scholarly journals Bcr-Abl-Mediated Protection from Apoptosis Downstream of Mitochondrial Cytochrome c Release

2004 ◽  
Vol 24 (23) ◽  
pp. 10289-10299 ◽  
Author(s):  
Paula B. Deming ◽  
Zachary T. Schafer ◽  
Jessica S. Tashker ◽  
Malia B. Potts ◽  
Mohanish Deshmukh ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Cytochrome ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Intact Cells ◽  
Caspase Recruitment Domain ◽  
Distinct Mechanism ◽  
Mitochondrial Cytochrome C

ABSTRACT Bcr-Abl, activated in chronic myelogenous leukemias, is a potent cell death inhibitor. Previous reports have shown that Bcr-Abl prevents apoptosis through inhibition of mitochondrial cytochrome c release. We report here that Bcr-Abl also inhibits caspase activation after the release of cytochrome c. Bcr-Abl inhibited caspase activation by cytochrome c added to cell-free lysates and prevented apoptosis when cytochrome c was microinjected into intact cells. Bcr-Abl acted posttranslationally to prevent the cytochrome c-induced binding of Apaf-1 to procaspase 9. Although Bcr-Abl prevented interaction of endogenous Apaf-1 with the recombinant prodomain of caspase 9, it did not affect the association of endogenous caspase 9 with the isolated Apaf-1 caspase recruitment domain (CARD) or Apaf-1 lacking WD-40 repeats. These data suggest that Apaf-1 recruitment of caspase 9 is faulty in the presence of Bcr-Abl and that cytochrome c/dATP-induced exposure of the Apaf-1 CARD is likely defective. These data provide a novel locus of Bcr-Abl antiapoptotic action and suggest a distinct mechanism of apoptosomal inhibition.

scholarly journals Reperfusion, not simulated ischemia, initiates intrinsic apoptosis injury in chick cardiomyocytes

2003 ◽  
Vol 284 (1) ◽  
pp. H141-H150 ◽  
Author(s):  
Terry L. Vanden Hoek ◽  
Yimin Qin ◽  
Kim Wojcik ◽  
Chang-Qing Li ◽  
Zuo-Hui Shao ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Ischemia Reperfusion ◽  
Mitochondrial Cytochrome ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Nuclear Condensation ◽  
Simulated Ischemia ◽  
Fluoromethyl Ketone ◽  
Mitochondrial Cytochrome C

Although ischemia-reperfusion (I/R) can initiate apoptosis, the timing and contribution of the mitochondrial/cytochrome c apoptosis death pathway to I/R injury is unclear. We studied the timing of cytochrome c release during I/R and whether subsequent caspase activation contributes to reperfusion injury in confluent chick cardiomyocytes. One-hour simulated ischemia followed by 3-h reperfusion resulted in significant cell death, with most cell death evident during the reperfusion phase and demonstrating mitochondrial cytochrome c release within 5 min after reperfusion. By contrast, cells exposed to prolonged ischemia for 4 h had only marginally increased cell death and no detectable cytochrome c release into the cytosol. Caspase activation could not be detected after ischemia only, but it significantly increased after reperfusion. Caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, Ac-Asp-Gln-Thr-Asp-H, or benzyloxycarbonyl-Leu-Glu (Ome)-His-Asp-(Ome)-fluoromethyl ketone given only at reperfusion significantly attenuated cell death and resulted in return of contraction. Antixoxidants decreased cytochrome c release, nuclear condensation, and cell death. These results suggest that reperfusion oxidants initiate cytochrome c release within minutes, and apoptosis within hours, significant enough to increase cell death and contractile dysfunction.

Cytochrome c release into cytosol with subsequent caspase activation during warm ischemia in rat liver

2001 ◽  
Vol 281 (4) ◽  
pp. G1115-G1123 ◽  
Author(s):  
Junpei Soeda ◽  
Shinichi Miyagawa ◽  
Kenji Sano ◽  
Junya Masumoto ◽  
Shun'Ichiro Taniguchi ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Dna Fragmentation ◽  
Warm Ischemia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dependent Manner ◽  
Mitochondrial Cytochrome ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Mitochondrial Cytochrome C

Apoptosis plays an important role in liver ischemia and reperfusion (I/R) injury. However, the molecular basis of apoptosis in I/R injury is poorly understood. The aims of this study were to ascertain when and how apoptotic signal transduction occurs in I/R injury. The apoptotic pathway in rats undergoing 90 min of warm ischemia with reperfusion was compared with that of rats undergoing prolonged ischemia alone. During ischemia, mitochondrial cytochrome c was released into the cytosol in a time-dependent manner in hepatocytes and sinusoidal endothelial cells, and caspase-3 and an inhibitor of caspase-activated DNase were cleaved. However, apoptotic manifestation and DNA fragmentation were not observed. After reperfusion, nuclear condensation, cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, and DNA fragmentation were observed and caspase-8 and Bid cleavage occurred. In contrast, prolonged ischemia alone induced necrosis rather than apoptosis. In summary, our results show that release of mitochondrial cytochrome c and caspase activation proceed during ischemia, although apoptosis is manifested after reperfusion.

scholarly journals Saussurea lappa Exhibits Anti-Oncogenic Effect in Hepatocellular Carcinoma, HepG2 Cancer Cell Line by Bcl-2 Mediated Apoptotic Pathway and Mitochondrial Cytochrome C Release

2021 ◽  
Vol 43 (2) ◽  
pp. 1114-1132
Author(s):  
Amal A. Alotaibi ◽  
Asmatanzeem Bepari ◽  
Rasha Assad Assiri ◽  
Shaik Kalimulla Niazi ◽  
Sreenivasa Nayaka ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cell ◽  
Mitochondrial Cytochrome ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Important Species ◽  
Saussurea Lappa ◽  
Butanol Extract ◽  
Mitochondrial Cytochrome C

Background and Objectives: Saussurea lappa (S. lappa) is an important species of the Asteraceae family with several purposes in traditional medicine. This study intended to explore the cytotoxic effect of S. lappa on HepG2 cancer cell proliferation. Materials and Methods: The effects of an S. lappa n-butanol extract on the induction of apoptosis were investigated by flow cytometry and mitochondrial cytochrome C-releasing apoptosis assay. Additionally, real-time PCR was employed to confirm apoptosis initiation. Further, qualitative estimation of the active constituent of S. lappa was done by gas chromatography–mass spectroscopy (GC–MS). Results: The cell viability study revealed that the n-butanol extract of S. lappa demonstrated potent cytotoxicity against HepG2 cancer cells, with an IC50 value of 56.76 μg/mL. Cell morphology with dual staining of acridine orange (AO)-ethidium bromide (EB) showed an increase in orange/red nuclei due to cell death by S. lappa n-butanol extract compared to control cells. Apoptosis, as the mode of cell death, was also confirmed by the higher release of cytochrome C from mitochondria, the increased expression of caspase-3 and bax, along with down regulation of Bcl-2. Conclusion: These findings conclude that S. lappa is a cause of hepatic cancer cell death through apoptosis and a potential natural source suggesting furthermore investigation of its active compounds that are responsible for these observed activities.

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