Inhibition of atypical PKC blocks ultraviolet-induced AP-1 activation by specifically inhibiting ERKs activation.
Since ultraviolet (UV) radiation is a major etiologic factor in the development of human skin cancers, investigating the signal transduction pathways initiated by UV radiation may help with the understanding of the molecular mechanisms of UV-induced carcinogenesis. Our previous studies demonstrated that UV-induced activator protein-1 (AP-1) activation is blocked by dominant negative atypical PKCs (aPKCs). Here we investigated the role of aPKC in UV-induced activation of mitogen activated protein (MAP) kinase family members which are considered to be the mediators of AP-1 activation. We found that UV radiation led to translocation of protein kinase C (PKC) zeta and activation of MAP kinase family members as well as an increase of AP-1-dependent transcription activation at the same dose range. Pretreatment of cells or mouse skin with antisense oligonucleotides of PKCzeta impaired UV-induced activation of AP-1 in JB6 cells as well as in AP-1-luciferase transgenic mice. It also inhibited UV-induced activation of ERKs but not of JNK and p38 kinases in JB6 cells. In contrast, no significant inhibition of AP-1 activation and MAP kinase activation were observed in cells treated with sense oligonucleotides of PKCzeta. Furthermore, overexpression of a dominant negative mutant of PKClambda/iota specifically inhibited activation of extracellular signal-regulated protein kinases (ERKs) but not of c-jun N-terminal kinases (JNKs) nor p38 kinases induced by UV radiation. These results demonstrated that inhibition of aPKC impairs UV-induced AP-1 activation via suppression of ERKs activation but not of JNKs or p38 kinase activation.
Huang
C
C
The Hormel Institute, University of Minnesota, Austin 55912, USA.
Li
J
J
Chen
N
N
Ma
W
W
Bowden
G T
GT
Dong
Z
Z
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004790:Enzyme Induction / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000528:radiation effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D011493:Protein Kinase C; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C115015:PKC-3 protein