Oral communication, CS16 / C78

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

Promotion of melanoma growth and survival through Glycogen Synthase Kinase-3 protein activity

SPEAKER D. Lang #whois submiter ?
AUTHOR(s) D. Lang, J.B. Mascarenhas, D. Wolfgeher, J.D. Kubic

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3 alpha and GSK-3 beta, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. Improper activity and expression of GSK-3 has been linked to the survival and proliferation of several cancer types including melanoma through an unknown mechanism. In this report, we demonstrate that GSK-3 alpha and GSK-3 beta are phosphorylated at Ser 21 and Ser 9 in many melanoma cell lines, respectively. Phosphorylation of these epitopes is known to inhibit some, but not all, kinase functions of GSK-3 proteins. In melanoma cells, GSK-3 actively promotes cell growth and survival, and blocking this activity, with small molecule inhibitor SB216763 or gene-specific siRNA, results in a decrease in proliferation, an increase in apoptosis and cellular morphological changes. These alterations coincide with a loss of PAX3, a transcription factor implicated in proliferation, survival and migration of developing melanoblasts and melanoma. While knockdown of either GSK-3 alpha and GSK-3 beta leads to a moderate phenotype, only inhibition of both isoforms causes significant phenotypic consequences and a decline in PAX3 protein levels, suggesting possible functional redundancy. We further show that GSK-3 beta directly interacts with and phosphorylates PAX3 at Ser205 and either Ser197 or Ser201 in vitro. These data support a model wherein GSK-3 regulates proliferation and survival of melanoma through phosphorylation and stabilization of PAX3.



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Université de Bordeaux 2 & Conseil Régional Aquitaine