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

Radiation resistance is a hallmark of human melanoma, and yet mechanisms un derlying this resistance are not well understood. We recently established t he role of ATF2 in this process, suggesting that stress kinases, which cont ribute 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 melanom a development and regulate its sensitivity to UV-induced apoptosis, Compari ng early- and late-stage melanoma cells revealed low expression of TRAF2 an d GCK in early-stage melanoma, which coincided with poor resistance to UV-i nduced, TNF-mediated apoptosis; forced expression of GCK alone or in combin ation with TRAF2 efficiently increased JNK and NF-kappa B activities, which coincided with increased protection against apoptosis, Conversely, forced expression of the dominant negative form of TRAF2 or GCK in late-stage mela noma cells reduced NF-kappa B activity and decreased Fas expression, result ing in a lower degree of UV-induced, Fas-mediated cell death. Our results i llustrate 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 duri ng melanoma progression.