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

Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J, Thompson CB - J. Cell Biol. (2003)

Bottom Line: In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Abramson Cancer Center, 421 Curie Blvd., BRB II/III, 445, Philadelphia, PA 19104-6160, USA. craig@mail.med.upenn.edu

ABSTRACT
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.

Show MeSH
Bax and Bak localized to the ER can initiate apoptosis. In addition to their mitochondrial localization and activity, Bax and Bak also reside at the ER. Upon ER stress treatment, Bax and Bak can initiate apoptosis from the ER.
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fig8: Bax and Bak localized to the ER can initiate apoptosis. In addition to their mitochondrial localization and activity, Bax and Bak also reside at the ER. Upon ER stress treatment, Bax and Bak can initiate apoptosis from the ER.

Mentions: Caspase 12 has been demonstrated to be specifically localized to the ER (Nakagawa et al., 2000). Although a required role for caspase 12 in the induction of apoptosis has not been established, the finding that caspase 12 cleavage is dependent on Bax and Bak suggests that caspase 12 processing lies downstream of Bax and Bak. Interestingly, expression of the ER-targeted Bak-cb5 resulted in a significant increase in caspase 12 processing, whereas expression of wild-type or the mitochondrial Bak-ActA resulted in preferential cleavage of caspase 7 and PARP. These data suggest that in addition to their role in mitochondrial apoptosis, Bax and Bak localized to the ER can initiate an alternative pathway of caspase activation that results in selective caspase 12 activation (Fig. 8)Figure 8.


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

Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J, Thompson CB - J. Cell Biol. (2003)

Bax and Bak localized to the ER can initiate apoptosis. In addition to their mitochondrial localization and activity, Bax and Bak also reside at the ER. Upon ER stress treatment, Bax and Bak can initiate apoptosis from the ER.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172724&req=5

fig8: Bax and Bak localized to the ER can initiate apoptosis. In addition to their mitochondrial localization and activity, Bax and Bak also reside at the ER. Upon ER stress treatment, Bax and Bak can initiate apoptosis from the ER.
Mentions: Caspase 12 has been demonstrated to be specifically localized to the ER (Nakagawa et al., 2000). Although a required role for caspase 12 in the induction of apoptosis has not been established, the finding that caspase 12 cleavage is dependent on Bax and Bak suggests that caspase 12 processing lies downstream of Bax and Bak. Interestingly, expression of the ER-targeted Bak-cb5 resulted in a significant increase in caspase 12 processing, whereas expression of wild-type or the mitochondrial Bak-ActA resulted in preferential cleavage of caspase 7 and PARP. These data suggest that in addition to their role in mitochondrial apoptosis, Bax and Bak localized to the ER can initiate an alternative pathway of caspase activation that results in selective caspase 12 activation (Fig. 8)Figure 8.

Bottom Line: In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Abramson Cancer Center, 421 Curie Blvd., BRB II/III, 445, Philadelphia, PA 19104-6160, USA. craig@mail.med.upenn.edu

ABSTRACT
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.

Show MeSH