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Silencing Bcl-2 inmodels of mantle celllymphoma isassociated withdecreases in cyclinD1, nuclearfactor-κB, p53, bax,and p27 levels Catherine TuckerAnita KapanenGhania Chikh2008 год

Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-κB, p53, bax, and p27 levels
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Аннотация: 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.
Год издания: 2008
Авторы: Catherine Tucker, Anita Kapanen, Ghania Chikh, Brad G. Hoffman, Alastair H. Kyle, Ian M. Wilson, Dana Masin, Randy D. Gascoyne, Marcel B. Bally, Richard Klasa
Издательство: American Association for Cancer Research
Источник: Molecular Cancer Therapeutics
Ключевые слова: Cancer-related Molecular Pathways, Cell death mechanisms and regulation, Molecular Biology Techniques and Applications
Другие ссылки: Molecular Cancer Therapeutics (HTML)
PubMed (HTML)