Unexpected pieces to the senescence puzzle

Abstract

Although initially described as the end state of cells after extended rounds of division in culture, it is now clear that cellular senescence induced by different stimuli plays an important role in tumor suppression in vivo. Three recent studies in Cell report that secreted proteins play an important role in enforcing the senescence response (Acosta et al., 2008; Kuilman et al., 2008; Wajapeyee et al., 2008). These new studies identify unanticipated contributors to this tumor-suppressing cell state.

Figure 1. Secreted proteins and oncogene-induced senescence

Expression of an oncogenic allele of BRAF (BRAF^V600E) in human cells induces senescence. Three recent genetic screens using cells expressing BRAF^V600E 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 BRAF^V600E-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.