Altered regulation of cell cycle machinery involved in interleukin-1-induced G(1) and G(2) phase growth arrest of A375S2 human melanoma cells.
Interleukin-1 (IL-1) inhibits the growth of A375S2 human melanoma cells by arresting them at G(1) and G(2) phases of the cell cycle. The arrests are preceded by a rapid decrease in kinase activities of cyclin E-Cdk2 and cyclin B1-Cdc2, which are critical for G(1)-S and G(2)-M progression, respectively. IL-1 quickly enhances the protein expression of the CDK inhibitor p21(cip1). The induced p21 binds preferentially to cyclin E-Cdk2, and the increase in p21 binding parallels the decrease in cyclin E-Cdk2 activity. Thus, p21 is likely to be responsible for the inhibition of cyclin E-Cdk2 activity and G(1) arrest. Coinciding with the decrease in cyclin B1-Cdc2 activity, there is an increase in tyrosine phosphorylation of Cdc2, suggesting that an increase in the inactive Tyr-15-phosphorylated form of Cdc2 is involved in the decrease in cyclin B1-Cdc2 activity and G(2) arrest. Furthermore, we found that IL-1 causes rapid dephosphorylation of p107, but not of pRb or p130, while the total protein levels of p130 are increased. Thus, IL-1 may exert its growth-arresting effects via p107 and p130 pathways rather than through pRb.
Murai
T
T
Department of Biological Evaluation, National Institute of Health Sciences, Osaka Branch, Hoenzaka 1-1-43, Chuo-ku, Osaka 540-0006, Japan. murai@nihs.go.jp
Nakagawa
Y
Y
Maeda
H
H
Terada
K
K
D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000378:metabolism; D016213:Cyclins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007375:Interleukin-1; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D018844:Cyclin-Dependent Kinases