Ca(2+)/calmodulin-dependent protein kinase (CaM-kinase) inhibitor KN-62 suppresses the activity of mitogen-activated protein kinase (MAPK), c-myc activation and human keratinocyte proliferation.
Autocrine growth of human epidermal keratinocytes can be maintained in subconfluent cell cultures in the absence of exogenous growth factors. We used this culture model to investigate the interactions between the mitogen-activated protein kinase (MAPK) pathway and Ca(2+)/calmodulin-dependent protein kinases (CaM-kinases) in autocrine keratinocyte proliferation. We have previously demonstrated that MAPK and protein kinase C (PKC) are both involved in keratinocyte proliferation in a complex set of interactions. Treatment of keratinocytes with PD98059, a potent inhibitor of MAPK kinase, inhibited the MAPK pathway, c-myc activation and autocrine keratinocyte proliferation. Application of the CaM-kinase inhibitor KN-62 also led to a strong inhibition of MAPK/c-myc activation and autocrine keratinocyte proliferation. Other inhibitors, such as wortmannin (selective and potent inhibitor of phosphatidylinositol 3-kinase) and AG 490 (JAK2 inhibitor) had weak effects on autocrine keratinocyte proliferation, MAPK and c-myc activation. Our results clearly demonstrate a crosstalk between CaM-kinase/MAPK pathways in transducing keratinocyte proliferation stimuli.
Praskova
M
M
Department of Biochemistry, University of Medicine, Zdrave 2 str., 1431 Sofia, Bulgaria.
Kalenderova
S
S
Miteva
L
L
Poumay
Y
Y
Mitev
V
V
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016271:Proto-Oncogene Proteins c-myc; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one