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PMID: 18267069 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Cell ·Vol. 132 ·No. 3 ·2008-02-08 ·Pages 363-74

Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR

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.

MeSH Terms
Amino Acid Substitution Animals Apoptosis Autocrine Communication Cell Line, Tumor Cell Proliferation Cellular Senescence Fibroblasts/cytology Humans Insulin-Like Growth Factor Binding Proteins/genetics,metabolism MAP Kinase Signaling System Melanocytes/cytology,metabolism Melanoma/genetics,metabolism Membrane Proteins/metabolism Mice Neoplasm Transplantation Nevus, Pigmented/metabolism Paracrine Communication Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins B-raf/genetics,metabolism RNA Interference Recombinant Proteins/genetics,metabolism Transplantation, Heterologous Tumor Suppressor Proteins/metabolism Up-Regulation
Chemicals
BNIP3L protein, human Insulin-Like Growth Factor Binding Proteins Membrane Proteins Proto-Oncogene Proteins Recombinant Proteins Tumor Suppressor Proteins insulin-like growth factor binding protein-related protein 1 BRAF protein, human Proto-Oncogene Proteins B-raf
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wajapeyee Narendra
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
Zhu Xiaochun
Mahalingam Meera
Green Michael R
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2007.12.032
Published
2008-02-08
Pages
363-74
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2266096
Subset
IM
Grants
Howard Hughes Medical Institute · United States
Corrections
CommentIn
PMID: 18267066
CommentIn
PMID: 18555773
External Links
PubMed source DOI: 10.1016/j.cell.2007.12.032 PMC Full Text View journal details
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