Specific Cleavage of Mcl-1 by Caspase-3 in Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis in Jurkat Leukemia T Cells

Weng, Changjiang; Li, Yuan; Xu, Dan; Shi, Yong; Tang, Hong

doi:10.1074/jbc.m412819200

Cited by 224 publications

(220 citation statements)

References 58 publications

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“…This could be the result of increased caspase activity (see Fig. 10B) as Mcl-1 is a caspase substrate (33)(34)(35)(36). Nevertheless, the fact that TAT-RasGAP 317-326 by itself does not induce a decrease of Mcl-1 suggests that Mcl-1 is not playing a direct role in the ability of the peptide to sensitize cancer cells to genotoxin-induced death.…”

Section: Tat-rasgap 317-326 -Induced Sensitization Of Tumor Cells Reqmentioning

confidence: 76%

TAT-RasGAP317-326 Requires p53 and PUMA to Sensitize Tumor Cells to Genotoxins

Michod

Widmann

2007

Molecular Cancer Research

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Although chemotherapy has revolutionized cancer treatment, the associated side effects induced by lack of specificity to tumor cells remain a challenging problem. We have previously shown that TAT-RasGAP 317-326 , a cell-permeable peptide derived from RasGAP, specifically sensitizes cancer cells to the action of genotoxins. The underlying mechanisms of this sensitization were not defined however. Here, we report that TAT-RasGAP 317-326 requires p53, but not the Ras effectors Akt and extracellular signal-regulated kinase, to mediate its tumor sensitization abilities. The TAT-RasGAP 317-326 peptide, although not modulating the transcriptional activity of p53 or its phosphorylation and acetylation status, nevertheless requires a functional p53 cellular status to increase the sensitivity of tumor cells to genotoxins. Genes regulated by p53 encode proapoptotic proteins, such as PUMA, and cell cycle control proteins, such as p21. The ability of TAT-RasGAP 317-326 to sensitize cancer cells was found to require PUMA but not p21. TAT-RasGAP 317-326 did not affect PUMA levels, however, but increased genotoxin-induced mitochondrial depolarization and caspase-3 activation. These results indicate that TAT-RasGAP 317-326 sensitizes tumor cells by activating signals that intersect with the p53 pathway downstream of, or at the level of, proapoptotic p53 target gene products to increase the activation of the mitochondrial death pathway. (Mol Cancer Res 2007;5(5):497 -507)

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Section: Tat-rasgap 317-326 -Induced Sensitization Of Tumor Cells Reqmentioning

confidence: 76%

TAT-RasGAP317-326 Requires p53 and PUMA to Sensitize Tumor Cells to Genotoxins

Michod

Widmann

2007

Molecular Cancer Research

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“…Our data for the first time suggest that the bc1 complex, the central component of the oxidative respiratory reaction chain and a center for free radical generation, could be targeted by casp.3. Several mitochondrial membrane proteins such as Bcl-2 and Mcl-1 have been identified to be cleaved by caspases, leading to the conversion of antiapoptosis molecules into a Bax-like death promoter and the permeabilization of outer membrane of mitochondria [42,43]. As a result, activated caspases are able to penetrate into the intermembrane space to cleave cyto.c1 for subsequent mitochondrial catastrophe.…”

Section: Discussionmentioning

confidence: 99%

Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release

Zhu

Wang

et al. 2011

Cell Res

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Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c (cyto.c) release. We discovered that cytochrome c1 (cyto.c1) in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 (casp.3). We found that cyto.c1 was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stresses or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated that this cleavage was closely linked with further cyto.c release and mitochondrial catastrophe. These mitochondrial events could be effectively blocked by expressing non-cleavable cyto.c1 (D106A) or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.c1 represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.

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“…Notch1-mediated regulation of Mcl-1 is independent of several major signaling pathways To elucidate the mechanisms of Notch1-mediated post-translational regulation of Mcl-1 in glioblastomas, we examined the signaling events known to be involved in post-translational regulation of the Mcl-1 protein. 22 First, we tested the involvement of caspase-mediated cleavage 24 and deubiquitination by USP9X 25 in the Notch1-dependent regulation of Mcl-1, but none of these mechanisms were responsible for Mcl-1 protein reduction following Notch1-knockdown (Supplementary Figures S4A and B). Furthermore, we observed activation of GSK3b (glycogen synthase kinase 3b) and JNK (c-Jun N-terminal kinase) after Notch1 downregulation (Supplementary Figure S4C).…”

Section: Elevated Notch1 Expression Is a Feature Of Glioblastomamentioning

confidence: 99%