Oral communication, CS22 / C107

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Alterations of cellular redox-sensitive pathways regulation in vitiligo melanocytes converge to stress-activated cellular senescence phenotype

BACKGROUND AND OBJECTIVES: Several in vitro and in vivo studies evidenced an alterated redox status and an increased susceptibility of vitiligo cells to pro-oxidant agents supporting the idea that imbalance of the cellular redox status might be the pathogenic clue in vitiligo. METHODS: In order to study intracellular pathways crucially involved in stress-dependent vitiligo cells damage, we focused on cAMP/PKA/CREB and MAPK-dependent signal transduction. RESULTS: We found a full correlation between ROS production, constitutive stimulation of antioxidant enzymes expression (Nrf2, HO-1, NQO1, SOD2 and catalase), activation of the stress activated protein kinase p38 MAPK, p53 nuclear localization, hyperphosphorylation of CREB and increased membrane cholesterol level. Notably, all these long-term effects of subcytotoxic oxidative stress are also “biomarkers” of premature cellular senescence. Consistent with the hypothesis that vitiligo melanocytes are inclined to acquire senescent phenotype, we demonstrated that vitiligo cells in vitro presented a significant increase in p16 and p21 expression that did not correlate with donor chronologic age. Chronic stimulation of mitogenic-activated signaling and downstream inhibition of cyclin-dependent kinases in presence of elevated level of cyclinD1 suggests that vitiligo melanocytes are prone to undergo to a hypermitogenic cell cycle arrest. Moreover, as predicted by the hypermitogenic arrest vitiligo cells showed attenuated responses to growth factors. In fact, despite the normal induction of cyclinD1 gene expression, cell proliferation remained largely inhibited for vitiligo melanocytes treated with α-MSH in minimal medium. CONCLUSION: We report for the first time robust evidences demonstrating that vitiligo melanocytes present alteration of redox homeostasis, membrane lipid composition, transduction pathways, and changes at mRNA and protein level of genes coding for cell-cycle regulators that altogether argue for a pathologic predisposition to stress-induced premature senescence.

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