Activation of Membrane-associated Procaspase-3 Is Regulated by Bcl-2

Krebs, Joseph F.; Armstrong, Robert C.; Srinivasan, Anu; Aja, Teresa; Wong, Angela; Aboy, Aileen; Sayers, Robert D.; Pham, Bryan; Vu, Tam; Hoang, Kim; Karanewsky, Donald S.; Leist, C.; Schmitz, A.; Wu, Joe C.; Tomaselli, Kevin J.; Fritz, Lawrence C.

doi:10.1083/jcb.144.5.915

Cited by 57 publications

(42 citation statements)

References 56 publications

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“…Thus, COX-2 expression may interfere with the maintenance of Bcl-2 and Bcl-x L patterns of expression in WT livers, perhaps making these livers more susceptible to apoptosis. Bcl-2 controls cytoplasmic events in part by blocking the activation of membrane-associated procaspases (50). Indeed, in our settings, caspase-3 activation was significantly reduced in COX-2 Ϫ/Ϫ livers as compared with control littermates after I/R injury, and it was accompanied by a reduced number of TUNEL-positive cells observed in the COX-2-deficient livers.…”

Section: Discussionmentioning

confidence: 53%

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

Hamada

Tsuchihashi

Avanesyan

et al. 2008

The Journal of Immunology

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Cyclooxygenase-2 (COX-2) is a prostanoid-synthesizing enzyme that is critically implicated in a variety of pathophysiological processes. Using a COX-2-deficient mouse model, we present data that suggest that COX-2 has an active role in liver ischemia/reperfusion (I/R) injury. We demonstrate that COX-2-deficient mice had a significant reduction in liver damage after I/R insult. The inability of COX-2−/− to elaborate COX-2 products favored a Th2-type response in these mice. COX-2−/− livers after I/R injury showed significantly decreased levels of IL-2, as well as IL-12, a cytokine known to have a central role in Th1 effector cell differentiation. Moreover, such livers expressed enhanced levels of the anti-inflammatory cytokine IL-10, shifting the balance in favor of a Th2 response in COX-2-deficient mice. The lack of COX-2 expression resulted in decreased levels of CXCL2, a neutrophil-activating chemokine, reduced infiltration of MMP-9-positive neutrophils, and impaired late macrophage activation in livers after I/R injury. Additionally, Bcl-2 and Bcl-xL were normally expressed in COX-2−/− livers after injury, whereas respective wild-type controls were almost depleted of these two inhibitors of cell death. In contrast, caspase-3 activation and TUNEL-positive cells were depressed in COX-2−/− livers. Therefore, our data support the concept that COX-2 is involved in the pathogenic events occurring in liver I/R injury. The data also suggest that potential valuable therapeutic approaches in liver I/R injury may result from further studies aimed at identifying specific COX-2-derived prostanoid pathways.

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Section: Discussionmentioning

confidence: 53%

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

Hamada

Tsuchihashi

Avanesyan

et al. 2008

The Journal of Immunology

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“…30 ± 34 It is believed that these zymogens are released into the cytosol prior to their activation by Cytochrome c and Apaf-1. 30 ± 34 The regulation of the membraneassociated caspase-3 was, however, distinct from that of cytosolic caspase-3; for example, membrane-associated caspase-3 was regulated by Bcl-2 but was insensitive to exogenous Cytochrome c whereas cytoplasmic caspase-3 was directly activated by Cytochrome c. 31 We have also seen a decrease in procaspases-9, -7 and -3 in the HM membrane fraction following exposure to cDDP but a decrease in proform was associated with an increase in processed forms, suggesting that processing of caspases may in fact take place in the membrane fraction. This was substantiated by the increase in DEVD cleavage activity in the HM fraction as well as cleavage of the substrate PKCd.…”

Section: Discussionmentioning

confidence: 99%

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

2001

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We have previously shown that the protein kinase C (PKC) signal transduction pathway regulates cell death by the DNA damaging agent cis-diamminedichloroplatinum(II) (cDDP). In the present study we have investigated how PKC influences the sequence of events that are triggered by cDDP-induced DNA damage. cDDP caused activation of caspases-8, -9, -3, -7 and cleavage of PKCd. Rottlerin, a selective inhibitor of novel PKCd, blocked activation of caspases, proteolytic activation of PKCd and cell death induced by cDDP. In contrast, Go È 6976, an inhibitor of conventional PKCa and bI, did not prevent cDDP-induced caspase activation and cDDP cytotoxicity. In HeLa cells, PKCd was distributed both in the cytosol and heavy membrane (HM) fraction containing mitochondria. While caspase-8 was primarily cytosolic, a small amount of caspases-9, -7 and -3 could be detected in the HM fraction. cDDP caused a time-dependent increase in Cytochrome c release from the mitochondria and processing of both cytosolic and membrane-associated caspases, as well as proteolytic cleavage of PKCd. Rottlerin attenuated late but not early release of Cytochrome c by cDDP. It, however, inhibited activation of caspases and proteolytic cleavage of PKCd in both cytosolic and HM fractions. The antiapoptotic effect of rottlerin was evident when it was added together with or following cDDP addition but not when added after cDDP was removed from the medium. Thus, the PKCd inhibitor acts at an early stage of the cDDP-induced cell death pathway that precedes caspase activation. Cell Death and Differentiation (2001) 8, 899 ± 908.

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“…They documented a diffuse cytosolic staining and a punctate cytosolic staining for caspase-3 expression by IHS using an antibody that recognizes the "uncleaved" form and demonstrated that patients with the diffuse-staining tumor had a significantly poorer prognosis as compared with those with the punctate-staining tumor. Recent studies have revealed that "uncleaved" caspase-3 is present in mitochondria as well as in cytoplasm [27][28][29], and Donoghue et al [18] speculated that punctate staining was seen when caspase-3 was localized in mitochondria. In the present study, we could not distinguish different caspase-3 staining patterns.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer

et al. 2001

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SUMMARY Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death. Whereas many studies on the clinical significance of apoptosis in the therapy of malignant tumors have been reported, little has been studied clinically on caspase-3. In the present study, the clinical significance of caspase-3 expression in resected nonsmall-cell lung cancer (NSCLC) and its correlation with incidence of apoptosis were examined. A total of 118 consecutive patients who had undergone complete resection for pathologic Stage I NSCLC were retrospectively reviewed. Caspase-3 expression was examined immunohistochemically using a polyclonal antibody that recognized uncleaved caspase-3. The 5-year survival rate for patients with strong expression of caspase-3 (66.6%) was significantly lower than that for patients with weak expression (82.1%, P ‫؍‬ 0.021). Expression of caspase-3 was not correlated with incidence of apoptosis, proliferative activity, or p53 status. Multivariate analysis confirmed that strong expression of caspase-3 was a significant factor to predict poor prognosis. These results suggest that enhanced expression of "uncleaved" caspase-3, that is, inactivated caspase-3, was correlated with poor prognosis in resected NSCLC.

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Activation of Membrane-associated Procaspase-3 Is Regulated by Bcl-2

Cited by 57 publications

References 56 publications

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer

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