Protein degradation, signaling, microRNAs and cancer

Every two years, biologists and oncologists gather in Lausanne, on the shores of Lake Geneva, to discuss the latest advances in research into the cell and molecular biology of cancer. Presentations at the most recent of these meetings covered a wide range of topics, a small selection of which is described here.Several talks were devoted to the cellular protein degradation machinery and its targets in the cell cycle. The protein p27 is an inhibitor of the kinase activity of the complex of cyclin-dependent kinase Cdk2 and cyclin E, and the destruction of p27 is normally required before a cell can enter S phase of the cell cycle. An essential role in p27 degradation has been assigned to the E3 ubiquitin ligase SCF-Skp2 (named after its components skp1, cullin and F-box protein). Willy Krek (Eidgen？ssische Technische Hochschule, Zürich, Switzerland) confirmed the importance of Skp2 in p27 degradation but presented the audience with a new ubiquitin-ligase partner for Skp2, a RING-domain containing protein called SAR1 (Skp2-associated RBCC protein 1) that belongs to the RBCC (ring finger, B box, coiled-coil) family. Both SAR1 and Skp2 are found in a complex with Cul1 (a core subunit also found in SCF) and the whole complex has been baptized CRF-Skp2 (for Cul1-RBCC-F-box complex containing Skp2). Specific inhibition of CRF-Skp2 results in accumulation of p27, in particular of the form phosphorylated on threonine 187, and in a slowdown in G1 phase. Krek proposes that CRF-Skp2 might be the real culprit in p27 degradation, and that SCF-Skp2 plays no role in this process - a suggestion that will be bound to create a stir in the cell-cycle field.However it happens, the degradation of p27 clears the path for entry into S phase, in which the cell is confronted with the task of replicating its DNA. Matthias Peter (Eidgen？ssische Technische Hochschule) stressed the role of ubiquitination in this process also. Cells of budding yeast (Saccharomyces cerevisiae) lacking Rtt101p, a rela