Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7
Graduate School of Biomedical Sciences; Howard Hughes Medical Institute, Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
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
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.
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Citation: Cell. 2008 Feb 8;132(3):363-74. Link to article on publisher's site