GSK-3 promotes cell survival, growth, and PAX3 levels in human melanoma cells.
GSK-3 is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3α and GSK-3β, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. In this article, we found that GSK-3 actively promoted cell growth and survival in melanoma cells, and blocking this activity with small-molecule inhibitor SB216763 or gene-specific siRNA decreased proliferation, increased apoptosis, and altered cellular morphology. These alterations coincided with loss of PAX3, a transcription factor implicated in proliferation, survival, and migration of developing melanoblasts. We further found that PAX3 directly interacted with and was phosphorylated in vitro on a number of residues by GSK-3β. In melanoma cells, direct inhibition of PAX3 lead to cellular changes that paralleled the response to GSK-3 inhibition. Maintenance of PAX3 expression protected melanoma cells from the anti-tumor effects of SB216763. These data support a model wherein GSK-3 regulates proliferation and morphology of melanoma through phosphorylation and increased levels of PAX3.
Department of Medicine, University of Chicago, Chicago, IL, USA.
Jennifer D
JD
Kubic
Joseph B
JB
Mascarenhas
Takumi
T
Iizuka
Don
D
Wolfgeher
Deborah
D
Lang
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction
D007211:Indoles; D008301:Maleimides; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C417521:SB 216763; D038362:Glycogen Synthase Kinase 3