Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.
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.
Wajapeyee
Narendra
N
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Serra
Ryan W
RW
Zhu
Xiaochun
X
Mahalingam
Meera
M
Green
Michael R
MR
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009508:Nevus, Pigmented / Q000378:metabolism; D019899:Paracrine Communication; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
C116838:BNIP3L protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf