Apoptosis, inflammatory bowel disease and carcinogenesis: Molecular level (Part 4)
Of note, three groups have been identified in Bcl-2 family members. Group A contains antiapoptotic proteins such as Bcl-2 and Bcl-xL that are characterized by four short conserved Bcl-2-homology (BH) domains (BH1-BH4), as well as a car-boxy-terminal hydrophobic transmembrane tail domain, which localizes the proteins to the outer mitochondrial membrane and endoplasmic reticulum (ER). Group B members exhibit proapoptotic activity. This group includes Bax and Bak and resembles Group A except for the lack of the amino-terminal BH4 domain. Group C contains a large group of proapoptotic molecules (eg, Bid and Bik) that are much less similar than Groups A and B and contain only the BH3 domain.
The proto-oncogene Bcl-2 is expressed in the mitochondrial membrane as well as in the contiguous membrane of the ER and nuclear envelope, mediating resistance against a wide range of apoptotic stimuli. The ER plays an important role in intracellular calcium homeostasis, and alterations in this homeostasis are implicated in the control of apoptosis. Bcl-2 decreases the free calcium concentration within the ER and suppresses apoptotic cell death. Moreover, experimental evidence suggests that Bcl-2 targeted to the ER can inhibit Myc-, but not etoposide-induced apoptosis in the rat-1 fibroblast cell line. On the other hand, the Bcl-2 family members Bax and Bak involve direct effects on the ER calcium pool with consequent sensitization of mitochondria to calcium-mediated fluxes and Cyt c release. These effects modulate the kinetics of Cyt c release and promote apoptosis.
Because Bcl-2 and Bcl-xL only inhibit apoptotic activities of mitochondria, the first (activated by low amounts of caspase 8) but not the second (activated by large amounts of caspase 8) pathway of active apoptosis is inhibited by these antiapoptotic proteins. On the other hand, passive forms of apoptosis involve the activation of Bid proteins that act exclusively via mitochondrial mechanisms; therefore, passive apoptosis, as caused by lymphokine withdrawal, is strongly inhibited by Bcl-2 and Bcl-xL. Best quality drugs are available at the best pharmacy that you can start shopping with right now whenever you need buy female viagra *only here, never having to doubt the choice made or the quality of the drug you get.