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result sql = Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation.

Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation.

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char = l;code = 108
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char = p;code = 112
char = a;code = 97
char = s;code = 115
char = e;code = 101
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char = l;code = 108
char = o;code = 111
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char = r;code = 114
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char = ;code = 32
char = p;code = 112
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char = t;code = 116
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char = a;code = 97
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char = o;code = 111
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char = e;code = 101
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
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char = r;code = 114
char = s;code = 115
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char = 2;code = 50
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char = a;code = 97
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char = t;code = 116
char = a;code = 97
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char = s;code = 115
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char = t;code = 116
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char = e;code = 101
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char = k;code = 107
char = i;code = 105
char = n;code = 110
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char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = o;code = 111
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char = a;code = 97
char = b;code = 98
char = l;code = 108
char = y;code = 121
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char = M;code = 77
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char = 1;code = 49
char = 3;code = 51
char = 2;code = 50
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char = t;code = 116
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char = e;code = 101
char = a;code = 97
char = t;code = 116
char = m;code = 109
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char = n;code = 110
char = t;code = 116
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char = r;code = 114
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char = s;code = 115
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char = l;code = 108
char = t;code = 116
char = e;code = 101
char = d;code = 100
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char = i;code = 105
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char = t;code = 116
char = r;code = 114
char = a;code = 97
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char = o;code = 111
char = c;code = 99
char = a;code = 97
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char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
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char = e;code = 101
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char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
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char = c;code = 99
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char = a;code = 97
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char = C;code = 67
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char = t;code = 116
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char = m;code = 109
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char = c;code = 99
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char = a;code = 97
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char = t;code = 116
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char = P;code = 80
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char = i;code = 105
char = t;code = 116
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char = o;code = 111
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char = f;code = 102
char = e;code = 101
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char = s;code = 115
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char = O;code = 79
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result sql = Emerging evidence implicates impaired protein degradation by the ubiquitin proteasome system (UPS) in Parkinson's disease; however cellular mechanisms underlying dopaminergic degeneration during proteasomal dysfunction are yet to be characterized. In the present study, we identified that the novel PKC isoform PKCdelta plays a central role in mediating apoptotic cell death following UPS dysfunction in dopaminergic neuronal cells. Inhibition of proteasome function by MG-132 in dopaminergic neuronal cell model (N27 cells) rapidly depolarized mitochondria independent of ROS generation to activate the apoptotic cascade involving cytochrome c release, and caspase-9 and caspase-3 activation. PKCdelta was a key downstream effector of caspase-3 because the kinase was proteolytically cleaved by caspase-3 following exposure to proteasome inhibitors MG-132 or lactacystin, resulting in a persistent increase in the kinase activity. Notably MG-132 treatment resulted in translocation of proteolytically cleaved PKCdelta fragments to mitochondria in a time-dependent fashion, and the PKCdelta inhibition effectively blocked the activation of caspase-9 and caspase-3, indicating that the accumulation of the PKCdelta catalytic fragment in the mitochondrial fraction possibly amplifies mitochondria-mediated apoptosis. Overexpression of the kinase active catalytic fragment of PKCdelta (PKCdelta-CF) but not the regulatory fragment (RF), or mitochondria-targeted expression of PKCdelta-CF triggers caspase-3 activation and apoptosis. Furthermore, inhibition of PKCdelta proteolytic cleavage by a caspase-3 cleavage-resistant mutant (PKCdelta-CRM) or suppression of PKCdelta expression by siRNA significantly attenuated MG-132-induced caspase-9 and -3 activation and DNA fragmentation. Collectively, these results demonstrate that proteolytically activated PKCdelta has a significant feedback regulatory role in amplification of the mitochondria-mediated apoptotic cascade during proteasome dysfunction in dopaminergic neuronal cells.

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