抗凋亡蛋白Mcl-1及Siah-1S在细胞凋亡中的作用机制研究
摘要
Mcl-1作为抗凋亡Bcl-2家族蛋白成员之一，可以阻断多种凋亡诱导剂所诱导的细胞凋亡，然而Mcl-1抑制细胞凋亡的分子机制并没有被完全地弄清楚。
在我们的研究中，我们发现Mcl-1可以和促凋亡Bcl-2家族蛋白Puma相互作用，它们之间的相互作用分别由Mcl-1的BH1结构域和Puma的BH3结构域介导。免疫荧光结果显示Mcl-1和Puma可以共定位于线粒体，暗示Mcl-1和Puma之间的结合是发生在线粒体上的。进一步的研究结果表明Mcl-1可以抑制Puma诱导的细胞凋亡，而且Mcl-1的BH1结构域对于其抗Puma诱导的细胞凋亡起着重要的作用。有意思的是，Mcl-1的蛋白稳定性可以被Puma提高，而且这种Mcl-1蛋白稳定性的提高是由于和Puma的直接结合而引起的，因为将Puma的BH3结构域去除之后，Puma就不再能提高Mcl-1的蛋白稳定性，我们同时也证明了Puma结合Mcl-1只能部分而不能完全地阻止Mcl-1的快速降解。最后我们发现除了PEST和BH1结构域介导Mcl-1的快速降解之外，还存在其它的降解信号，而且位于Mcl-1蛋白的C末端。我们的这些结果第一次清楚地阐明了Mcl-1可以和Puma相互作用，而且暗示了Mcl-1可能通过和Puma结合而提高自身稳定性最终行使抗凋亡的功能。
另外，我们在研究中发现促凋亡Bcl-2家族蛋白Noxa的蛋白水平在喜树碱(CPT)诱导的细胞凋亡中可以被上调，而且这一过程是不依赖于p53的。除此之外，我们证明了P13K／Akt信号通路在CPT诱导的Noxa上调过程中起着非常重要的作用。luciferase assay以及CREB knock-down的实验结果进一步显示CREB介导了CPT诱导的Noxa转录水平的上调。更重要的是，用RNAi的方法将Noxa的蛋白水平抑制之后可以显著地抑制CPT诱导的细胞凋亡，暗示Noxa在CPT诱导细胞凋亡的过程中起着非常重要的作用。有意思的是，Mcl-1的蛋白水平也可以通过P13K／Akt信号通路而被CPT上调。通过免疫共沉淀实验，我们证明了不管有没有CPT处理的情况下Noxa都可以和Mcl-1相互作用，说明Noxa和Mcl-1之间应该存在一个平衡，从而调节细胞凋亡。通过抑制Mcl-1的蛋白水平以及在细胞内过量表达Mcl-1的实验，我们发现Mcl-1蛋白水平的抑制会使得细胞对于CPT诱导的细胞凋亡更加的敏感，而过量表达Mcl-1则可以显著地抑制CPT以及CPT和LY294002诱导的细胞凋亡。综合这些结果说明Noxa和Mcl-1之间的平衡可以调节细胞对于CPT诱导细胞凋亡的敏感度。
综上所述，我们的实验结果暗示了Mcl-1可以通过和Puma以及Noxa相互作用从而发挥其抗凋亡功能。
Siah-1(seven in absentia homolog)可以和SIP(Siah-1-interacting protein)，Skp1，以及Ebi相互作用形成一个泛素连接酶复合物从而降解β-catenin。在我们的研究中，我们发现了一个新的Siah-1剪切异构体并将它命名为Siah-1S，Siah-1S被证明是通过自身剪切而产生的。有意思的是，Siah-1在剪切的过程中产生的内含子并不符合经典的内含子边界：GT-AG或AT-AC。通过比较Siah-1和Siah-1S的蛋白半衰期，我们发现Siah-1S比Siah-1更加的不稳定；和Siah-1类似，Siah-1S也可以发生自身泛素化并最终通过泛素-蛋白酶体途径而被降解。Siah-1S可以提高β-catenin的蛋白水平以及增强Tcf／Lef的转录活性，而且Siah-1S可以对抗Siah-1对于Etoposide诱导的细胞凋亡的增强作用。另外我们发现Siah-1S不仅可以和Siah-1结合形成异源二聚体，也可以和自身形成同源二聚体。和Siah-1~*Siah-1二聚体不同，Siah-1~*Siah-1S、以及Siah-1S~*Siah-1S都失去了和SIP的结合能力，这个结果可以部分地解释为什么Siah-1S可以行使Siah-1的dominant negative抑制子的作用。最后我们证明了Siah-1S可以在体外促进肿瘤细胞的成瘤能力，暗示Siah-1S可能在肿瘤的形成过程中发挥了重要的作用。
Mcl-1, a member of Bcl-2 family, is capable of blocking apoptosis induced by various apoptotic stimuli, however, the mechanism by which Mcl-1 inhibits apoptosis has not been conclusively determined.
