Summary Degradation by the 26S proteasome of specific proteins that have been targeted by the ubiquitin pathway is the major intracellular non-lysosomal proteolytic mechanism and is involved in a broad range of processes, such as cell cycle progression, antigen presentation and control of gene expression. Recent work, reviewed here, has shown that this pathway is often the target of cancer-related deregulation and can underlie processes, such as oncogenic transformation, tumour progression, escape from immune surveillance and drug resistance.

The results of hepatic arterial chemotherapy with fotemustine produced a high response rate and survival similar to chemoembolization therapy. It involves no major toxicity and preserves the quality of life. To assess further its effectiveness, a randomized study to compare hepatic intraarterial versus intravenous chemotherapy is being planned.

We have investigated the usefulness of the fission yeast Schizosaccharomyces pombe as a model organism for the discovery of novel modes of drug resistance in human cells. In fission yeast, overexpression of the essential pad1 ؉ gene confers pleiotropic drug resistance through a pathway involving an AP-1 transcription factor encoded by pap1 ؉ . We have identified POH1, a human pad1 homologue that can substitute fully for pad1 ؉ and induce AP-1-dependent drug resistance in fission yeast. POH1 also confers P-glycoprotein-independent resistance to taxol (paclitaxel), doxorubicin, 7-hydroxystaurosporine, and ultraviolet light when transiently overexpressed in mammalian cells. Poh1 is a previously unidentified component of the human 26 S proteasome, a multiprotein complex that degrades proteins targeted for destruction by the ubiquitin pathway. Hence, Poh1 is part of a conserved mechanism that determines cellular susceptibility to cytotoxic agents, perhaps by influencing the ubiquitin-dependent proteolysis of transcription factors.