Activation of the mitogen-activated protein kinase (MAPK) pathway targets the putative tumor suppressor protein inducible cAMP early repressor (ICER) to ubiquitin-mediated proteasomal degradation [Yehia et al. JBC 2001; 276: 35272-35279]. We demonstrate that ICER proteasomal degradation is implicated in Ras/MAPK-mediated melanoma tumorigenesis. In a system using Tyr/Tet-Ras INK4a-/- transgenic mice and melanoma cells in culture termed R545 cells isolated from Tyr/Tet-Ras INK4a-/- mice [Chin et al. Nature 1999; 400: 468-472], melanoma genesis and melanoma maintenance is strictly dependent upon expression of H-RasV12G. We found that ICER protein was not expressed during melanoma genesis but was strongly expressed in regressing melanomas. Similarly in R545 cells, ICER protein expression was negatively regulated by H-RasV12G. The expression of ICER mRNA was not affected by H-RasV12G expression, suggesting that ICER regulation was post-translational. Indeed, pharmacological inhibition of Ras activity or the proteasome abolished the degradation of ICER caused by H-RasV12G expression indicating that RAS oncogene regulates the expression of ICER protein by targeting ICER to proteasomal degradation. By engineering clones of R545 melanoma cells stably transfected with ICER we were able to determine the prerequisite for Ras-induced tumorigenesis. The reconstitution of physiological levels of ICER showed a significant decrease in cell growth, as well as inhibition of anchorage-independent cell growth and tumorigenicity in nude mice. ICER was found to efficiently repress the expression of cyclin D1 in R545 cells due to the binding of ICER to the CRE in the cyclin D1 promoter. Taken together, we postulate that ICER protein might be targeted to degradation in human tumors where Ras is mutated.