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-kappaB 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-kappaB 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. Oncogene (2000) 19, 933 - 942.