Proteolytic activation of proapoptotic kinase PKCdelta is regulated by overexpression of Bcl-2: implications for oxidative stress and environmental factors in Parkinson's disease.
We previously demonstrated that the organochlorine pesticide dieldrin, a potential chemical risk factor for development of Parkinson's disease (PD), impairs mitochondrial function and promotes apoptosis in dopaminergic PC12 cells. We further demonstrated that caspase-3-dependent proteolytic activation of a member of the novel PKC family, protein kinase Cdelta (PKCdelta), contributes to apoptotic cell death in dopaminergic cells. In the present study, we report that the proapoptotic function of PKCdelta can be regulated by overexpression of the mitochondrial anti-apoptotic protein Bcl2 in dieldrin-treated dopaminergic cells. Exposure to dieldrin (30 or 100 micro M) for 3 h produced a dose-dependent increase in caspase-3 activation and DNA fragmentation in vector-transfected PC12 cells. Overexpression of human Bcl-2 in PC12 cells completely suppressed dieldrin-induced caspase-3 activation and DNA fragmentation. Furthermore, dieldrin-induced proteolytic activation of PKCdelta was also remarkably reduced in Bcl-2-overexpressed cells. Together, these results suggest that the proapoptotic function of PKCdelta can be regulated by mitochondrial redox modulators during neurodegenerative processes.
Kanthasamy
A G
AG
Department of Biomedical Sciences Iowa State University, Ames, Iowa 50011, USA. akanthas@iastate.edu
Kitazawa
M
M
Kaul
S
S
Yang
Y
Y
Lahiri
D K
DK
Anantharam
V
V
Kanthasamy
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D004026:Dieldrin / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D005822:Genetic Vectors; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014162:Transfection
D019253:Proto-Oncogene Proteins c-bcl-2; C087857:protein kinase C gamma; D011493:Protein Kinase C; D010450:Endopeptidases; D004026:Dieldrin