De-regulation of ubiquitin-dependent proteolysis and the pathogenesis of malignant melanoma

Malignant melanoma is similar to the other types of cancer in terms that the pathogenesis of this lethal disease includes abnormal activation of proteins that mediate oncogenic signaling as well as inhibition of anti-proliferative and pro-apoptotic protein regulators. Activity of both types of cellular regulators is often dependent on their abundance and is determined by the rate of proteolysis via the ubiquitin pathway. Aberrations in ubiquitin-dependent degradation of regulatory proteins frequently occur in human cancers including malignant melanoma. Melanoma cells that re-program ubiquitin-dependent proteolysis toward accelerated degradation of protein regulators of tumor suppression and abnormal stabilization of oncogenic proteins are likely to gain an advantage in growth and survival. Specific characteristics of melanoma biology include rapid metastasizing and resistance to conventional anticancer therapy. Exploration of these traits should place an emphasis on a subset of the signal transduction pathways that are governed by a number of key protein regulators whose stability and activity becomes deregulated during progression of malignant melanoma. Targeting the ubiquitination and degradation of these pivotal proteins may provide a promising new therapeutic approach to treatment of this disease.