Mitochondrial Translocation of Protein Kinase C δ in Phorbol Ester-induced Cytochrome c Release and Apoptosis

Majumder, Pradip K.; Pandey, Pramod; Sun, Xiangao; Cheng, Keding; Datta, Rakesh; Saxena, Satya; Kharbanda, Surender; Küfe, Donald

doi:10.1074/jbc.c000048200

Cited by 282 publications

(202 citation statements)

References 22 publications

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“…In addition, accumulation of CF-dPKC in the mitochondria is responsible for mitochondrial damage induced by a proteasome inhibitor (Durrant et al, 2004). Furthermore, mitochondrial dPKC triggers cytochrome c release via loss of mitochondrial membrane potential, and thereby activation of caspase-3 (Majumder et al, 2000). Interestingly, release of cytochrome c from the mitochondria was seen as early as 10 mins after CCA release in the current study, which corresponded to the time course of dPKC translocation.…”

Section: Hypothermia Reduces Subcellular Translocation Of Delta Protesupporting

confidence: 61%

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

Shimohata

Zhao

Sung

et al. 2007

J Cereb Blood Flow Metab

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Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (dPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on dPKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of dPKC (CF-dPKC) increased after stroke. Both hypothermia (301C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated dPKC in the penumbra. Other hallmarks of dPKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-dPKC increases in the mitochondria and nuclei. Conversely, a specific dPKC activator, wdRACK, decreased the neuroprotective effect of hypothermia. Finally, dPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of dPKC translocation. Both cytochrome c release and dPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing dPKC activation after stroke.

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Section: Hypothermia Reduces Subcellular Translocation Of Delta Protesupporting

confidence: 61%

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

Shimohata

Zhao

Sung

et al. 2007

J Cereb Blood Flow Metab

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“…It is possible that the early release of mitochondrial cytochrome c activates the caspase cascade, leading in turn to dPKC activation and/or cleavage, which in a negative feedback loop, further hampers mitochondrial function. dPKC translocation to the mitochondria from the cytoplasm has been observed in human U-937 cells when treated with H 2 O 2 (Majumder et al, 2000). This study also hypothesized that mitochondrial targeting by dPKC is required, at least in part, for the apoptotic response of cells to oxidative stress.…”

Section: Newton 2001mentioning

confidence: 64%

Protein Kinase C Delta Cleavage Initiates an Aberrant Signal Transduction Pathway after Cardiac Arrest and Oxygen Glucose Deprivation

Raval

Dave

Prado

et al. 2005

J Cereb Blood Flow Metab

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Protein kinase C (PKC) isozymes have been known to mediate a variety of complex and diverse cellular functions. dPKC has been implicated in mediating apoptosis. Using two models of cerebral ischemia, cardiac arrest in rats and oxygen glucose deprivation (OGD) in organotypic hippocampal slices, we tested whether an ischemic insult promoted dPKC cleavage during the reperfusion and whether the upstream pathway involved release of cytochrome c and caspase 3 cleavage. We showed that cardiac arrest/OGD significantly enhanced dPKC translocation and increased its cleavage at 3 h of reperfusion. Since dPKC is one of the substrates for caspase 3, we next determined caspase 3 activation after cardiac arrest and OGD. The maximum decrease in levels of procaspase 3 was observed at 3 h of reperfusion after cardiac arrest and OGD. We also determined cytochrome c release, since it is upstream of caspase 3 activation. Cytochrome c in cytosol increased at 1 h of reperfusion after cardiac arrest/OGD. Inhibition of either dPKC/caspase 3 during OGD and early reperfusion resulted in neuroprotection in CA1 region of hippocampus. Our results support the deleterious role of dPKC in reperfusion injury. We propose that early cytochrome c release and caspase 3 activation promote dPKC translocation/cleavage.

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“…23 In addition, mitochondrial translocation of PKCd has been associated with apoptotic cell death in several cell types, including keratinocytes, 38 U-937 and MCF-7 cells. 39 Furthermore, PKC activator induced release of Cytochrome c and rottlerin attenuated Cytochrome c release by PKC activators. 39 Rottlerin by itself, however, contributed to a detectable release of Cytochrome c. 39 This is consistent with our observation that rottlerin caused a small release of Cytochrome c even without any cDDP treatment and that it inhibited Cytochrome c release when cells were exposed to cDDP for a prolonged period.…”

Section: Discussionmentioning

confidence: 93%

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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Mitochondrial Translocation of Protein Kinase C δ in Phorbol Ester-induced Cytochrome c Release and Apoptosis

Cited by 282 publications

References 22 publications

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

Protein Kinase C Delta Cleavage Initiates an Aberrant Signal Transduction Pathway after Cardiac Arrest and Oxygen Glucose Deprivation

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

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