The ubiquitin-proteasome system and cancer.

The ubiquitin proteasome system (UPS) has emerged from obscurity to be seen as a major player in all regulatory processes in the cell. The concentrations of key proteins in diverse regulatory pathways are controlled by post-translational ubiquitination and degradation by the 26 S proteasome. These regulatory cascades include growth-factor-controlled signal-transduction pathways and multiple points in the cell cycle. The cell cycle is orchestrated by a combination of cyclin-dependent kinases, kinase inhibitors and protein phosphorylation, together with the timely and specific degradation of cyclins and kinase inhibitors at critical points in the cell cycle by the UPS. These processes provide the irreversibility needed for movement of the cycle through gap 1 (G1), DNA synthesis (S), gap 2 (G2) and mitosis (M). The molecular events include cell-size control, DNA replication, DNA repair, chromosomal rearrangements and cell division. It is doubtful whether these events could be achieved without the temporally and spatially regulated combination of protein phosphorylation and ubiquitin-dependent degradation of key cell-cycle regulatory proteins. The oncogenic transformation of cells is a multistep process that can be triggered by mutation of genes for proteins involved in regulatory processes from the cell surface to the nucleus. Since the UPS has critical functions at all these levels of control, it is to be expected that UPS activities will be central to cell transformation and cancer progression.