The ubiquitin-proteasome system in glioma cell cycle control

Malignant gliomas constitute a spectrum of poorly differentiated primary brain tumors of astrocytic or oligodendroglial origin with a marked resistance to treatment, a high tendency of recurrence and a poor prognosis [1,2].Deregulation of cell cycle in most cancer cell types, including glioma is a critical mechanism of development, progression, and resistance to treatment [3]. Aberrant function of critical regulators of the cell cycle generally results in modification of growth, differentiation and apoptotic properties of the cell. Knowledge of the regulatory mechanisms that govern the function of cell cycle controllers is critical to enable design of new or use of already existing inhibitors with the aim of inducing a cell cycle related anticancer effect.The ubiquitin-proteasome system (UPS) is long-known as a cellular tool for the marking and proteolytic degradation of proteins involved in a wide variety of structural and functional roles inside the cell. The UPS includes the “ubiquitously” expressed 76-amino acid protein ubiquitin (Ub), the multisubunit protein organelle 26S proteasome, consisting of one 20S catalytic and two 19S regulatoty subunits, and finally, a 3-step enzymatic cascade of Ub-activating (E1), Ub-conjugating (E2) and Ub-ligase (E3) enzymes which attach ubiquitin to the target protein [4,5].In cancer, a great number of cellular proteins with various roles, including cell cycle control, either comprise direct targets of an aberrant degradation machinery or have a close structural or/and functional connection with abnormal ubiquitin- or ubiquitin like-ligases, deubiquitinating enzymes and UPS-regulated signaling factors and pathways [6-8]. In this context, the involvement of UPS in cell cycle regulation is critical.The earliest evidence indicative of an association between the stability of cell cycle proteins and UPS in gliomas concerns the cyclin-dependent kinase inhibitor p27, which was proved to be degraded in a proteasome-dependent manner [9,1