Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells.
The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G(0)/G(1) phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E-Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor.
Kortylewski
M
M
Department of Biochemistry, RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Heinrich
P C
PC
Kauffmann
M E
ME
Böhm
M
M
MacKiewicz
A
A
Behrmann
I
I
D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016160:Retinoblastoma Protein; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one