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Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis.
Ocak S, Pedchenko TV, Chen H, Harris FT, Qian J, Polosukhin V, Pilette C, Sibille Y, Gonzalez AL, Massion PP
(2012) Eur Respir J 39: 1171-80
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Apoptosis, Carcinoma in Situ, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Cycle, Cell Line, Cell Proliferation, Cell Transformation, Neoplastic, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung, Lung Neoplasms, Male, Middle Aged, Receptor, Notch3, Receptors, Notch, Receptors, Polymeric Immunoglobulin, Transfection
Show Abstract · Added March 5, 2014
Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis. pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression. Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues. pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.
0 Communities
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22 MeSH Terms
Role of STRAP in regulating GSK3β function and Notch3 stabilization.
Kashikar ND, Zhang W, Massion PP, Gonzalez AL, Datta PK
(2011) Cell Cycle 10: 1639-54
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Ankyrins, Axin Protein, Cell Line, Tumor, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Lithium Chloride, Molecular Sequence Data, Neoplasm Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Receptor, Notch3, Receptors, Notch, Repressor Proteins, Sequence Alignment, Ubiquitination
Show Abstract · Added March 5, 2014
Glycogen synthase kinase 3β (GSK3β) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit β-catenin/Smad3 and tau protein to GSK3β, respectively, it is not clear how many of the other GSK3β substrates are recruited to it. Here, we have established the binding of GSK3β with a novel scaffold protein, STRAP, through its WD40 domains. In a new finding, we have observed that STRAP, GSK3β and Axin form a ternary complex together. We show for the first time that intracellular fragment of Notch3 (ICN3) binds with GSK3β through the ankyrin repeat domain. This binding between STRAP and GSK3β is reduced by small-molecule inhibitors of GSK3β. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region, and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies indicate that STRAP reduces ubiquitination of ICN3, suggesting a role of STRAP in stabilizing ICN3. This is supported by the fact that STRAP and Notch3 are co-upregulated and co-localized in 59% of non-small cell lung cancers, as observed in an immunohistochemical staining of tissue microarrays. These results provide a potential mechanism by which STRAP regulates GSK3β function and Notch3 stabilization and further support the oncogenic functions of STRAP.
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21 MeSH Terms
Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim.
Konishi J, Yi F, Chen X, Vo H, Carbone DP, Dang TP
(2010) Oncogene 29: 589-96
MeSH Terms: Animals, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, Cell Line, Tumor, ErbB Receptors, Erlotinib Hydrochloride, Female, MAP Kinase Signaling System, Membrane Proteins, Mice, Mice, Nude, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Quinazolines, RNA, Small Interfering, Receptor, Notch3, Receptors, Notch, Xenograft Model Antitumor Assays
Show Abstract · Added March 7, 2014
Notch signaling is a highly conserved pathway important for normal embryonic development and cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the epidermal growth factor receptor (EGFR) pathway was also inhibited, suggesting significant cross-talk between the two pathways. How Notch3 and epidermal growth factor receptor-mitogen-activated protein kinase (EGFR-MAPK) pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein, via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using gamma-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were observed to be enhanced compared with either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR-ras-MAPK signaling. Thus, our data support the hypothesis that Notch3 not only has a crucial role in lung cancer through regulating apoptosis, but also cooperates with the EGFR-MAPK pathway in modulating Bim.
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20 MeSH Terms
Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers.
Haruki N, Kawaguchi KS, Eichenberger S, Massion PP, Olson S, Gonzalez A, Carbone DP, Dang TP
(2005) Cancer Res 65: 3555-61
MeSH Terms: Apoptosis, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Down-Regulation, Dual Specificity Phosphatase 1, Enzyme Inhibitors, ErbB Receptors, Humans, Immediate-Early Proteins, Lung Neoplasms, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 1, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Quinazolines, Receptor, Notch3, Receptors, Cell Surface, Receptors, Notch, Transfection, Tyrphostins
Show Abstract · Added March 5, 2014
Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.
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24 MeSH Terms
Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice.
Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP
(2003) Oncogene 22: 1988-97
MeSH Terms: Adenocarcinoma, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Epithelial Cells, Gene Expression Regulation, Developmental, Genes, Lethal, Genes, Synthetic, Lung, Lung Neoplasms, Metaplasia, Mice, Mice, Transgenic, Morphogenesis, Organ Specificity, Promoter Regions, Genetic, Protein Structure, Tertiary, Proto-Oncogene Proteins, Pulmonary Surfactant-Associated Protein C, Receptor, Notch3, Receptor, Notch4, Receptors, Cell Surface, Receptors, Notch, Recombinant Fusion Proteins
Show Abstract · Added August 13, 2010
Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type II pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.
1 Communities
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25 MeSH Terms
Chromosome 19 translocation, overexpression of Notch3, and human lung cancer.
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP
(2000) J Natl Cancer Inst 92: 1355-7
MeSH Terms: Adult, Carcinoma, Non-Small-Cell Lung, Carcinoma, Small Cell, Chromosome Mapping, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 19, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Karyotyping, Lung Neoplasms, Mesothelioma, Proto-Oncogene Proteins, RNA, Messenger, Receptor, Notch3, Receptors, Cell Surface, Receptors, Notch, Translocation, Genetic, Tumor Cells, Cultured, Up-Regulation
Added March 5, 2014
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21 MeSH Terms