Gene expression profiling of malignant mesothelioma cell lines: cDNA array study

Kettunen, Eeva; Nissén, Anna‐Maria; Ollikainen, Tiina; Taavitsainen, M.; Tapper, Johanna; Mattson, K.; Linnainmaa, Kaija; Knuutila, Sakari; El–Rifai, Wael

doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1094>3.3.co;2-d

Cited by 13 publications

(16 citation statements)

References 24 publications

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“…Cellular Transformation by Human JAGGED1-Although aberrant misexpression of DSL proteins has been documented in several tumor types, a causal role in oncogenesis has not been demonstrated (29,(47)(48)(49). Here, we report that expression of JAGGED1 transforms RKE cells in culture.…”

Section: Discussionmentioning

confidence: 82%

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

Ascano

Beverly

Capobianco

2003

Journal of Biological Chemistry

111

113

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JAGGED1 is a member of the Delta/Serrate/Lag-2 (DSL) family of proteins that are cell-bound ligands for Notch receptors. Initiation of Notch signaling occurs through a series of proteolytic events upon the binding of Notch to a DSL protein presented on neighboring cells. Whether DSL proteins themselves are capable of initiating an intrinsic signaling mechanism within the cell they are expressed is not known. Aberrant misexpression of JAGGED1 and DELTA1 has been documented in several human tumors; however, the mechanism by which misexpression of JAGGED1 contributes to oncogenesis has not been elucidated. We report that expression of human JAGGED1 transforms RKE cells in culture, therefore providing a model system to elucidate the function of DSL proteins. JAGGED1-mediated transformation occurs in a dose-dependent manner and requires a PDZ-ligand at the C terminus. Mutation of the PDZ-ligand did not affect the ability of JAGGED1 to initiate Notch signaling in neighboring cells. However, the PDZ-ligand is required for changes in the expression of JAGGED1 target genes and transcriptional activation of luciferase reporter constructs. Our data indicate the existence of a novel PDZ-dependent signaling pathway intrinsic to JAGGED1. We propose a bi-directional signaling model such that DSL proteins may have two distinct functions: to initiate Notch signaling in a neighboring cell and to initiate a PDZ-dependent signaling mechanism in the DSL-expressing cell. Moreover, we conclude that this intrinsic signaling mechanism of JAGGED1 may partly provide a link between aberrant misexpression of JAGGED1 and tumorigenesis.

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Section: Discussionmentioning

confidence: 82%

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

Ascano

Beverly

Capobianco

2003

Journal of Biological Chemistry

111

113

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“…In MM, different molecular alterations lead to cyclin D overexpression or cyclin D-CDK hyperactivity (Kettunen et al, 2001;Lee et al, 2007) and a correlation between high cyclin D1 expression and decreased p27 level has also been shown . Consistent with the role of SRC in inducing cyclin D1 gene (CCND1) expression at the transcriptional level (Sinibaldi et al, 2000), we observed a significant CCND1 mRNA downregulation in MSTO-211H and REN cells treated with SI83 and SI91 for 72 h (Figure 3e), which was confirmed also at the protein level (Figure 3f).…”

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 96%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo [3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclindependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a wellestablished adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.

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“…We have successfully used the microarray technique for detecting altered expression patterns in several forms of cancer, including malignant mesothelioma, sarcomas and leukaemia (Wolf et al, 2000;Aalto et al, 2001;Kettunen et al, 2001). In this study we describe the use of cDNA array technology for the detection of specific expression patterns for pulmonary adenocarcinomas, and describe genes that are differentially expressed in primary lung tumours as compared to normal lung tissue.…”

Section: Introductionmentioning

confidence: 99%

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

et al. 2002

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No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semiquantitative real-time RT -PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The downregulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

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Gene expression profiling of malignant mesothelioma cell lines: cDNA array study

Cited by 13 publications

References 24 publications

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

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