The University of Texas MD Anderson Cancer Center, Science Park, Department of Molecular Carcinogenesis, Smithville, Texas, United States of America ; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America.
PLoS One. 2014 Jan 10;9(1):e84388. doi: 10.1371/journal.pone.0084388. eCollection 2014.
Acute heat shock can induce apoptosis through a canonical pathway involving the upstream activation of caspase-2, followed by BID cleavage and stimulation of the intrinsic pathway. Herein, we report that the BH3-only protein BIM, rather than BID, is essential to heat shock-induced cell death. We observed that BIM-deficient cells were highly resistant to heat shock, exhibiting short and long-term survival equivalent to Bax(-/-)Bak(-/-) cells and better than either Bid(-/-) or dominant-negative caspase-9-expressing cells. Only Bim(-/-) and Bax(-/-)Bak(-/-) cells exhibited resistance to mitochondrial outer membrane permeabilization and loss of mitochondrial inner membrane potential. Moreover, while dimerized caspase-2 failed to induce apoptosis in Bid(-/-) cells, it readily did so in Bim(-/-) cells, implying that caspase-2 kills exclusively through BID, not BIM. Finally, BIM reportedly associates with MCL-1 following heat shock, and Mcl-1(-/-) cells were indeed sensitized to heat shock-induced apoptosis. However, pharmacological inhibition of BCL-2 and BCL-X(L) with ABT-737 also sensitized cells to heat shock, most likely through liberation of BIM. Thus, BIM mediates heat shock-induced apoptosis through a BAX/BAK-dependent pathway that is antagonized by antiapoptotic BCL-2 family members.
急性热休克可通过涉及半胱天冬酶-2 上游激活的经典途径诱导细胞凋亡，随后 BID 切割并刺激内在途径。在此，我们报告 BH3 仅蛋白 BIM 而非 BID 对于热休克诱导的细胞死亡是必不可少的。我们观察到 BIM 缺陷细胞对热休克高度耐受，表现出与 Bax(-/-)Bak(-/-)细胞相当的短期和长期存活，优于 Bid(-/-)或显性失活 caspase-9 表达细胞。只有 Bim(-/-)和 Bax(-/-)Bak(-/-)细胞表现出对线粒体外膜通透性和线粒体内膜电位丧失的抗性。此外，虽然二聚化的 caspase-2 未能在 Bid(-/-)细胞中诱导细胞凋亡，但它在 Bim(-/-)细胞中很容易诱导凋亡，这意味着 caspase-2 通过 BID 而不是 BIM 杀死细胞。最后，据报道 BIM 可与热休克后 MCL-1 结合，而 Mcl-1(-/-)细胞确实对热休克诱导的细胞凋亡敏感。然而，用 ABT-737 抑制 BCL-2 和 BCL-X(L)的药理学抑制也使细胞对热休克敏感，这很可能是通过 BIM 的释放。因此，BIM 通过 BAX/BAK 依赖性途径介导热休克诱导的细胞凋亡，该途径被抗凋亡 BCL-2 家族成员拮抗。
