Endoplasmic reticulum (ER) stress activates caspase-12 in murine cells, triggering the ER stress-specific cascade for implementation of apoptosis. In C2C12 murine myoblast cells, activation of the cascade occurs without release of cytochrome c from mitochondria, suggesting that the cascade is independent of mitochondrial damage. Stable overexpression of Bcl-xL in C2C12 cells suppressed activation of caspase-12 and apoptosis. In ER-stressed cells, but not in normal cells, Bcl-xL was co-immunoprecipitated with Bim, a pro-apoptotic member of the Bcl-2 family, suggesting that Bcl-xL sequesters Bim, thereby inhibiting the apoptotic signaling. Fractionation of C2C12 cells revealed that ER stress led to translocation of Bim from a dynein-rich compartment to the ER, while stable overexpression of Bcl-xL suppressed accumulation of Bim on the ER. Although the toxic effect of Bim had been previously observed only at the mitochondrial outer membrane, overexpression of a Bim derivative, Bim(ER), targeted at the surface of the ER led to apoptosis. A C2C12 transfectant overexpressing the caspase-12 suppressor protein was resistant to Bim(ER), suggesting that the toxic effect of Bim on the ER is dependent on activation of caspase-12. Knockdown of Bim by RNA interference provided cells resistant to ER stress. These results suggest that translocation of Bim to the ER in response to ER stress is an important step toward activation of caspase-12 and initiation of the ER stress-specific caspase cascade.
机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Wei, MC
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Zong, WX
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Zong, WX
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Cheng, EHY
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Cheng, EHY
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Lindsten, T
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Lindsten, T
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Panoutsakopoulou, V
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Panoutsakopoulou, V
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Ross, AJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Ross, AJ
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Roth, KA
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Roth, KA
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MacCregor, GR
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
MacCregor, GR
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Thompson, CB
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Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USAUniv Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Thompson, CB
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Korsmeyer, SJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
机构:
Univ Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
Zhang, KZ
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Kaufman, RJ
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Univ Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Zong, WX
;
Lindsten, T
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Lindsten, T
;
Ross, AJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Ross, AJ
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MacGregor, GR
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
MacGregor, GR
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Thompson, CB
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Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USAUniv Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Wei, MC
;
Zong, WX
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Zong, WX
;
Cheng, EHY
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Cheng, EHY
;
Lindsten, T
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Lindsten, T
;
Panoutsakopoulou, V
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Panoutsakopoulou, V
;
Ross, AJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Ross, AJ
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Roth, KA
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Roth, KA
;
MacCregor, GR
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
MacCregor, GR
;
Thompson, CB
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h-index: 0
机构:
Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USAUniv Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Thompson, CB
;
Korsmeyer, SJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
机构:
Univ Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
Zhang, KZ
;
Kaufman, RJ
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机构:
Univ Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Biol Chem, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Zong, WX
;
Lindsten, T
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Lindsten, T
;
Ross, AJ
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
Ross, AJ
;
MacGregor, GR
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机构:Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA
MacGregor, GR
;
Thompson, CB
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机构:
Univ Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USAUniv Penn, Abramson Family Canc Res Inst, Dept Med, Philadelphia, PA 19104 USA