Uteroglobin/Clara Cell 10‐kDa Family of Proteins: Nomenclature Committee Report

Klug, Jörg; Beier, H. M.; Bernard, Alfred; Chilton, Beverly S.; Fleming, T. Corwin; Lehrer, RI; Miele, Lucio; Pattabiraman, Nagarajan; Singh, Gurmukh

doi:10.1111/j.1749-6632.2000.tb05549.x

Cited by 133 publications

(89 citation statements)

References 40 publications

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“…We also compared the in vivo ability of L19-UG-IL2 and L19-IL2 to inhibit the growth of F9 teratocarcinoma in syngeneic mice. When the tumors reached a volume of nearly 0.3 cm 3 , groups of animals were treated for 6 days with daily intravenous injections of 250,000 units of IL2 as L19-IL2, L19-UG-IL2, or saline alone. The results depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here we describe a novel approach based on the use of uteroglobin (UG) 3 as a skeleton for the generation of polyvalent/polyspecific recombinant proteins. Human UG is a small (15.8 kDa) globular, nonglycosylated, and homodimeric secreted protein that was discovered independently by two groups in the 1960s in rabbit uterus (1,2), and it is the first member of a new superfamily of proteins, the so-called Secretoglobins (Scgb) (3). UG is present in the blood at a concentration of about 15 g/ml and is found in urine and in other body fluids.…”

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confidence: 99%

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Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins

Ventura

Sassi

Fossati

et al. 2009

Journal of Biological Chemistry

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We report a novel strategy to engineer and express stable and soluble human recombinant polyvalent/polyspecific fusion proteins. The procedure is based on the use of a central skeleton of uteroglobin, a small and very soluble covalently linked homodimeric protein that is very resistant to proteolytic enzymes and to pH variations. Using a human recombinant antibody (scFv) specific for the angiogenesis marker domain B of fibronectin, interleukin 2, and an scFv able to neutralize tumor necrosis factor-␣, we expressed various biologically active uteroglobin fusion proteins. The results demonstrate the possibility to generate monospecific divalent and tetravalent antibodies, immunocytokines, and dual specificity tetravalent antibodies. Furthermore, compared with similar fusion proteins in which uteroglobin was not used, the use of uteroglobin improved properties of solubility and stability. Indeed, in the reported cases it was possible to vacuum dry and reconstitute the proteins without any aggregation or loss in protein and biological activity.The generation of recombinant polyvalent and/or polyspecific fusion proteins for use as components of novel drugs is still hindered by factors that limit their production, storage, and use, chief of which are issues related to instability and/or inadequate solubility. Here we describe a novel approach based on the use of uteroglobin (UG) 3 as a skeleton for the generation of polyvalent/polyspecific recombinant proteins. Human UG is a small (15.8 kDa) globular, nonglycosylated, and homodimeric secreted protein that was discovered independently by two groups in the 1960s in rabbit uterus (1, 2), and it is the first member of a new superfamily of proteins, the so-called Secretoglobins (Scgb) (3). UG is present in the blood at a concentration of about 15 g/ml and is found in urine and in other body fluids. The UG monomer is composed of about 70 amino acids, depending on the species, and is organized in a four ␣-helix secondary structure; the two subunits are joined in an antiparallel fashion by disulfide bridges established between two highly conserved cysteine residues in amino-and carboxyl-terminal positions (4) (see Fig. 1). The exact functions of UG are not yet clear, but the protein has been reported to have antiinflammatory properties due to its ability to inhibit the soluble phospholipase A 2 . Moreover, UG contains a central hydrophobic cavity able to accommodate hydrophobic molecules such as progesterone, retinol, and prostaglandin D 2 . Theoretically, this cavity could be loaded with different types of therapeutic hydrophobic substances and delivered to targets (for exhaustive reviews on UG, see Refs. 5, 6and references therein).The high solubility and stability of UG to pH and temperature variations, its resistance to proteases, and its homodimeric structure prompted us to consider the protein as a candidate linker for the generation of polyvalent and polyspecific recombinant proteins. We demonstrate here that the use of UG as a linker could provide a general method for...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins

Ventura

Sassi

Fossati

et al. 2009

Journal of Biological Chemistry

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“…Human mammaglobin (MGB) belongs to the uteroglobin/ Clara cell protein family of small epithelial secretory proteins [126,127] and was discovered by Watson and Fleming [128] in their isolation of sequence fragments that were abundantly expressed in breast tumors relative to normal breast tissue. The MGB1 promoter contains a polyoma enhancer-related motif which is associated with over-expression of HER-2 in breast cancer [129].…”

