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Gene Review

Scgb1a1  -  secretoglobin, family 1A, member 1...

Mus musculus

Synonyms: Blastokinin, CC10, CC16, CCPBP, CCSP, ...
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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


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


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


  1. Multiple mechanisms for oxygen-induced regulation of the Clara cell secretory protein gene. Ramsay, P.L., Luo, Z., Major, A., Park, M.S., Finegold, M., Welty, S.E., Kwak, I., Darlington, G., Demayo, F.J. FASEB J. (2003) [Pubmed]
  2. Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Zheng, F., Kundu, G.C., Zhang, Z., Ward, J., DeMayo, F., Mukherjee, A.B. Nat. Med. (1999) [Pubmed]
  3. Uteroglobin: a novel cytokine? Mukherjee, A.B., Kundu, G.C., Mantile-Selvaggi, G., Yuan, C.J., Mandal, A.K., Chattopadhyay, S., Zheng, F., Pattabiraman, N., Zhang, Z. Cell. Mol. Life Sci. (1999) [Pubmed]
  4. Interleukin-4 alters epithelial cell differentiation and surfactant homeostasis in the postnatal mouse lung. Jain-Vora, S., Wert, S.E., Temann, U.A., Rankin, J.A., Whitsett, J.A. Am. J. Respir. Cell Mol. Biol. (1997) [Pubmed]
  5. Uteroglobin promoter-targeted c-MYC expression in transgenic mice cause hyperplasia of Clara cells and malignant transformation of T-lymphoblasts and tubular epithelial cells. Geick, A., Redecker, P., Ehrhardt, A., Klocke, R., Paul, D., Halter, R. Transgenic Res. (2001) [Pubmed]
  6. Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Zhang, Z., Kundu, G.C., Yuan, C.J., Ward, J.M., Lee, E.J., DeMayo, F., Westphal, H., Mukherjee, A.B. Science (1997) [Pubmed]
  7. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. Mandal, A.K., Zhang, Z., Ray, R., Choi, M.S., Chowdhury, B., Pattabiraman, N., Mukherjee, A.B. J. Exp. Med. (2004) [Pubmed]
  8. The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo. Lim, L., Zhou, H., Costa, R.H. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  9. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Hong, K.U., Reynolds, S.D., Giangreco, A., Hurley, C.M., Stripp, B.R. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  10. Normal function and lack of fibronectin accumulation in kidneys of Clara cell secretory protein/uteroglobin deficient mice. Reynolds, S.D., Mango, G.W., Gelein, R., Bøe, I.M., Lund, J., Stripp, B.R. Am. J. Kidney Dis. (1999) [Pubmed]
  11. Bleomycin induces strain-dependent alterations in the pattern of epithelial cell-specific marker expression in mouse lung. Daly, H.E., Baecher-Allan, C.M., Barth, R.K., D'Angio, C.T., Finkelstein, J.N. Toxicol. Appl. Pharmacol. (1997) [Pubmed]
  12. Clara cell secretory protein-deficient mice differ from wild-type mice in inflammatory chemokine expression to oxygen and ozone, but not to endotoxin. Johnston, C.J., Finkelstein, J.N., Oberdörster, G., Reynolds, S.D., Stripp, B.R. Exp. Lung Res. (1999) [Pubmed]
  13. Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Reynolds, S.D., Hong, K.U., Giangreco, A., Mango, G.W., Guron, C., Morimoto, Y., Stripp, B.R. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) [Pubmed]
  14. Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding protein alpha and the homeodomain factor Nkx2.1/thyroid transcription factor-1. Cassel, T.N., Berg, T., Suske, G., Nord, M. J. Biol. Chem. (2002) [Pubmed]
  15. Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice. Yoshikawa, S., Miyahara, T., Reynolds, S.D., Stripp, B.R., Anghelescu, M., Eyal, F.G., Parker, J.C. J. Appl. Physiol. (2005) [Pubmed]
