By reverse transcriptase-polymerase chain reaction, enzymelinked immunosorbent assay, and immunohistochemistry, MGSA-α, -β, -γ, and CXCR2 mRNA expression and proteins are detected in 7 out of 10 human melanoma lesions. The biological consequence of constitutive expression of the MGSA/GRO chemokine in immortalized melanocytes was tested in SCID and nude mouse models. Continuous expression of MGSA/GRO-α, -β, or -γ in immortalized melan-a mouse melanocytes results in nearly 100% tumor formation for each of the clones tested, whereas clones expressing only the neomycin resistance vector form tumors <10% of the time. Moreover, antibodies to the MGSA/GRO proteins slow or inhibit the formation of tumors in the SCID mouse model and block the angiogenic response to conditioned medium from the tumor-producing clones. Transcription of the MGSA/ GRO chemokines is regulated by an enhancesomelike complex comprised of the nuclear factor-κB (NF-κB), HMG(I)Y, IUR, and Sp1 elements. In Hs294T melanoma cells the half life of the IκB protein is shortened in comparison to normal retinal epithelial cells, facilitating the endogenous nuclear localization of NF-κB. We propose that this endogenous nuclear NF-κB, working in concert with the 115-κDa IUR-binding factor, promotes constitutive expression of MGSA/GRO genes.