The key event in the intrinsic pathway of apoptosis is mitochondrial outer membrane permeabilization and the release of apoptogenic proteins. These results agree with the widely accepted symmetric model for the dimerization of these proteins and also suggest that other regions, different from the α6 helix, could be involved in the oligomerization of BH3-in groove dimers. Bax and Bak’s mutants lacking the BH3 domain were still able to associate and give BiFC signals, suggesting the existence of alternative surfaces of interaction between two Bax or Bak molecules. We have also applied the BiFC technique to explore the different molecular models proposed for Bax and Bak oligomerization. ![]() Furthermore, our results point to differences in the regulation of Bax and Bak activation by proteins of the antiapoptotic and BH3-only subfamilies. Despite the limitations of this technique, present data suggest that native proteins of the Bcl-2 family acting inside living cells establish a complex network of interactions, which would fit nicely into “mixed” models recently proposed by others. In the present work, we have studied interactions between different members of the Bcl-2 family in living cells via the BiFC technique. Mitochondrial permeabilization depends on the formation of oligomers of the effector proteins Bax and Bak after an activation event mediated by BH3-only proteins and regulated by antiapoptotic members of the Bcl-2 family. ![]() Permeabilization of the outer mitochondrial membrane, regulated by pro- and antiapoptotic members of the Bcl-2 family of proteins, is essential for the release of apoptogenic factors leading to caspase activation, cell dismantlement, and death. ![]() Proteins of the Bcl-2 family are key regulators of the intrinsic pathway of apoptosis, and alterations in some of these proteins are frequently found in cancer cells. Evasion of apoptosis is one of the hallmarks of cancer cells.
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