Partial Cleavage of RasGAP by Caspases Is Required for Cell Survival in Mild Stress Conditions

Yang, Jiang-Yan; Michod, David; Walicki, Joël; Murphy, Brona M.; Kasibhatla, Shailaja; Martin, Séamus J.; Widmann, Christian

doi:10.1128/mcb.24.23.10425-10436.2004

Cited by 82 publications

(107 citation statements)

References 59 publications

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“…The Ras GTPase-activating protein (RasGAP) protein is cleaved at several sites by caspase-3, with the first cleavage occurring soon during apoptosis and favoring the second one. 33,34 The first cleavage allows generation of an anti-apoptotic fragment, whereas the second cleavage converts it in smaller proapoptotic fragments. In this instance, sequential cleavage supports a model in which RasGAP functions as a sensor of caspase activity to determine whether cell will survive or not.…”

Section: Discussionmentioning

confidence: 99%

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

et al. 2006

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Activation of the MET tyrosine kinase receptor by hepatocyte growth factor/scatter factor is classically associated with cell survival. Nonetheless, stress stimuli can lead to a caspase-dependent cleavage of MET within its juxtamembrane region, which generate a proapoptotic 40 kDa fragment (p40 MET). We report here that p40 MET is in fact generated through an additional caspase cleavage of MET within its extreme C-terminal region, which removes only few amino acids. We evidenced a hierarchical organization of these cleavages, with the C-terminal cleavage favoring the juxtamembrane one. As a functional consequence, the removal of the last amino acids of p40 MET increases its apoptotic capacity. Finally, cells expressing a MET receptor mutated at the C-terminal caspase site are unable to generate p40 MET and are resistant to apoptosis, indicating that generation of p40 MET amplifies apoptosis. These results revealed a two-step caspase cleavage of MET resulting in the reshaping of this survival receptor to a proapoptotic factor.

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Section: Discussionmentioning

confidence: 99%

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

et al. 2006

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“…RasGAP has first been identified as a Ras regulator (38), but this protein has also been shown to bear two caspase-3 cleavage sites and cleaved during apoptosis (2,3,5). The NH 2 -terminal fragment resulting from the first cleavage event on RasGAP (called fragment N; ref.…”

Section: Discussionmentioning

confidence: 99%

“…Lentiviruses were produced as described (5). Lentivirus-containing supernatants were collected 36 h after transfection, 0.45 Am filtered, and frozen at À80jC.…”

Section: Lentiviral Infectionmentioning

confidence: 99%

“…At low levels of caspase activity, RasGAP is cleaved into two fragments (4). The NH 2 -terminal fragment (fragment N) seems to be a general blocker of apoptosis downstream of caspase activation and is in fact crucially required for the survival of stressed cells (5). At higher levels of caspase activity, fragment N is further cleaved into fragments N1 and N2, abrogating its antiapoptotic activity (4,6).…”

Section: Introductionmentioning

confidence: 99%

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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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“…SH domains of p120-GAP function as effectors by associating with several tyrosine-phosphorylated proteins [5], which induce Ras-dependent gene expression [6] and repress adhesion [7]. In addition, p120-GAP is involved in Ras transformation [8,9], cell survival [10,11,12] tumor cell invasion [13], and v-Src-induced cytoskeletal disruption [14]. Based on these findings, p120-GAP proteins show promise as a target for anticancer approaches [11].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of ras-GAP genes is reversed by a MEK inhibitor and doxorubicin in v-Ki-ras-transformed NIH/3T3 fibroblasts

Hashii

Fukuda

Nomura

et al. 2007

Biochemical and Biophysical Research Communications

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Partial Cleavage of RasGAP by Caspases Is Required for Cell Survival in Mild Stress Conditions

Cited by 82 publications

References 59 publications

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

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

Up-regulation of ras-GAP genes is reversed by a MEK inhibitor and doxorubicin in v-Ki-ras-transformed NIH/3T3 fibroblasts

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