Involvement of protein kinase C in crystalline silica-induced activation of the MAP kinase and AP-1 pathway.
Crystalline silica has long been well established as a fibrogenic agent, and recent evidence has implicated it as a potential human carcinogen. However, the mechanisms of silica-induced disease development and progression are not well understood. Our previous studies demonstrated that crystalline silica is able to activate activator protein-1 (AP-1) through mitogen-activated protein kinase (MAPK) pathways. The present study investigates the possible involvement of protein kinase C (PKC) in silica-induced activation of the MAPK/AP-1 signal transduction pathway. Treatment of mouse epidermal cells (JB6 cell line) with freshly fractured silica stimulated translocation of PKCalpha and PKCepsilon from the cytosol to the membrane and activated AP-1 transcription activity. Pretreatment of cells with PKC inhibitors, including RO-32-0432, calphostin C, and bisindolylmaleimide I, inhibited silica-induced AP-1 activation and phosphorylation of ERKs and p38 kinase. These inhibitory effects by PKC inhibitors were dose dependent. Furthermore, overexpression of dominant negative mutant (DNM) of PKCalpha or PKCepsilon markedly blocked AP-1 activation as well as phosphorylation of ERKs and p38 kinase induced by freshly fractured silica. These results demonstrate that PKCalpha and PKCepsilon are essential in silica-induced AP-1 activation through the MAP kinase (ERKs and p38 kinases) pathway.
Ding
Min
M
Pathology and Physiology Research Branch, NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505, USA. mid5@cdc.gov
Huang
Chuanshu
C
Lu
Yongju
Y
Bowman
Linda
L
Castranova
Vince
V
Vallyathan
Val
V
D000818:Animals; D002460:Cell Line; D003460:Crystallization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D012822:Silicon Dioxide / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000502:physiology; D014162:Transfection
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009281:Naphthalenes; D011758:Pyrroles; D018808:Transcription Factor AP-1; C085989:Ro 32-0432; D012822:Silicon Dioxide; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; C058819:calphostin C; C070515:bisindolylmaleimide I