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  • Online Resource  (5)
  • American Association for Cancer Research (AACR)  (5)
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  • Online Resource  (5)
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  • American Association for Cancer Research (AACR)  (5)
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  • 1
    Online Resource
    Online Resource
    Abstract 296: Protein kinase D regulates Rho GTPase activity through rhotekin
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 296-296
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 296-296
    Abstract: The Protein Kinase D (PKD) family of serine / threonine kinases comprises PKD1,PKD2, and PKD3 and is grouped under the calcium / calmodulin - dependent protein kinase (CAMK) superfamily. PKDs play an important role in various biological processes including proliferation, adhesion, migration, cell shape, survival and apoptosis. Identification of the putative target substrates for this kinase family would provide a deeper insight into their role in the physiological and pathological processes. In the present study, we identified rhotekin (RTKN), an effector protein of small GTPase Rho, as a potential substrate of PKDs. Using the consensus PKD substrate sequence motif scan approach, we identified Ser435 in the C-terminal region of rhotekin as the potential phosphorylatable residue. We generated a phospho-specific antibody corresponding to Ser435 and could validate that Ser435 is indeed the critical amino acid targeted by PKD2 in vivo in HEK-293T cells. The phospho-mimecking mutant of rhotekin (Ser435Glu) when transfected into HEK-293T cells resulted in the increase of endogenous active RhoA GTPase levels, as determined from the Rho activation assay. Rho GTPases were shown to be an important upstream molecules regulating PKD activity in the process of cancer cell migration. However, our results demonstrate for the first time the role of PKDs in the regulation of RhoGTP activity levels. Considering the role of RhoGTPases in various cellular processes, our results provide a hint to the potential regulation of various cellular processes by PKDs through phosphorylation of rhotekin and thereby regulating the activity of RhoGTPases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 296.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-296
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 9 ( 2006-05-01), p. 4662-4671
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 9 ( 2006-05-01), p. 4662-4671
    Abstract: Pancreatic cancer is characterized by its invasiveness, early metastasis, and the production of large amounts of extracellular matrix (ECM). We analyzed the influence of type I collagen and fibronectin on the regulation of cellular adhesion in pancreatic cancer cell lines to characterize the role of ECM proteins in the development of pancreatic cancer. We show that collagen type I is able to initiate a disruption of the E-cadherin adhesion complex in pancreatic carcinoma cells. This is due to the increased tyrosine phosphorylation of the complex protein β-catenin, which correlates with collagen type I–dependent activation of the focal adhesion kinase and its association with the E-cadherin complex. The activation and recruitment of focal adhesion kinase to the E-cadherin complex depends on the interaction of type I collagen with β1-containing integrins and an integrin-mediated activation of the cellular kinase Src. The disassembly of the E-cadherin adhesion complex correlates with the nuclear translocation of β-catenin, which leads to an increasing expression of the β-catenin-Lef/Tcf target genes, cyclin D1 and c-myc. In addition to that, cells grown on collagen type I show enhanced cell proliferation. We show that components of the ECM, produced by the tumor, contribute to invasiveness and metastasis by reducing E-cadherin–mediated cell-cell adhesion and enhance proliferation in pancreatic tumor cells. (Cancer Res 2006; 66(9): 4662-71)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-2804
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Specialized DNA Arrays for the Differentiation of Pancreatic Tumors
    American Association for Cancer Research (AACR) ; 2005
    In:  Clinical Cancer Research Vol. 11, No. 22 ( 2005-11-15), p. 8048-8054
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 22 ( 2005-11-15), p. 8048-8054