In our study, we report that Mcl-1 is able to interact with Puma, a proapoptotic member of Bcl-2 family. Their binding sites are mapped to BH3 (Bcl-2 homology) domain of Puma and BH1 domain of Mcl-1, respectively. Mcl-1 and Puma are shown to coiocalize at the mitochondria by immunostaining. The level of Mcl-1 is increased when coexpressed with Puma, indicating Puma is able to stabilize Mcl-1. Puma binding to Mcl-1 via its BH3 domain is the prerequisite for this effect, which is further supported by the finding that Puma mutant lacking BH3 domain no longer promotes Mcl-1 protein stability. We also show that BH1 domain is essential for Mcl-1 to inhibit Puma-induced apoptosis, since Mcl-1 mutant lacking BH1 domain completely abrogates its protective function. In addition, we conclude that binding of Puma to BH1 domain of Mcl-1 is necessary, but not sufficient to prevent rapid degradation of Mcl-1. In addition to PEST and BH1 domain, some additional degradation signal is expected to reside in the C-terminal region of Mcl-1. In conclusion, our results provide the first evidence that the interaction between Mcl-1 and Puma may represent a novel mechanism by which Mcl-1 prevents apoptosis by increasing its stability through binding to Puma.
We also demonstrate that BH3-only protein Noxa is upregulated during Camptothecin-induced apoptosis, which is independent of p53. In addition, we show that PI3k/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and CREB knock-down experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. More importantly, blocking CPT-induced Noxa using specific siRNA significantly reduces the apoptosis response, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, we find that Mcl-1 is also upregulated through PI3k/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, we demonstrate that Noxa is able to interact with Mcl-1 to form the complex in CPT treated or untreated cells, suggesting that the balance between Noxa and Mcl-1 may regulate cells' susceptibility to CPT-induced apoptosis. In supporting of this conclusion, knock-down of Mcl-1 is shown to potentiate CPT-induced apoptosis, however, ectopic overexpression of Mcl-1 is able to rescue from apoptosis induced by CPT or CPT and LY294002.
In summary, these data suggest that Mcl-1 plays its antiapoptotic role in apoptosis partly by binding to Puma or Noxa.
Siah-1 (seven in absentia homolog) is known to cause indirect degradation ofβ-catenin through formation of a complex with SIP, Skp1 and Ebi. Here we report the characterization of a novel splice variant of human Siah-1, designated Siah-1S, which is produced by an alternative splicing mechanism. The novel intron/exon junctions used to generate Siah-1S follow a non-conventional CT-AC rule. Siah-1S exhibits an even shorter half-life than Siah-1 and is able to catalyse self-ubiquitination that results in its subsequent degradation by Proteasome. Siah-1S is shown to upregulateβ-catenin-dependent Tcf/Lef transcriptional activation and antagonize Siah-1's potentiation effect on the apoptosis induced by Etoposide in MCF-7 cells. Additionally, Siah-1S is found to interact with Siah-1 to form heterodimer or with itself to form homodimer. Unlike homodimer Siah-1 ~*Siah-1, neither Siah-1 ~*Siah-1S nor Siah-1S~*Siah-1S is able to bind to SIP (Siah-1-interacting protein), which may explain the underlying mechanism for Siah-1S's dominant negative effect on Siah-1. Importantly, results from in vitro soft agar assay demonstrated that Siah-1S displays a promotion effect on cells tumorigenecity.
