Effects of the CDK-inhibitor CYC202 on p38 MAPK, ERK1/2 and c-Myc activities in papillomavirus type 16 E6- and E7-transformed human keratinocytes.
In the present study, we have investigated the effect of the chemical CDK-inhibitor CYC202 on E6 and E7-transformed keratinocytes, in which the function of the cellular cell cycle inhibitor p21Cip1 is abrogated by the viral genes. The cyto-toxicity and the inhibition of the cell growth were analysed by MTT assay and analysis of DNA synthesis respectively. The effect on some signalling molecules was tested by Western blot analysis. CYC202 effectively inhibited the proliferation of E6 and E7 keratinocytes in a dose-dependent manner. Treatment with CYC202 strongly increased the activity of p38 MAP kinase. Furthermore, it inhibited ERK1/2 at the highest concentration used and had no effect on the activity of JNK1/2. CYC202 also increased the phosphorylation of HSP27 and decreased the phosphorylation and DNA-binding activity of the transcriptional regulator c-Myc, in correlation with the corresponding upstream kinases p38 MAPK and ERK1/2. Our results provide additional data for the anti-proliferative actions and potency of the chemical CDK-inhibitor CYC202.
Atanasova
Ganka N
GN
Department of Chemistry, Medical University of Sofia, 1431 Sofia, Bulgaria.
Isaeva
Antonia R
AR
Zhelev
Nikolai
N
Poumay
Yves
Y
Mitev
Vanyo I
VI
D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured / Q000187:drug effects / Q000821:virology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D012097:Repressor Proteins / Q000502:physiology*; D000077546:Roscovitine; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*