    Abstract: Purpose: Malignant tumors of the pancreas are frequently indistinguishable from inflammatory tumors arising in the context of a chronic pancreatitis with the use of conventional imaging techniques. Thus, cytologic analysis of cells obtained by abdominal ultrasound, computed tomography, or endoscopic ultrasound–guided fine needle aspiration biopsy is required for diagnosis. However, the reliability of cytologic analyses of pancreatic fine needle aspirates remains unsatisfactory, with a diagnostic accuracy of ≤80%. The purpose of the current study was therefore to develop a novel diagnostic approach based on expression profiling of biopsy material using a specialized diagnostic cDNA array. Experimental Design: Previous gene expression profiling studies were reevaluated to design a 558-feature diagnostic array. Minimal amounts of residual material from pancreatic cytology samples as well as surgically resected tumor and control tissue specimens were analyzed using the diagnostic array and a newly developed statistical classification system. Results and Conclusions: Our diagnostic approach resulted in 95% accurate differentiation between ductal adenocarcinomas and nonmalignant tumors of the pancreas. The diagnostic array, in conjunction with conventional diagnostic procedures, is thus suitable to significantly improve the reliability of pancreatic cancer diagnostics and can be expected to become a valuable new tool in the routine workup of suspect masses in the pancreas.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-05-1274
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Sp1 Is Required for Transforming Growth Factor-β–Induced Mesenchymal Transition and Migration in Pancreatic Cancer Cells
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 4 ( 2007-02-15), p. 1563-1570
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 4 ( 2007-02-15), p. 1563-1570
    Abstract: Transition from a sessile epithelial phenotype to a migrating mesenchymal phenotype is a crucial step in transforming growth factor-β (TGF-β)–induced pancreatic cancer cell migration and invasion. These profound morphologic and functional alterations are associated with characteristic changes in TGF-β–regulated gene expression, defined by rapid repression of epithelial markers and a strong and sustained transcriptional induction of mesenchymal markers such as the intermediate filament vimentin. In this study, we have analyzed the role of the transcription factor Sp1 in TGF-β–induced and Smad-mediated gene regulation during epithelial to mesenchymal transition (EMT) and migration of pancreatic cancer cells. Here, we show that Sp1 is required for TGF-β–induced EMT, and that this function is especially mediated through transcriptional induction of vimentin. Our results emphasize the functional relevance of vimentin in TGF-β–induced EMT because prevention of its induction strongly reduces cell migration. Altogether, this study helps to better understand the role of Sp1 in TGF-β–induced progression of pancreatic cancer. It suggests that Sp1, via transcriptional induction of vimentin, cooperates with activated Smad complexes in mesenchymal transition and migration of pancreatic cancer cells upon TGF-β stimulation. [Cancer Res 2007;67(4):1563–70]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-1670
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2006
    In:  Molecular Cancer Research Vol. 4, No. 11 ( 2006-11-01), p. 861-872
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 4, No. 11 ( 2006-11-01), p. 861-872
    Abstract: c-myc promoter silencing is a key step in epithelial cell growth inhibition by transforming growth factor β (TGFβ). During carcinogenesis, however, epithelial cells escape from c-myc repression and consequently become refractory to TGFβ-mediated antiproliferation. Here, we assessed the role of the repressor, KLF11, in TGFβ-induced growth inhibition in normal epithelial as well as pancreatic carcinoma cells. Endogenous KLF11 was stably down-regulated by RNA interference technology, and the functional consequences were studied by proliferation assays, reporter assays, DNA binding studies, and expression analyses. Coimmunoprecipitation and glutathione S-transferase pulldown assays were conducted to define KLF11-Smad3 interaction and U0126 was administered to examine the effects of the extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase on complex formation and c-myc promoter binding of KLF11 and Smad3 in pancreatic cancer cells. In TGFβ-stimulated normal epithelial cells, nuclear KLF11, in concert with Smad3, binds to and represses transcription from the core region of the TGFβ-inhibitory element (TIE) of the c-myc promoter. Disruption of KLF11-Smad3 interaction or small interfering RNA–mediated knockdown of endogenous KLF11 strongly diminishes Smad3-TIE promoter binding and repression, and consequently impairs TGFβ-mediated growth inhibition. In pancreatic cancer cells with oncogenic Ras mutations, hyperactive ERK counteracts TGFβ-induced c-myc repression and growth inhibition through at least two mechanisms, i.e., via disruption of KLF11-Smad3 complex formation and through inhibition of KLF11-Smad3 binding to the TIE element. Together, these results suggest a central role for KLF11 in TGFβ-induced c-myc repression and antiproliferation and identifies a novel mechanism through which ERK signaling antagonizes the tumor suppressor activities of TGFβ in pancreatic cancer cells with oncogenic Ras mutations. (Mol Cancer Res 2006;4(11):861–72)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-06-0081
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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