Section: Human Mammaglobinmentioning

confidence: 99%

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

Friel

Corcoran

Crown

et al. 2010

Breast Cancer Res Treat

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Early detection of cancer is vital to improved overall survival rates. At present, evidence is accumulating for the clinical value of detecting occult tumor cells in peripheral blood, plasma, and serum specimens from cancer patients. Both molecular and cellular approaches, which differ in sensitivity and specificity, have been used for such means. Circulating tumor cells and extracellular nucleic acids have been detected within blood, plasma, and sera of cancer patients. As the presence of malignant tumors are clinically determined and/or confirmed upon biopsy procurement-which in itself may have detrimental effects in terms of stimulating cancer progression/metastases-minimally invasive methods would be highly advantageous to the diagnosis and prognosis of breast cancer and the subsequent tailoring of targeted treatments for individuals, if reliable panels of biomarkers suitable for such an approach exist. Herein, we review the current advances made in the detection of such circulating tumor cells and nucleic acids, with particular emphasis on extracellular nucleic acids, specifically extracellular mRNAs and discuss their clinical relevance.

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“…1). The founding member of the secretoglobin superfamily of proteins (2), UG, is constitutively expressed at a high level in the pulmonary mucosal epithelial cells of virtually all mammals including mice. We previously reported that compared with wild type (WT) littermates, the lungs of the UG-knock-out (UG-KO) mice express markedly higher levels of Th2 cytokines and manifest exaggerated airway inflammatory response to allergens marked by elevated levels of eosinophil infiltration (3,4).…”

Section: Uteroglobin (Ug)mentioning

confidence: 99%

Uteroglobin Suppresses SCCA Gene Expression Associated with Allergic Asthma

Ray

Choi

Zhang

et al. 2005

Journal of Biological Chemistry

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Uteroglobin (UG), the founding member of the Secretoglobin superfamily, is a potent anti-inflammatory protein constitutively expressed at a high level in the airway epithelia of all mammals. 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. Notably, these responses are suppressed by recombinant UG treatment (Mandal, A. K., Zhang, Z., Ray, R., Choi, M. S., Chowdhury, B., Pattabiraman, N., and Mukherjee, A. B. (2004) J. Exp. Med. 199, 1317-1330). Recent reports indicate that human orthologs of murine squamous cell carcinoma antigen-2 (SCCA-2/serpinb3a), a serine proteaseinhibitor, are overexpressed in the airways of asthmatic patients. We report here that compared with wild type littermates, UG-KO mouse lungs express markedly elevated levels of SCCA-2 mRNA and protein, which are augmented by allergen-challenge. Most importantly, these effects are abrogated by recombinant UG treatment. We further demonstrate that treatment of cultured human bronchial epithelial cells with IL-4 or IL-13 stimulates phosphorylation of STAT-1 and STAT-6 leading to SCCA-1 (SERPINB3) and SCCA-2 (SERPINB4) gene expression. We propose that: (i) IL-4-and IL-13-stimulated SCCA gene expression is mediated via STAT-1 and STAT-6 activation, and (ii) by suppressing the production, and most likely by interfering with the signaling of these cytokines, UG inhibits SCCA gene expression associated with airway inflammation in asthma. Uteroglobin (UG)1 is a steroid-inducible, homodimeric, multifunctional secreted protein with potent anti-inflammatory and immunomodulatory properties (reviewed in Ref. 1). The founding member of the secretoglobin superfamily of proteins (2), UG, is constitutively expressed at a high level in the pulmonary mucosal epithelial cells of virtually all mammals including mice. We previously reported that compared with wild type (WT) littermates, the lungs of the UG-knock-out (UG-KO) mice express markedly higher levels of Th2 cytokines and manifest exaggerated airway inflammatory response to allergens marked by elevated levels of eosinophil infiltration (3, 4). All of these are characteristically found in human airway inflammatory diseases such as bronchial asthma in which sensitivity to allergens play a critical pathogenic role.Recently, it has been reported that the expression of squamous cell carcinoma antigens (SCCA), cysteine, and chymotrypsin proteinase inhibitors of the ovalbumin/serpin family (reviewed in Ref. 5; Ref. 6) is markedly elevated in the airway epithelia of patients with bronchial asthma (7). Consistent with these findings, it has also been reported that SCCA protein targets a potent allergen and an extrinsic cysteine proteinase in house-dust mites, which is thought to play a pathogenic role in allergic asthma (8), although the physiological role(s) of SCCA is yet to be defined.In humans, SCCA-1 and SCCA-2 genes enc...

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Uteroglobin/Clara Cell 10‐kDa Family of Proteins: Nomenclature Committee Report

Cited by 133 publications

References 40 publications

Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins

Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

Uteroglobin Suppresses SCCA Gene Expression Associated with Allergic Asthma

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