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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2007-3-13
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pubmed:abstractText |
In this study, the authors investigated the expression of activin receptor-like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT-PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF-beta sensitive PANC-1 and COLO-357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF-beta/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC-1-caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC-1-caALK1-derived tumors. In vitro, this mutant efficiently blocked TGF-beta-induced epithelial-to-mesenchymal transdifferentiation and suppressed TGF-beta/ALK5-mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF-beta target gene whose protein product, GADD45beta, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5-independent growth inhibition and by blocking TGF-beta/ALK5-mediated epithelial-to-mesenchymal transdifferentiation and, possibly, invasion and metastatic progression.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Activin Receptors, Type I,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Differentiation,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/GADD45A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/GADD45B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Transforming Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Smad Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0020-7136
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pubmed:author |
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pubmed:copyrightInfo |
(c) 2007 Wiley-Liss, Inc.
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
120
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1641-51
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17230504-Activin Receptors, Type I,
pubmed-meshheading:17230504-Adenocarcinoma,
pubmed-meshheading:17230504-Animals,
pubmed-meshheading:17230504-Antigens, Differentiation,
pubmed-meshheading:17230504-Cell Cycle Proteins,
pubmed-meshheading:17230504-Cell Differentiation,
pubmed-meshheading:17230504-Cell Proliferation,
pubmed-meshheading:17230504-Cells, Cultured,
pubmed-meshheading:17230504-Epithelial Cells,
pubmed-meshheading:17230504-Female,
pubmed-meshheading:17230504-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:17230504-Genes, Tumor Suppressor,
pubmed-meshheading:17230504-Humans,
pubmed-meshheading:17230504-Immunoblotting,
pubmed-meshheading:17230504-Immunohistochemistry,
pubmed-meshheading:17230504-Mesoderm,
pubmed-meshheading:17230504-Mice,
pubmed-meshheading:17230504-Mice, Inbred BALB C,
pubmed-meshheading:17230504-Mice, SCID,
pubmed-meshheading:17230504-Nuclear Proteins,
pubmed-meshheading:17230504-Pancreatic Neoplasms,
pubmed-meshheading:17230504-Promoter Regions, Genetic,
pubmed-meshheading:17230504-RNA, Messenger,
pubmed-meshheading:17230504-Receptors, Transforming Growth Factor beta,
pubmed-meshheading:17230504-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:17230504-Signal Transduction,
pubmed-meshheading:17230504-Smad Proteins,
pubmed-meshheading:17230504-Transcriptional Activation,
pubmed-meshheading:17230504-Transfection,
pubmed-meshheading:17230504-Transforming Growth Factor beta,
pubmed-meshheading:17230504-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2007
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pubmed:articleTitle |
Antitumor activity of ALK1 in pancreatic carcinoma cells.
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pubmed:affiliation |
Department of General Surgery and Thoracic Surgery, UKSH, Campus Kiel, Arnold-Heller-Str. 7, 24105 Kiel, Germany. hungefroren@chirurgie-sh.de
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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