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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2007-2-1
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pubmed:abstractText |
Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phosphorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-alpha were able to inhibit HC11-Int3 colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-alpha tyrosine kinases in the context of Int3 signaling.
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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/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Milk Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NOTCH4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-abl,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-kit,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Platelet-Derived Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Platelet-Derived Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Notch,
http://linkedlifedata.com/resource/pubmed/chemical/imatinib,
http://linkedlifedata.com/resource/pubmed/chemical/whey acidic proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0950-9232
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
26
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
662-72
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16878155-Animals,
pubmed-meshheading:16878155-Antineoplastic Agents,
pubmed-meshheading:16878155-Blotting, Northern,
pubmed-meshheading:16878155-Cell Differentiation,
pubmed-meshheading:16878155-Cell Proliferation,
pubmed-meshheading:16878155-Cell Transformation, Neoplastic,
pubmed-meshheading:16878155-Cells, Cultured,
pubmed-meshheading:16878155-Female,
pubmed-meshheading:16878155-Immunoprecipitation,
pubmed-meshheading:16878155-Mammary Glands, Animal,
pubmed-meshheading:16878155-Mammary Neoplasms, Experimental,
pubmed-meshheading:16878155-Mammary Tumor Virus, Mouse,
pubmed-meshheading:16878155-Mice,
pubmed-meshheading:16878155-Mice, Transgenic,
pubmed-meshheading:16878155-Milk Proteins,
pubmed-meshheading:16878155-Phosphorylation,
pubmed-meshheading:16878155-Piperazines,
pubmed-meshheading:16878155-Protein-Tyrosine Kinases,
pubmed-meshheading:16878155-Proto-Oncogene Proteins,
pubmed-meshheading:16878155-Proto-Oncogene Proteins c-abl,
pubmed-meshheading:16878155-Proto-Oncogene Proteins c-kit,
pubmed-meshheading:16878155-Pyrimidines,
pubmed-meshheading:16878155-RNA, Small Interfering,
pubmed-meshheading:16878155-Receptor, Platelet-Derived Growth Factor alpha,
pubmed-meshheading:16878155-Receptor, Platelet-Derived Growth Factor beta,
pubmed-meshheading:16878155-Receptors, Notch,
pubmed-meshheading:16878155-Reverse Transcriptase Polymerase Chain Reaction
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pubmed:year |
2007
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pubmed:articleTitle |
Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis.
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pubmed:affiliation |
Oncogenetics Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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pubmed:publicationType |
Journal Article
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