [21].
• When monkey CC10 was compared with rabbit uteroglobin (progesterone binding protein), two polar residues of Tyr-21 and Thr-60, important for progesterone binding specificity, were substituted for Phe-21 and Met-60, and thus monkey CC10 may not have a binding capacity with progesterone [22].

Physical interactions of Scgb1a1

• RESULTS: Levels of UG binding to Fn were similar in patients with IgA nephropathy and healthy controls [23].

Regulatory relationships of Scgb1a1

• We propose that mechanical activation of the cPLA2 pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction of proinflammatory products produced by this pathway [15].
• Transgenic mice in which fibroblast growth factor (FGF)-10 was expressed in the lungs of fetal and postnatal mice were generated with a doxycycline-inducible system controlled by surfactant protein (SP) C or Clara cell secretory protein (CCSP) promoter elements [24].
• This report demonstrates that Clara cell 10-kDa protein (CC10) mRNA levels are regulated by interferon-gamma (IFN-gamma) [25].
• Despite being qualitatively similar, increases in IL-6 and MT mRNA expression were enhanced in CCSP -/- mice with respect to coexposed 129 strain wild-type mice [26].
• Clara cell secretory protein (CCSP) is expressed abundantly within the conducting airway epithelium and is thought to have immunoregulatory functions [27].

Other interactions of Scgb1a1

• In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs [28].
• Survival of CCSP-IL-4 mice following bacterial administration was markedly improved compared with that of control mice [29].
• Expanded expression of the proximal epithelial cell markers CC10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lungs [30].
• Clara cell secretory protein (CC10) is a steroid-inducible protein, and its in vivo function is currently unclear [31].
• All injury variables except myeloperoxidase were significantly greater in the CCSP-/- mice relative to wild-type mice [15].

Analytical, diagnostic and therapeutic context of Scgb1a1

• To assess the role of CC10 during NE differentiation, we studied CC10-deficient mouse lungs by immunohistochemistry and digital imaging [17].
• Nevertheless, the UG gene-knockout mice provide a valuable animal model for investigation of human glomerulopathies in general and familial Fn-deposit glomerulopathy in particular [19].
• CC10 expression in vivo was determined by immunocytochemistry and Western blotting [32].
• To determine whether CCSP deficiency results in altered lung gene expression, high-density cDNA microarrays were used to profile gene expression in the total lung RNA of wild-type and CCSP(-/-) mice [33].
• The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden [34].

References