Abstract
Decreased Fas expression during tumor progression often results in a loss of Fas-ligand (FasL)-mediated apoptosis. Human and mouse melanoma exhibit an inverse correlation between the degree of Fas cell surface expression, tumorigenicity, and metastatic capacity. The expression of dominant negative Stat3 or c-Jun in melanoma cells efficiently increased Fas expression and sensitized cells to FasL-induced apoptosis. Stat3+/- as well as c-Jun-/- cells exhibited increased Fas cell surface expression and higher sensitivity to FasL-mediated apoptosis. Suppression of Fas expression by Stat3 and c-Jun is uncoupled from Stat3-mediated transcriptional activation. Our findings indicate that Stat3 oncogenic activities could also be mediated through its cooperation with c-Jun, resulting in downregulation of Fas surface expression, which is implicated in the tumor's ability to resist therapy and metastasize.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / radiation effects
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fas Ligand Protein
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Fibroblasts
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Gene Expression Regulation*
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Humans
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Melanoma / genetics
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Melanoma / pathology
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Melanoma / radiotherapy
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Membrane Glycoproteins / metabolism
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Mice
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Promoter Regions, Genetic / genetics
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Protein Binding / radiation effects
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Proto-Oncogene Proteins c-jun / antagonists & inhibitors
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Radiation Tolerance / genetics
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Radiation Tolerance / radiation effects
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Response Elements / genetics
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STAT3 Transcription Factor
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Sequence Deletion / genetics
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factor AP-1 / metabolism
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Transcription, Genetic / genetics*
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Transcriptional Activation / genetics
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Tumor Cells, Cultured
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Ultraviolet Rays
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Up-Regulation / genetics
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fas Receptor / biosynthesis
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fas Receptor / genetics*
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fas Receptor / metabolism
Substances
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DNA-Binding Proteins
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Trans-Activators
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Transcription Factor AP-1
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fas Receptor
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DNA