Secreting Tumor Suppression
| Autor: | Yuchen Chien, Scott W. Lowe |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Senescence medicine.medical_specialty IGFBP7 medicine.medical_treatment Apoptosis Biology Article General Biochemistry Genetics and Molecular Biology Insulin-like growth factor-binding protein Internal medicine medicine Animals Humans Melanoma Cellular Senescence Nevus Pigmented Biochemistry Genetics and Molecular Biology(all) Growth factor Binding protein medicine.disease Insulin-Like Growth Factor Binding Proteins Endocrinology biology.protein Cancer research Melanocytes Cell aging |
| Zdroj: | Cell. 132(3):339-341 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2008.01.022 |
| Popis: | 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 pro-apoptotic 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. |
| Databáze: | OpenAIRE |
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