IGFBP7 induces senescence or apoptosis in BRAF-mutated cells, according to Cell paper.



Howard Hughes Medical Institute (HHMI) researchers say that they have uncovered a protein that stops the growth of melanoma and turns it into a harmless mole. Also known as nevi,   moles and melanoma often result from the same genetic mutation, BRAF.


The biological pathway that differentiates the two, though, was previously unknown, report the scientists. BRAF is part of a signaling system that is important for cell growth and proliferation. The BRAF mutation found in nevi and melanoma increases the activity of the BRAF protein.


The investigators used RNAi to perform a genome-wide search for the proteins involved. They found 17 genes that were required for activated BRAF to induce either senescence or suicide, creating moles. The HHMI group say that three of the associated proteins are required for both the senescence and apoptosis pathways.


The identity of one of those proteins, insulin-like growth factor binding protein 7 (IGFBP7), surprised the researchers. Not much was known about IGFBP7, except that it was secreted. A secreted protein does not stay inside the cell that produces it but instead is released from the cell and moves through the blood to other cells.“We would have thought this process would be purely intracellular,” says Michael Green, M.D., Ph.D., one of the authors.


The team therefore focused their attention on IGFBP7 because its presence suggested something intriguing: If one otherwise healthy melanocyte begins expressing BRAF, the IGFBP7 it produces can enter cells around it, prompting lots of melanocytes to switch off.


The researchers exposed human melanoma cells in culture to recombinant IGFBP7. The protein had the same genetic code as the human version but was produced using genetically modified insect cells. The melanoma cells that were treated with IGFBP7 committed suicide.


The researchers also injected the protein into the bloodstream of mice on to which human melanoma tumors had been grafted. IGFBP7 entered the tumor cells and stopped their growth.


The study is published in the February 8 issue of Cell.








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