p38 kinase-dependent and -independent Inhibition of protein kinase C zeta and -alpha regulates nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes.
In articular chondrocytes, nitric oxide (NO) production triggers dedifferentiation and apoptotic cell death that is regulated by the converse functions of two mitogen-activated protein kinase subtypes, extracellular signal-regulated kinase (ERK) and p38 kinase. Since protein kinase C (PKC) transduces signals that influence differentiation, survival, and apoptosis of various cell types, we investigated the roles and underlying molecular mechanisms of action of PKC isoforms in NO-induced dedifferentiation and apoptosis of articular chondrocytes. We report here that among the expressed isoforms, activities of PKCalpha and -zeta were reduced during NO-induced dedifferentiation and apoptosis. Inhibition of PKCalpha activity was independent of NO-induced activation of ERK or p38 kinase and occurred due to blockage of expression. On the other hand, PKCzeta activity was inhibited as a result of NO-induced p38 kinase activation and was observed prior to proteolytic cleavage by a caspase-mediated process to generate enzymatically inactive fragments. Inhibition of PKCalpha or -zeta activities potentiated NO-induced apoptosis, whereas ectopic expression of these isoforms significantly reduced the number of apoptotic cells and blocked dedifferentiation. Ectopic expression of PKCalpha or -zeta did not affect p38 kinase or ERK but inhibited the p53 accumulation and caspase-3 activation that are required for NO-induced apoptosis of chondrocytes. Therefore, our results collectively indicate that p38 kinase-independent and -dependent inhibition of PKCalpha and -zeta, respectively, regulates NO-induced apoptosis and dedifferentiation of articular chondrocytes.
Kim
Song-Ja
SJ
Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Kim
Han-Gyul
HG
Oh
Chun-Do
CD
Hwang
Sang-Gu
SG
Song
Woo-Keun
WK
Yoo
Yung-Joon
YJ
Kang
Shin-Sung
SS
Chun
Jang-Soo
JS
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002358:Cartilage, Articular / Q000166:cytology* / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D017931:DNA Primers; D004789:Enzyme Activation; D006868:Hydrolysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051571:Protein Kinase C-alpha; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta
D053148:Caspase 3; D020169:Caspases; D017931:DNA Primers; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta