Contribution of extracellular signal-regulated kinases to the IL-1-induced growth inhibition of human melanoma cells A375.
The role of ERK1/2 in the IL-1-induced growth inhibition was investigated using human melanoma A375-6 cells. A selective inhibitor of ERK1/2 pathway, PD98059 and a selective inhibitor of p38MAPK, SB203580 each alone significantly reversed the IL-1-induced growth inhibition of A375-6 cells. Co-treatment with PD98059 and SB203580 completely reversed the IL-1-induced growth inhibition. ERK1/2 was constitutively activated in A375-6 cells, and IL-1 further augmented ERK activation. Antiproliferative effect of IL-1 was attenuated by the expression of dominant negative form of ERK2. IL-1 induced cell cycle arrest in G(0)/G(1) phase, expression of p21 and p27 proteins, and down-regulation of cyclin D/cyclin-dependent kinase (CDK) 2 and CDK4 activities. These effects of IL-1 were reversed by PD98059. PD98059 also reversed the IL-1-induced hypophosphorylation of RB protein (pRB) and down-regulation of E2F activity. These findings demonstrate that ERK1/2 contribute to the IL-1-induced growth inhibition through induction of CDK inhibitors, down-regulation of CDK activity, pRB phosphorylation and E2F activity.
Arakawa
Tomohiro
T
Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho 3-1, Nagoya 467-8603, Japan.
Yamamura
Takanori
T
Hattori
Takayuki
T
Hayashi
Hidetoshi
H
Mori
Akiko
A
Yoshida
Ayako
A
Uchida
Chiharu
C
Kitagawa
Masatoshi
M
Onozaki
Kikuo
K
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D005419:Flavonoids; D006131:Growth Inhibitors; D007375:Interleukin-1; D047428:Protein Kinase Inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one