Murai T, Nakagawa Y, Maeda H, Terada K
Department of Biological Evaluation, National Institute of Health Sciences, Osaka Branch, Hoenzaka 1-1-43, Chuo-ku, Osaka 540-0006, Japan.
J Biol Chem. 2001 Mar 2;276(9):6797-806. doi: 10.1074/jbc.M009355200. Epub 2000 Nov 29.
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.
白细胞介素-1（IL-1）通过使A375S2人黑素瘤细胞停滞于细胞周期的G1期和G2期来抑制其生长。在停滞之前，细胞周期蛋白E-Cdk2和细胞周期蛋白B1-Cdc2的激酶活性迅速下降，它们分别对G1-S期和G2-M期的进程至关重要。IL-1迅速增强细胞周期蛋白依赖性激酶抑制剂p21（cip1）的蛋白表达。诱导产生的p21优先与细胞周期蛋白E-Cdk2结合，p21结合的增加与细胞周期蛋白E-Cdk2活性的下降平行。因此，p21可能是细胞周期蛋白E-Cdk2活性抑制和G1期停滞的原因。与细胞周期蛋白B1-Cdc2活性下降同时发生的是，Cdc2的酪氨酸磷酸化增加，这表明无活性的Tyr-15磷酸化形式的Cdc2增加与细胞周期蛋白B1-Cdc2活性下降和G2期停滞有关。此外，我们发现IL-1导致p107迅速去磷酸化，但不导致pRb或p130去磷酸化，而p130的总蛋白水平增加。因此，IL-1可能通过p107和p130途径而非通过pRb发挥其生长停滞作用。
