Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

By W. Zong, Chi Li, G. Hatzivassiliou, T. Lindsten, Qian-chun Yu, Junying Yuan, Craig B. Thompson. Journal of Cell Biology, 2003

637 citations recorded by the source corpus.

Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax − / − bak − / − cells. In bax − / − bak − / − cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/68d20b72d3a96a8778fbd225c745df3bd69f6e78

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In Epidemiology

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2. J. Malhotra
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4. Afshin Samali
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In Molecular Biology

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Citations in the corpus

• Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? (2007, positive): “BH3 domain (Bcl2-homology domain 3)-only containing proapoptotic factors, such as BAX (Bcl2-associated X protein) and BAK (Bcl-2 homologous antagonist/killer), are present at the mitochondrial and ER membranes (123, 169).”
• The role of the unfolded protein response in tumour development: friend or foe? (2004, neutral): “fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=581">BAX , might also be involved in releasing cytochrome c from the mitochondria, as cells devoid of these genes are resistant to ER-specific apoptosi”
• The Bcl-2 family: roles in cell survival and oncogenesis (2003, background): “…initiated from the ER in response to the stress imposed by disrupted calcium homeostasis or excess unfolded proteins (Nakagawa et al., 2000; Wei et al., 2001; Zong et al., 2001; Scorrano et al., 2003), and they may function directly on the ER as well as on mitochondria (Zong et al., 2003).”
• Regulation of apoptosis by endoplasmic reticulum pathways (2003, background): “Interestingly, Zong et al., 2003 found that caspase-12 processing is abolished in BAX, BAK-1-cells, and caspase-12 cleavage could be induced by the expression of ER-targeted BAK.”
• A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. (2005, background): “CANCER CELL : NOVEMBER 2005 A recent study showed that Bax and Bak can also localize in the endoplasmic reticulum (ER) and that ER stress can trigger caspase-12 activation (Zong et al., 2003).”
• From acute ER stress to physiological roles of the Unfolded Protein Response (2006, background): “The available data suggest that upon encountering ER stress, proapoptotic Bcl2-related proteins, Bak and Bax, undergo conformational alteration in the ER membrane to permit Ca2þ efflux into the cytoplasm.(38,39) In vitro experiments support the idea that the increase in Ca2þ concentration (from micr”
• Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. (2005, background): “Furthermore, sequestration by VDAC2 would only account for Bak located on the outer mitochondrial membrane but not that on other membranes (Zong et al. 2003).”
• Mediators of endoplasmic reticulum stress‐induced apoptosis (2006, background): “These findings indicate that stress signals are relayed from the ER to mitochondria, and that ER stress-induced apoptosis, similar to mitochondrialmediated apoptosis, is also regulated by the BCL2 family of proteins (Boya et al, 2002; Hacki et al, 2000; Zong et al, 2003).”