  16. Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Bellusci, S., Furuta, Y., Rush, M.G., Henderson, R., Winnier, G., Hogan, B.L. Development (1997) [Pubmed]
  17. Attenuation of pulmonary neuroendocrine differentiation in mice lacking Clara cell secretory protein. Castro, C.M., Yang, Y., Zhang, Z., Linnoila, R.I. Lab. Invest. (2000) [Pubmed]
  18. Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. Wuenschell, C.W., Sunday, M.E., Singh, G., Minoo, P., Slavkin, H.C., Warburton, D. J. Histochem. Cytochem. (1996) [Pubmed]
  19. Uteroglobin: physiological role in normal glomerular function uncovered by targeted disruption of the uteroglobin gene in mice. Mukherjee, A.B., Kundu, G.C., Mandal, A.K., Pattabiraman, N., Yuan, C.J., Zhang, Z. Am. J. Kidney Dis. (1998) [Pubmed]
  20. Uteroglobin suppresses SCCA gene expression associated with allergic asthma. Ray, R., Choi, M., Zhang, Z., Silverman, G.A., Askew, D., Mukherjee, A.B. J. Biol. Chem. (2005) [Pubmed]
  21. Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke. Yang, Y., Zhang, Z., Mukherjee, A.B., Linnoila, R.I. J. Biol. Chem. (2004) [Pubmed]
  22. Monkey Clara cell 10 kDa protein (CC10): a characterization of the amino acid sequence with an evolutional comparison with humans, rabbits, rats, and mice. Hashimoto, S., Nakagawa, K., Sueishi, K. Am. J. Respir. Cell Mol. Biol. (1996) [Pubmed]
  23. In human IgA nephropathy uteroglobin does not play the role inferred from transgenic mice. Coppo, R., Chiesa, M., Cirina, P., Peruzzi, L., Amore, A. Am. J. Kidney Dis. (2002) [Pubmed]
  24. FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo. Clark, J.C., Tichelaar, J.W., Wert, S.E., Itoh, N., Perl, A.K., Stahlman, M.T., Whitsett, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2001) [Pubmed]
  25. Interferon-gamma regulation of Clara cell gene expression: in vivo and in vitro. Magdaleno, S.M., Wang, G., Jackson, K.J., Ray, M.K., Welty, S., Costa, R.H., DeMayo, F.J. Am. J. Physiol. (1997) [Pubmed]
  26. Clara cell secretory protein deficiency increases oxidant stress response in conducting airways. Mango, G.W., Johnston, C.J., Reynolds, S.D., Finkelstein, J.N., Plopper, C.G., Stripp, B.R. Am. J. Physiol. (1998) [Pubmed]
  27. Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways. Reynolds, S.D., Reynolds, P.R., Pryhuber, G.S., Finder, J.D., Stripp, B.R. Am. J. Respir. Crit. Care Med. (2002) [Pubmed]
  28. Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Bellusci, S., Henderson, R., Winnier, G., Oikawa, T., Hogan, B.L. Development (1996) [Pubmed]
  29. Interleukin-4 enhances pulmonary clearance of Pseudomonas aeruginosa. Jain-Vora, S., LeVine, A.M., Chroneos, Z., Ross, G.F., Hull, W.M., Whitsett, J.A. Infect. Immun. (1998) [Pubmed]
  30. The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung. Lu, M.M., Yang, H., Zhang, L., Shu, W., Blair, D.G., Morrisey, E.E. Dev. Dyn. (2001) [Pubmed]
  31. Cutting edge: altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein. Chen, L.C., Zhang, Z., Myers, A.C., Huang, S.K. J. Immunol. (2001) [Pubmed]
  32. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. Hung, C.H., Chen, L.C., Zhang, Z., Chowdhury, B., Lee, W.L., Plunkett, B., Chen, C.H., Myers, A.C., Huang, S.K. J. Allergy Clin. Immunol. (2004) [Pubmed]
  33. Altered lung gene expression in CCSP-null mice suggests immunoregulatory roles for Clara cells. Watson, T.M., Reynolds, S.D., Mango, G.W., Boe, I.M., Lund, J., Stripp, B.R. Am. J. Physiol. Lung Cell Mol. Physiol. (2001) [Pubmed]
  34. Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Yang, S.C., Batra, R.K., Hillinger, S., Reckamp, K.L., Strieter, R.M., Dubinett, S.M., Sharma, S. Cancer Res. (2006) [Pubmed]
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