PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis.
The protein kinase C (PKC) family of serine/threonine kinases regulates diverse cellular function, including cell death, proliferation and survival. In particular, PKC delta governs the cellular homeostatic response against hypoxic stress. Autophagy, a lysosome-dependent degradative pathway, and apoptosis are two fundamental cellular pathways that respond to stress conditions, such as hypoxia, oxidative stress and nutrient starvation. Recently, we uncovered a novel role for PKC delta in the early stage of hypoxic response where PKC delta activates autophagy by promoting JNK1-mediated Bcl-2 phosphorylation and dissociation of the Bcl-2/Beclin 1 complex. Whereas acute hypoxic stress promotes autophagy, we have previously reported that prolonged hypoxic stress caused the cleavage of PKC delta by caspase-3, resulting in the nuclear translocation of a constitutively active catalytic fragment of PKC delta, PKC delta-CF. Moreover, PKC delta-CF also serves a feed-forward function for the reciprocal PKC delta and caspase-3 proteolytic activation. Here, we discussed the requirement for PKC delta and JNK1 for hypoxia-induced autophagy, and the kinetic relationship among Bcl-2/Beclin 1 interaction, caspase-3 activation and the steady-state level of Beclin 1 during hypoxic exposure. Based on these results, we propose a model for understanding the PKC delta-dependent crosstalk mechanisms between autophagy and apoptosis, both induced by hypoxic stress. These findings collectively support a pivotal role for PKC delta in regulating hypoxic stress with hitherto unappreciated significance.
Chen
Jo-Lin
JL
Department of Clinical and Molecular Pharmacology, City of Hope National Medical Center, Duarte, California 91010, USA.
Lin
H Helen
HH
Kim
Kwang-Jin
KJ
Lin
Anning
A
Ou
J-H James
JH
Ann
David K
DK
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1; D015687:Cell Hypoxia; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011506:Proteins; D051745:Protein Kinase C-delta; D048055:Mitogen-Activated Protein Kinase 8