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Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis

Oncogene volume 19, pages 933–942 (2000)Cite this article

Abstract

Radiation resistance is a hallmark of human melanoma, and yet mechanisms underlying this resistance are not well understood. We recently established the role of ATF2 in this process, suggesting that stress kinases, which contribute to regulation of ATF2 stability and activity, play an important role in the acquisition of such resistance. Here we demonstrate that changes in the expression and respective activities of TRAF2/GCK occur during melanoma development and regulate its sensitivity to UV-induced apoptosis. Comparing early- and late-stage melanoma cells revealed low expression of TRAF2 and GCK in early-stage melanoma, which coincided with poor resistance to UV-induced, TNF-mediated apoptosis; forced expression of GCK alone or in combination with TRAF2 efficiently increased JNK and NF-κB activities, which coincided with increased protection against apoptosis. Conversely, forced expression of the dominant negative form of TRAF2 or GCK in late-stage melanoma cells reduced NF-κB activity and decreased Fas expression, resulting in a lower degree of UV-induced, Fas-mediated cell death. Our results illustrate a mechanism in which protection from, or promotion of, UV-induced melanoma cell death depends on the nature of the apoptotic cascade (TNF or Fas) and on the availability of TRAF2/GCK, whose expression increases during melanoma progression.

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Abbreviations

FasL:

Fas ligand

TRAF2:

tumor receptor associated factor 2

GCK:

germinal center kinase

UVC:

ultraviolet light C

AP1:

activator protein 1

RIP:

receptor interacting protein

NIK:

NF-κB-inducing kinase

HOS:

human homologue of Slimb

IAP:

inhibitory apoptosis proteins

JNK:

Jun amino terminal kinase

TNFR1:

tumor necrosis factor receptor 1

TCF:

ternary complex factor

CREB:

Cyclic AMP responsive element binding protein

CHX:

cycloheximide

EMSA:

electrophoretic mobility shift assay

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Acknowledgements

We thank Drs van Dam, DA Sassoon, JS Economou, D Ballard, M Karin, JM Kyriakis and R Davis for providing expression vectors, Dr M Herlyn for LU1205, WM1552 and WM1650 melanoma cells, Ø Fodstad for HHMSX, FEMX and THX melanoma cells and M Green for NEB for phosphoantibodies. We also thank SY Fuchs for discussion and Dania Alarcon-Vargas for editorial comments. Support from the National Cancer Institute through grant CA 51995 (to Z Ronai) is gratefully acknowledged.

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

    Vladimir N Ivanov & Ze'ev Ronai

  2. Laboratory of Immunoregulation, National Institutes of Health, Bethesda, MD 20892, Maryland, USA

    John H Kehrl

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Ivanov, V., Kehrl, J. & Ronai, Z. Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis. Oncogene 19, 933–942 (2000). https://doi.org/10.1038/sj.onc.1203415

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