The expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/ or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short-term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity-dependent growth promoting function of UCHL1 via the activation of the mitogen-activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose-dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K-Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients.Ubiquitination plays a key role in the post-translational modification of proteins and regulates in combination with phosphorylation and other post-translational alterations a number of cellular processes such as differentiation, proliferation, apoptosis and neoplastic transformation. The ubiquitination of proteins is controlled by so called deubiquitinating enzymes (DUB), which revert the binding between ubiquitin (ub) and their substrates, 1 protect proteins from proteasomal degradation and recycle ub-molecules of poly-ub chains. The DUB family is categorized into five different groups: (i) the ubiquitin carboxyl-terminal hydrolases (UCH), (ii) the ubiquitinspecific proteases (USP), (iii) the ovarial tumor proteases, (iv) the protein domain proteases of the Machado-Josef-disease and (v) the Jab1/MPN domain associated metalloproteinases. 2 The UCH family member UCHL1, also known as PGP9.5, GAD or PARK5, is a cysteine protease with a molecular weight of approximately 25 kDa. Next to its hydrolase activity UCHL1 also possesses ligase activity, 3,4 thereby the protein repertoire is multivalent regulated by its involvement in the cellular protein degradation and stabilization processes as well as in the homeostasis of the ub balance. Although UCHL1 is mainly expressed in neuronal and neuroendocrine tissues and represents about 2% of the total protein content of the brain, 3 it is also found in the tubule epithelium of the kidney, 5,6 in ovary 7 as well as in testis. 8 In neurodegenerative diseases such as Alzheimer's (AD) or Parkinson's disease (PD), an altered expression of UCHL1 could be indicated 9,10 suggesting that...
