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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.

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ER-targeted Bak can induce selective cleavage of caspase 12, but not of caspase 7.bax−/−bak−/− cells were infected with GFP vector control, Bak-IRES-GFP, Bak-ActA-IRES-GFP, Bak-cb5-IRES-GFP, and Bak-ΔC-IRES-GFP at a high multiplicity. After infection, cells were lysed. Caspase 12, caspase 7, or PARP were detected by immunoblotting using respective antibodies.
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fig7: ER-targeted Bak can induce selective cleavage of caspase 12, but not of caspase 7.bax−/−bak−/− cells were infected with GFP vector control, Bak-IRES-GFP, Bak-ActA-IRES-GFP, Bak-cb5-IRES-GFP, and Bak-ΔC-IRES-GFP at a high multiplicity. After infection, cells were lysed. Caspase 12, caspase 7, or PARP were detected by immunoblotting using respective antibodies.

Mentions: As caspase 12 cleavage is dependent on Bax and Bak, and the ER-targeted Bak can lead to apoptosis, we determined whether expression of the ER-targeted Bak in bax−/−bak−/− cells results in caspase 12 processing. Wild-type Bak and the ER- and mitochondria-targeted Bak mutants were retrovirally expressed in bax−/−bak−/− MEFs. Expression of Bak-cb5 resulted in cleavage of caspase 12, whereas little caspase 12 cleavage was observed in wild-type Bak–expressing cells, and virtually no caspase 12 cleavage was observed in Bak-ActA–expressing cells (Fig. 7)Figure 7.


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)

ER-targeted Bak can induce selective cleavage of caspase 12, but not of caspase 7.bax−/−bak−/− cells were infected with GFP vector control, Bak-IRES-GFP, Bak-ActA-IRES-GFP, Bak-cb5-IRES-GFP, and Bak-ΔC-IRES-GFP at a high multiplicity. After infection, cells were lysed. Caspase 12, caspase 7, or PARP were detected by immunoblotting using respective antibodies.
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Related In: Results  -  Collection

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

fig7: ER-targeted Bak can induce selective cleavage of caspase 12, but not of caspase 7.bax−/−bak−/− cells were infected with GFP vector control, Bak-IRES-GFP, Bak-ActA-IRES-GFP, Bak-cb5-IRES-GFP, and Bak-ΔC-IRES-GFP at a high multiplicity. After infection, cells were lysed. Caspase 12, caspase 7, or PARP were detected by immunoblotting using respective antibodies.
Mentions: As caspase 12 cleavage is dependent on Bax and Bak, and the ER-targeted Bak can lead to apoptosis, we determined whether expression of the ER-targeted Bak in bax−/−bak−/− cells results in caspase 12 processing. Wild-type Bak and the ER- and mitochondria-targeted Bak mutants were retrovirally expressed in bax−/−bak−/− MEFs. Expression of Bak-cb5 resulted in cleavage of caspase 12, whereas little caspase 12 cleavage was observed in wild-type Bak–expressing cells, and virtually no caspase 12 cleavage was observed in Bak-ActA–expressing cells (Fig. 7)Figure 7.

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
Related in: MedlinePlus