4406 Malignant Pleural Mesothelioma (MPM) is an aggressive, asbestos-related locally recurrent thoracic cancer with no effective curative options, affecting about 3000 new patients in the United States annually. Despite advances in cancer treatment, the median survival rate remains low and most patients die within two years after diagnosis. We have recently shown that U95 Affymetrix ologonucleotide microarray platform could be used for the identification of markers of survival and progression among series of 21 MPM cases Pass HI. et al. Clin Cancer Res. 10: 849-859, 2004. For this study we wanted to identify the aberrations in ubiquitin-proteasome proteolytic pathway (UPP) regulatory proteins that were critical to the pathogenesis of MPM. 241 genes involved in the UPP pathway were compared based on survival time, tumor stage, and histology using t-test analysis with a ninety five percent confidence interval. The software used for the calculations was “Genesight” from Biodiscovery Inc. Twenty-four genes showed significant difference between designated short- ( 1year) term survivors. We observed proteasome alpha subunits 5 and 7 were predominantly overexpressed among short-survivors whereas ubiquitin-activating enzyme E1 was profoundly overexpressed among long-term MPM patient tumor samples. We observed thirty-three genes were differentially expressed among epithelioid and biphasic histotypes. Ubiquitin carrier protein was expressed at low levels among epithelioid MPMs compared to biphasic histotypes. Fifteen genes were significantly altered among stage I and II combined versus stage III cases. Ubiquitin specific proteases 1, 10, 14 were expressed at low levels amomg majority of stage I and II tumors. Increased chymotryptic activity associated with proteasome subunit beta 5 was also observed among six MPM patient derived cell lines compared to MeT5A immortalized mesothelial cells. Taken together, these results indicate that protein ubiquitination and degradation have important role in mesothelioma tumorigenesis that could be utilized for the development of more effective targeted therapies for this fatal disease.