在我们的研究中，我们发现Mcl-1可以和促凋亡Bcl-2家族蛋白Puma相互作用，它们之间的相互作用分别由Mcl-1的BH1结构域和Puma的BH3结构域介导。免疫荧光结果显示Mcl-1和Puma可以共定位于线粒体，暗示Mcl-1和Puma之间的结合是发生在线粒体上的。进一步的研究结果表明Mcl-1可以抑制Puma诱导的细胞凋亡，而且Mcl-1的BH1结构域对于其抗Puma诱导的细胞凋亡起着重要的作用。有意思的是，Mcl-1的蛋白稳定性可以被Puma提高，而且这种Mcl-1蛋白稳定性的提高是由于和Puma的直接结合而引起的，因为将Puma的BH3结构域去除之后，Puma就不再能提高Mcl-1的蛋白稳定性，我们同时也证明了Puma结合Mcl-1只能部分而不能完全地阻止Mcl-1的快速降解。最后我们发现除了PEST和BH1结构域介导Mcl-1的快速降解之外，还存在其它的降解信号，而且位于Mcl-1蛋白的C末端。我们的这些结果第一次清楚地阐明了Mcl-1可以和Puma相互作用，而且暗示了Mcl-1可能通过和Puma结合而提高自身稳定性最终行使抗凋亡的功能。
另外，我们在研究中发现促凋亡Bcl-2家族蛋白Noxa的蛋白水平在喜树碱(CPT)诱导的细胞凋亡中可以被上调，而且这一过程是不依赖于p53的。除此之外，我们证明了P13K／Akt信号通路在CPT诱导的Noxa上调过程中起着非常重要的作用。luciferase assay以及CREB knock-down的实验结果进一步显示CREB介导了CPT诱导的Noxa转录水平的上调。更重要的是，用RNAi的方法将Noxa的蛋白水平抑制之后可以显著地抑制CPT诱导的细胞凋亡，暗示Noxa在CPT诱导细胞凋亡的过程中起着非常重要的作用。有意思的是，Mcl-1的蛋白水平也可以通过P13K／Akt信号通路而被CPT上调。通过免疫共沉淀实验，我们证明了不管有没有CPT处理的情况下Noxa都可以和Mcl-1相互作用，说明Noxa和Mcl-1之间应该存在一个平衡，从而调节细胞凋亡。通过抑制Mcl-1的蛋白水平以及在细胞内过量表达Mcl-1的实验，我们发现Mcl-1蛋白水平的抑制会使得细胞对于CPT诱导的细胞凋亡更加的敏感，而过量表达Mcl-1则可以显著地抑制CPT以及CPT和LY294002诱导的细胞凋亡。综合这些结果说明Noxa和Mcl-1之间的平衡可以调节细胞对于CPT诱导细胞凋亡的敏感度。
综上所述，我们的实验结果暗示了Mcl-1可以通过和Puma以及Noxa相互作用从而发挥其抗凋亡功能。
Siah-1(seven in absentia homolog)可以和SIP(Siah-1-interacting protein)，Skp1，以及Ebi相互作用形成一个泛素连接酶复合物从而降解β-catenin。在我们的研究中，我们发现了一个新的Siah-1剪切异构体并将它命名为Siah-1S，Siah-1S被证明是通过自身剪切而产生的。有意思的是，Siah-1在剪切的过程中产生的内含子并不符合经典的内含子边界：GT-AG或AT-AC。通过比较Siah-1和Siah-1S的蛋白半衰期，我们发现Siah-1S比Siah-1更加的不稳定；和Siah-1类似，Siah-1S也可以发生自身泛素化并最终通过泛素-蛋白酶体途径而被降解。Siah-1S可以提高β-catenin的蛋白水平以及增强Tcf／Lef的转录活性，而且Siah-1S可以对抗Siah-1对于Etoposide诱导的细胞凋亡的增强作用。另外我们发现Siah-1S不仅可以和Siah-1结合形成异源二聚体，也可以和自身形成同源二聚体。和Siah-1~*Siah-1二聚体不同，Siah-1~*Siah-1S、以及Siah-1S~*Siah-1S都失去了和SIP的结合能力，这个结果可以部分地解释为什么Siah-1S可以行使Siah-1的dominant negative抑制子的作用。最后我们证明了Siah-1S可以在体外促进肿瘤细胞的成瘤能力，暗示Siah-1S可能在肿瘤的形成过程中发挥了重要的作用。
Mcl-1, a member of Bcl-2 family, is capable of blocking apoptosis induced by various apoptotic stimuli, however, the mechanism by which Mcl-1 inhibits apoptosis has not been conclusively determined.
