Interleukin-1-induced growth inhibition of human melanoma cells - Interleukin-1-induced antizyme expression is responsible for ornithine decarboxylase activity down-regulation

被引:35
作者
Yang, D [1 ]
Hayashi, H [1 ]
Takii, T [1 ]
Mizutani, Y [1 ]
Inukai, Y [1 ]
Onozaki, K [1 ]
机构
[1] NAGOYA CITY UNIV, FAC PHARMACEUT SCI, DEPT HYG CHEM, MIZUHO KU, NAGOYA, AICHI 467, JAPAN
关键词
D O I
10.1074/jbc.272.6.3376
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interleukin (IL)-1 is a multi-functional cytokine and regulates cell growth either positively or negatively. Previous studies have shown that IL-1-induced ornithine decarboxylase (ODC) activity down-regulation is involved in the anti-proliferative effect of IL-1 on human A375 melanoma cells. In this study, we examined the IL-1 alpha-induced molecular events resulting in ODC activity down-regulation in C2-1, a A375 cell. Line stably transfected with human type I IL-1 receptor, Recombinant human (rh) IL-1 alpha inhibited the growth and down-regulated the ODC activity of C2-1 cells in a dose-dependent manner. Kinetics studies showed that both the DNA synthesis and ODC activity of C2-1 cells progressively decreased horn 12 h after IL-1 addition, Northern hybridization showed that IL-1 had no influence on ODC mRNA level. However, rhIL-1 induced both a decrease of ODC protein and an ODC-inhibiting activity in IL-1-treated C2-1 cells. IL-1 specifically up-modulated the mRNA level of antizyme, a protein essential for ODC regulation, but had little effect on its stability. IL-1-induced antizyme up-modulation preceded IL-1-induced down-regulation of ODC protein, ODC activity, and DNA synthesis in C2-1 cells. Run-on transcription analysis confirmed that the increased antizyme mRNA expression was due to elevated antizyme gene transcription. Furthermore, the action of IL-1 to inhibit the ODC activity and growth of C2-1 cells was blocked by expressing the antisense RNA of human antizyme in C2-1 cells. These results suggest that IL-1-induced antizyme expression is responsible for IL-1-induced ODC activity down-regulation in human melanoma cells.
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页码:3376 / 3383
页数:8
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