L4+L5 extra reading Flashcards
bcl2 family
qian et al. (2022)
members of the b-cell lymphoma 2 (bcl2) protein family are key regulators with pro and anti-apoptotic activities. these reguators are held in a fine, delicate balance in healthy cells. they can cause cancer cells to irreversibly head toward cell death or conversley allow cells to permanently escape apoptosis and make themselves a malignant clone. bcl2 family members have been identifitied and classified according to their domains and functions. characterised by the presence of short, conserved sequece regions (bcl-2 homology (BH) motifs), the proteins of the bcl2 families are classified into three subgroups i.e: the anti-apoptotic/pro-survival proteins represented by bcl-2 and BCL-XL, the pro apoptotic proteins represented by BAX and Bak, and the pro-apoptotic BH3-only proteins represented by BAD and BID.
anticancer therapy
qian et al. (2022) since the expression of bcl-2 proteins in tumour cells is much higher than that in normal cells, inhibitors targeting it have little effect on normal cells. consequently overcoming the resistance of tumour cells to apoptosis by inhibiting bcl-2 anti-apoptotic protein is a novel therapeutic reigemen. for instance venetoclax, , a selective bcl2 inhibitor is approved for treating chronic lymphocytic leukemia and acute myeloid leukemia.
ESCRT in apoptosis
Yang et al. (2022)
The endosomal sorting complex required for transport (ESCRT) machinery plays a key role in the repair of damaged plasma membranes with puncta form and removes pores from the plasma membrane in regulated cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy. ESCRT-I overexpression and ESCRT-III-associated charged multivesicular body protein (CHMP) 4B participate in apoptosis, and the ESCRT-1 protein TSG 101 maintains low levels of ALIX and ALG-2 and prevents predisposition to apoptosis.
Under pathological conditions, the ESCRT-III-associated protein CHMP4B could also interact with ALIX-ALG-2 and participate in the endolysosomal system or cell apoptosis. CHMP4B mutation prevented early programmed cell death caused by overexpression of ALIX (49). However, increasing CHMP4B levels were accompanied by the upregulation of Fas receptor (Fas), Fas ligand (FasL), active caspase-8, and caspase-3 in neurons, which implicated a proapoptotic function in neuronal cells induced by hemin stimulation following intracerebral hemorrhage (ICH) via the extrinsic apoptotic pathway (50) ( Figure 1 and Table 1 ).
ROS production
Kim et al. (2017)
the FADD/caspase-8/Bid/cytochrome c axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis.
They found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors.
ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome c release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-α- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome c spontaneously elevated ROS production.
In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome c release.
