Characterisation of Mcl‐1 cleavage during apoptosis of haematopoietic cells

Clohessy, John G.; Zhuang, Jianguo; Brady, Hugh J.M.

doi:10.1111/j.1365-2141.2004.04949.x

Cited by 70 publications

(78 citation statements)

References 49 publications

(73 reference statements)

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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: 78%

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: 78%

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

Michod

Widmann

2007

Molecular Cancer Research

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“…Upon activation of caspase-3 in the apoptotic process induced by chemotherapeutic agents, Mcl-1 is cleaved into two fragments: 28 kDa Mcl-1 128-350 and 17 kDa Mcl-1 (34). In contrast to the precursor p42 Mcl-1, p28 Mcl-1 128-350 displays a proapoptotic function (34).…”

Section: Ponatinib Elicits Mcl-1 Downregulation Through Accelerating mentioning

confidence: 99%

“…In contrast to the precursor p42 Mcl-1, p28 Mcl-1 128-350 displays a proapoptotic function (34). To further characterize the effect of caspase-3 on Mcl-1, we exposed mast cells to ponatinib with or without Z-DEVD-fmk (a specific inhibitor of caspase-3).…”

Section: Ponatinib Elicits Mcl-1 Downregulation Through Accelerating mentioning

confidence: 99%

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Jin

Ding

Pan

2014

Molecular Cancer Therapeutics

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Gain-of-function mutations of membrane receptor tyrosine kinase KIT, especially gatekeeper D816V point mutation in KIT, render kinase autoactivation, disease progression, and poor prognosis. D816V KIT is found in approximately 80% of the patients with systemic mastocytosis, and is resistant to the first and second generations of tyrosine kinase inhibitors (TKI). The purpose of this investigation was aimed at exploring whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl, was active against D816V KIT. We discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT-expressing cells in culture and nude mouse xenografted tumor. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of b-catenin at the site Y654, suppressed the translocation of b-catenin, and inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g., AXIN2, c-MYC, and CCND1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive systemic mastocytosis or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinibresistant D814Y KIT. Our findings warrant a clinical trial of ponatinib in patients with systemic mastocytosis harboring D816V KIT. Mol Cancer Ther; 13(5); 1217-30. Ó2014 AACR.

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“…Pharmacologic inhibition of proteasome function by MG-132 failed to abrogate the EXEL-0862-mediated decline of Mcl-1 indicating that downregulation of this protein is mediated by a proteasome-independent mechanism (Figure 6b) cleaved products. 21 The S-19 antibody strongly recognizes the pro-form Mcl-1 and the 28 kDa cleavage products, but not other type of cleavage products. 22 To further explore the mechanism of Mcl-1 degradation, we monitored the expression of Mcl-1 by …”

Section: Exel-0862 Induces Downregulation Of Mcl-1mentioning

confidence: 99%

The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1

et al. 2007

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The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptoralpha (FIP1L1-PDGFR-a) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-a, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-aexpressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-a gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-a-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-a and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinibresistant T674I FIP1L1-PDGFR-a-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-a-positive HES.

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Characterisation of Mcl‐1 cleavage during apoptosis of haematopoietic cells

Cited by 70 publications

References 49 publications

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

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

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1

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