In our study, we report that Mcl-1 is able to interact with Puma, a proapoptotic member of Bcl-2 family. Their binding sites are mapped to BH3 (Bcl-2 homology) domain of Puma and BH1 domain of Mcl-1, respectively. Mcl-1 and Puma are shown to coiocalize at the mitochondria by immunostaining. The level of Mcl-1 is increased when coexpressed with Puma, indicating Puma is able to stabilize Mcl-1. Puma binding to Mcl-1 via its BH3 domain is the prerequisite for this effect, which is further supported by the finding that Puma mutant lacking BH3 domain no longer promotes Mcl-1 protein stability. We also show that BH1 domain is essential for Mcl-1 to inhibit Puma-induced apoptosis, since Mcl-1 mutant lacking BH1 domain completely abrogates its protective function. In addition, we conclude that binding of Puma to BH1 domain of Mcl-1 is necessary, but not sufficient to prevent rapid degradation of Mcl-1. In addition to PEST and BH1 domain, some additional degradation signal is expected to reside in the C-terminal region of Mcl-1. In conclusion, our results provide the first evidence that the interaction between Mcl-1 and Puma may represent a novel mechanism by which Mcl-1 prevents apoptosis by increasing its stability through binding to Puma.
We also demonstrate that BH3-only protein Noxa is upregulated during Camptothecin-induced apoptosis, which is independent of p53. In addition, we show that PI3k/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and CREB knock-down experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. More importantly, blocking CPT-induced Noxa using specific siRNA significantly reduces the apoptosis response, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, we find that Mcl-1 is also upregulated through PI3k/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, we demonstrate that Noxa is able to interact with Mcl-1 to form the complex in CPT treated or untreated cells, suggesting that the balance between Noxa and Mcl-1 may regulate cells' susceptibility to CPT-induced apoptosis. In supporting of this conclusion, knock-down of Mcl-1 is shown to potentiate CPT-induced apoptosis, however, ectopic overexpression of Mcl-1 is able to rescue from apoptosis induced by CPT or CPT and LY294002.
In summary, these data suggest that Mcl-1 plays its antiapoptotic role in apoptosis partly by binding to Puma or Noxa.
Siah-1 (seven in absentia homolog) is known to cause indirect degradation ofβ-catenin through formation of a complex with SIP, Skp1 and Ebi. Here we report the characterization of a novel splice variant of human Siah-1, designated Siah-1S, which is produced by an alternative splicing mechanism. The novel intron/exon junctions used to generate Siah-1S follow a non-conventional CT-AC rule. Siah-1S exhibits an even shorter half-life than Siah-1 and is able to catalyse self-ubiquitination that results in its subsequent degradation by Proteasome. Siah-1S is shown to upregulateβ-catenin-dependent Tcf/Lef transcriptional activation and antagonize Siah-1's potentiation effect on the apoptosis induced by Etoposide in MCF-7 cells. Additionally, Siah-1S is found to interact with Siah-1 to form heterodimer or with itself to form homodimer. Unlike homodimer Siah-1 ~*Siah-1, neither Siah-1 ~*Siah-1S nor Siah-1S~*Siah-1S is able to bind to SIP (Siah-1-interacting protein), which may explain the underlying mechanism for Siah-1S's dominant negative effect on Siah-1. Importantly, results from in vitro soft agar assay demonstrated that Siah-1S displays a promotion effect on cells tumorigenecity.
引文
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