Regulation of Bax in Human Malignant Cells
【摘要】：正Evasion of apoptosis is a major contributor to the development of cancer. The relative expression (or activity) of various anti - apoptotic and pro - apoptotic Bcl - 2 family proteins is a critical determinant of apoptosis sensitivity . Pro - apoptotic Bcl - 2 family member Bax is a crucial protein in the induction of apoptosis and its activation is required for this process. Native (inactive) Bax is a global cytosolic protein. The activation step for Bax requires its conformational change, translocation to mitochondria, membrane insertion and oligomerization. Bax activation can be triggered by BH - 3 - only proteins, such as Bid and PUMA. We have found that Bax protein is instable in the malignant B - cells. Bax degradation activity is associated with clinical prognosis of chronic lymphocytic leukaemia (CLL). Ubiquitin/proteasome system plays a central role in the degradation of short - lived proteins and thus regulates basic cellular processes including cell transformation, signal transduction and apoptosis. We conformed that Bax degradation is ubiquitin/proteasome - dependent in the malignant B - cells. Bax can be stabilized and activated by the proteasome inhibitor, PS - 341. It was detected that Bax protein contains a destabilizing domain within its hydrophobic core and this domain is responsible for the recognition and / or conjugation for the ubiquitin system. Bax is vulnerable to ubiq-uitin - dependent degradation during its conformational change. Understanding the fundamental mechanisms how Bax is regulated in cancer cells provides an insight into its potential role in tumourigenesis and anti - cancer therapy.