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  • Original Paper
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p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-κB activity and Fas expression

Oncogene volume 19, pages 3003–3012 (2000)Cite this article

Abstract

Identifying mechanisms that underlie the resistance of human melanoma to radiation and chemotherapy is expected to assist in developing new strategies for the treatment of this tumor type. We recently demonstrated that through up-regulation of TNFα, ATF2 increases the resistance of late stage melanoma cells to apoptosis induced by UV-irradiation. In elucidating the role of ATF2 kinases, we now demonstrate that ASK1/MKK6/p38 elicits suppression of Fas expression. ASK1/p38 downregulates the expression of a Fas via NF-κB/SP1 site on the Fas promoter. Deletion or mutation of NF-κB/SP1 within the Fas promoter abrogates p38 effect. ASK1/p38 silences the Fas promoter by inhibition of IκBα phosphorylation – thereby limiting NF-κB activity. Forced expression of a dominant negative form of p38 (p38-ASP) or treatment with p38 pharmacological inhibitor, SB203580, increases NF-κB activity, Fas expression and the levels of UVC-induced apoptosis in late stage melanoma cells. Inhibition of p38 activity also restored NF-κB activity and Fas expression in early-phase melanoma cells, suggesting that p38 elicited suppression of Fas expression is not restricted to late phase melanoma. Identifying p38-mediated down-regulation of Fas expression illustrates a novel regulatory pathway by which ASK1/MKK6/p38 alters the degree and nature of the UV-induced apoptosis of melanoma cells.

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Abbreviations

AP1:

activator protein-1

ASK1:

apoptosis signal-regulating kinase 1

ATF2:

activating transcription factor 2

FasL:

Fas ligand

NF-κB:

nuclear factor kappa B

PI:

propidium iodide

TNFα:

tumor necrosis factor alpha

TNFR:

tumor necrosis factor receptor

TRAF2:

tumor necrosis factor receptor associated factor 2

GFP:

green fluorescent protein

IκB:

inhibitor NF-κB

IKK:

IκB kinase

MAPK:

mitogen-activated protein kinase

MFI:

medium fluorescence intensity

MKK:

MAPK kinase

CHX:

cycloheximide

NFAT:

nuclear factor of activated T lymphocytes

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Acknowledgements

We thank Drs H van Dam, H Ichijo, JS Economu, CV Paya, D Ballard, LB Owen-Schaub, M Karin and R Davis for providing expression vectors, Dr M Herlyn for LU1205 and WM1552 melanoma cells and Dr SY Fuchs for helpful discussion. Support from the National Cancer Institute through grant CA51995 (to Z Ronai) is gratefully acknowledged.

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  1. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Vladimir N Ivanov & Ze'ev Ronai

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  1. Vladimir N Ivanov
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Ivanov, V., Ronai, Z. p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-κB activity and Fas expression. Oncogene 19, 3003–3012 (2000). https://doi.org/10.1038/sj.onc.1203602

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