Unexpected pieces to the senescence puzzle

Expression of an oncogenic allele of BRAF (BRAFV600E) in human cells induces senescence. Three recent genetic screens using cells expressing BRAFV600E identified the secreted proteins (green) insulin-like growth factor binding protein 7 (IGFBP7), interleukin 8 (IL-8), and interleukin 6 (IL-6) as essential mediators of BRAFV600E-dependent senescence. These unexpected observations provide new insights into the overlapping yet distinct mechanisms of the p53 and RB tumor suppressor pathway activation, which induces the senescence response. IGFBP7 expression is mediated by activating protein 1 (AP-1. IGFBP7 inhibits the MEK mitogen activated kinase pathway via the upregulation of the Raf inhibitory protein (RKIP) but promotes p16 expression. The transcription factor (blue) C/EBP (CCAAT-enhancer-binding protein) promotes IL-6 expression. IL-6 activity is mediated by its receptor IL-6R. The chemokine receptor CXCR or its ligands IL-8 and GRO-α promote p53-dependent senescence. IL-8 upregulation is dependent upon the transcripton factors C/EBP and NFκB.

Publication

Unexpected pieces to the senescence puzzle. (2008) Karen Cichowski, et al. Cell. 2008 Jun 13;133(6):958-961. Figure: F1. All organisms Danio rerio Homo sapiens

Disease mentions