Title

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

UMMS Affiliation

Graduate School of Biomedical Sciences; Howard Hughes Medical Institute, Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date

2008-02-13

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

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.

DOI of Published Version

10.1016/j.cell.2007.12.032

Source

Cell. 2008 Feb 8;132(3):363-74. Link to article on publisher's site

Journal/Book/Conference Title

Cell

Related Resources

Link to Article in PubMed

PubMed ID

18267069

Link to Full Text

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