Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7
UMass Chan AffiliationsProgram in Molecular Medicine
Howard Hughes Medical Institute, Program in Gene Function and Expression
Graduate School of Biomedical Sciences
KeywordsAmino 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
Medicine and Health Sciences
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AbstractExpression 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.
SourceCell. 2008 Feb 8;132(3):363-74. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32826
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