Common Delayed Senescence of Melanocytes from Multiple Primary Melanoma Patients

766 into the dorsal skin of C57BL/6J mice 3 times a week for 1 week. Epidermal thickness was significantly increased in TNS4-overexpressing mice by 70% compared with that in control mice (P < 0.05) despite comparable inflammation (CD45and K6-positive cells) and infection efficacy (GFP-positive cells) (Figure 2c). Consistently, the number of Ki67-positive cells was significantly higher in TNS4-overexpressing mice than in control mice (TNS4 vs. GFP 1⁄4 63% vs. 21%, P < 0.05) (Figure 2d). TNS4 not only regulates several receptor tyrosine kinases but also functions as an important linker between integrins and receptor tyrosine kinase signaling pathways (Muharram et al., 2014). TNS4 interactswith ITGB1andMET, increasing the protein stability of two receptors and leading to increased survival and proliferation of cancer cells (Muharram et al., 2014). Although many downstream signaling cascades linking integrins to proliferation have been identified, the specific components conveying integrin signals across adhesion complexes have not been identified (Moreno-Layseca and Streuli, 2014). Although we could not exclude the possibility that TNS4 might be regulated by integrins other than ITGB4, our findings showed that TNS4induced keratinocyte proliferation is mediated by activation of the ITGB4, FAK, and ERK signaling pathway. Collectively, our results indicate that TNS4 associates with ITGB4 and transmits integrin signals (Muharram et al., 2014) to FAK and ERK and that this downstream signaling cascade promotes cell proliferation in normal