The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-kappaB [NF-kappaB (p50/p65)] play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-kappaB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-kappaB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-kappaB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-kappaB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.