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    Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7

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    Authors
    Wajapeyee, Narendra
    Serra, Ryan W.
    Zhu, Xiaochun
    Mahalingam, Meera
    Green, Michael R.
    UMass Chan Affiliations
    Program in Molecular Medicine
    Howard Hughes Medical Institute, Program in Gene Function and Expression
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    2008-02-13
    Keywords
    Amino Acid Substitution; Animals; *Apoptosis; Autocrine Communication; *Cell Aging; Cell Line, Tumor; Cell Proliferation; Fibroblasts; Humans; Insulin-Like Growth Factor Binding Proteins; MAP Kinase Signaling System; Melanocytes; Melanoma; Membrane Proteins; Mice; Neoplasm Transplantation; Nevus, Pigmented; Paracrine Communication; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; RNA Interference; Recombinant Proteins; Transplantation, Heterologous; Tumor Suppressor Proteins; Up-Regulation
    Life Sciences
    Medicine and Health Sciences
    
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    http://dx.doi.org/10.1016/j.cell.2007.12.032
    Abstract
    Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.
    Source
    Cell. 2008 Feb 8;132(3):363-74. Link to article on publisher's site
    DOI
    10.1016/j.cell.2007.12.032
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32826
    PubMed ID
    18267069
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    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.cell.2007.12.032
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