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rdf:type |
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lifeskim:mentions |
umls-concept:C0026336,
umls-concept:C0026339,
umls-concept:C0079419,
umls-concept:C0174680,
umls-concept:C0332281,
umls-concept:C0334634,
umls-concept:C0376515,
umls-concept:C0441889,
umls-concept:C0521447,
umls-concept:C0547047,
umls-concept:C0598086,
umls-concept:C0598388,
umls-concept:C1415887,
umls-concept:C1419040,
umls-concept:C1420433,
umls-concept:C1424666
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pubmed:issue |
4
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pubmed:dateCreated |
2008-4-16
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pubmed:abstractText |
Molecular mechanisms responsible for lymphoma resistance to apoptosis often involve the bcl-2 pathway. In this study, we investigated the cell signaling pathways activated in bcl-2-overexpressing human mantle cell lymphoma cell lines (JVM-2 and Z-138) that have been treated with oblimersen, a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Z-138 cells expressed higher levels of bcl-2 and were more sensitive to the effects of bcl-2 silencing, mediated by oblimersen or bcl-2 small interfering RNA, in vitro. Tumors derived following injection of Z-138 cells were sensitive to oblimersen as judged by decreases in tumor growth rate and decreases in cell proliferation (as measured by Ki-67). Immunohistochemistry and Western blot analysis of oblimersen-treated Z-138 tumors revealed a dose-dependent decrease in bcl-2 levels and an associated increase in the proapoptotic proteins caspase-3 and caspase-9. Silencing bcl-2 in Z-138 xenografts revealed an associated dose-dependent suppression of bax, a decrease in nuclear factor-kappaB and phospho-nuclear factor-kappaB, and transient loss of p53 levels. Coimmunoprecipitation studies suggest that the latter observation is mediated by an association between bcl-2 and phospho-mdm2. Bcl-2 silencing also led to p27 down-regulation and coimmunoprecipitation studies point to a role for bcl-2 in regulation of p27 localization/degradation. Bcl-2 silencing was also correlated with loss of cyclin D1a protein levels but not cyclin D1b levels. Coimmunoprecipitation studies indicate that bcl-2 may mediate its effects on cyclin D1a via interaction with p38 mitogen-activated protein kinase as well as a previously unreported interaction between bcl-2 and cyclin D1a.
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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/Bax protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mdm2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, Antisense,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Rag2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Thionucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-2-Associated X Protein,
http://linkedlifedata.com/resource/pubmed/chemical/oblimersen
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1535-7163
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
7
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
749-58
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18375822-Animals,
pubmed-meshheading:18375822-Apoptosis,
pubmed-meshheading:18375822-Blotting, Western,
pubmed-meshheading:18375822-Cell Proliferation,
pubmed-meshheading:18375822-Cyclin D,
pubmed-meshheading:18375822-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:18375822-Cyclins,
pubmed-meshheading:18375822-DNA-Binding Proteins,
pubmed-meshheading:18375822-Disease Models, Animal,
pubmed-meshheading:18375822-Gene Silencing,
pubmed-meshheading:18375822-Humans,
pubmed-meshheading:18375822-Immunoenzyme Techniques,
pubmed-meshheading:18375822-Immunoprecipitation,
pubmed-meshheading:18375822-Lymphoma, Mantle-Cell,
pubmed-meshheading:18375822-Male,
pubmed-meshheading:18375822-Mice,
pubmed-meshheading:18375822-Mice, Knockout,
pubmed-meshheading:18375822-Mice, Transgenic,
pubmed-meshheading:18375822-NF-kappa B,
pubmed-meshheading:18375822-Neoplasm Proteins,
pubmed-meshheading:18375822-Oligonucleotides, Antisense,
pubmed-meshheading:18375822-Phosphorylation,
pubmed-meshheading:18375822-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:18375822-Proto-Oncogene Proteins c-mdm2,
pubmed-meshheading:18375822-RNA, Messenger,
pubmed-meshheading:18375822-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:18375822-Thionucleotides,
pubmed-meshheading:18375822-Tumor Suppressor Protein p53,
pubmed-meshheading:18375822-Xenograft Model Antitumor Assays,
pubmed-meshheading:18375822-bcl-2-Associated X Protein
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pubmed:year |
2008
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pubmed:articleTitle |
Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-kappaB, p53, bax, and p27 levels.
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pubmed:affiliation |
Department of Advanced Therapeutics, BC Cancer Research Center, Vancouver, British Columbia, Canada V5Z 1L3. ctucker@bccrc.ca
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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