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Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma.

Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Research Abstract Details 

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  • Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Abstract Text:

    louis cheslerLouis Chesler,chris schlieveChris Schlieve,david d goldenbergDavid D Goldenberg,anna kenneyAnna Kenney,grace kimGrace Kim,alex mcmillanAlex McMillan,katherine k matthayKatherine K Matthay,david rowitchDavid Rowitch,william a weissWilliam A Weiss,

    Amplification of MYCN occurs commonly in neuroblastoma. We report that phosphatidylinositol 3-kinase (PI3K) inhibition in murine neuroblastoma (driven by a tyrosine hydroxylase-MYCN transgene) led to decreased tumor mass and decreased levels of Mycn protein without affecting levels of MYCN mRNA. Consistent with these observations, PI3K inhibition in MYCN-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis. To clarify the importance of Mycn as a target of broad-spectrum PI3K inhibitors, we transduced wild-type N-myc and N-myc mutants lacking glycogen synthase kinase 3beta phosphorylation sites into human neuroblastoma cells with no endogenous expression of myc. In contrast to wild-type N-myc, the phosphorylation-defective mutant proteins were stabilized and were resistant to the antiproliferative effects of PI3K inhibition. Our results show the importance of Mycn as a therapeutic target in established tumors in vivo, offer a mechanistic rationale to test PI3K inhibitors in MYCN-amplified neuroblastoma, and represent a therapeutic approach applicable to a broad range of cancers in which transcription factors are stabilized through a PI3K-dependent mechanism.

    Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Publishing Authors By Initials

    l cheslerL Chesler,c schlieveC Schlieve,dd goldenbergDD Goldenberg,a kenneyA Kenney,g kimG Kim,a mcmillanA McMillan,kk matthayKK Matthay,d rowitchD Rowitch,wa weissWA Weiss,

    For similar abstracts research abstracts see: abstracts research

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    Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Journal Published:

    PUBLICATION TYPE: Research Support, Non-U.S. Gov

    Journal: Cancer research

    VOLUME: 66

    Page Numbers: 8139-46

    Journal Abbreviation:

    ISSN: 1538-7445

    DAY: 15

    MONTH: Aug

    YEAR: 2006

    Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Information

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    LANGUAGE: eng

    NlmUniqueID: 2984705

    Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Keywords Mesh Terms:

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    Grant and Affiliation Information for Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma.

    AFFILIATION: Department of Neurology, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA. cheslerl@peds.ucsf.edu

    Country: United States

    United States Research PublicationUnited States Research Publication

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    MEDLINETA: Cancer Res

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