Different requirements for the cytostatic and apoptotic effects of type I Interferons - Induction of apoptosis requires ARF but not p53 in osteosarcoma cell lines
Different requirements for the cytostatic and apoptotic effects of type I Interferons - Induction of apoptosis requires ARF but not p53 in osteosarcoma cell lines
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DOI：
10.1074/jbc.m313830200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Colamonici, OR
中科院分区：
文献类型：
--
作者：
Sandoval, R;Xue, JP;Colamonici, OR
细胞生长的调节是I型干扰素（IFN）最重要的作用之一。这种反应可能涉及细胞生长抑制作用或诱导细胞凋亡，这取决于细胞环境。通常在携带肿瘤抑制基因突变的肿瘤细胞系中研究I型IFN的生长抑制反应，因此，生长抑制作用可能会受到这些重要细胞增殖调节因子失活的影响。在这份报告中，我们探讨了ARF-p53通路在I型IFN生长抑制作用中的作用。我们发现p53仅在表达p14（ARF）的细胞中被诱导（在小鼠细胞中为p19（ARF））。令人惊讶的是，小鼠胚胎成纤维细胞是空的p19（ARF）或P53，甚至在转化致癌RAS，响应以及野生型的生长抑制作用的I型IFN。类似地，人ARF（-/-）U2 OS和P53（-/-）SAOS-2细胞显示细胞增殖显著降低。然而，只有SAOS-2或U2 OS重建与诱导型p14（ARF）进行细胞凋亡的IFN β治疗的反应，并没有抑制显性负性p53的表达。这些数据表明：（i）至少在特定的细胞类型中，I型IFN诱导细胞凋亡需要P53非依赖性的ARF途径，（ii）I型IFN的细胞抑制和促细胞凋亡作用采用不同的途径。
The regulation of cell growth is one of the most important effects of type I interferons (IFNs). This response may involve a cytostatic effect or the induction of apoptosis depending on the cell context. Often the growth-inhibitory response of type I IFNs is studied in tumor cell lines carrying mutations of tumor suppressor genes, and therefore, the growth-inhibitory effect can be influenced by inactivation of these important regulators of cell proliferation. In this report, we explored the role of the ARF-p53 pathway in the growth-inhibitory effect of type I IFNs. We found that p53 is only induced in cells that express p14(ARF) (p19(ARF) in mouse cells). Surprisingly, mouse embryonal fibroblasts that are null for p19(ARF) or P53, even after transformation with oncogenic RAS, respond as well as wild type to the growth-inhibitory effect of type I IFNs. Similarly, human ARF(-/-) U2OS and P53(-/-) SAOS-2 cells show a significant decrease in cell proliferation. However, only SAOS-2 or U2OS reconstituted with inducible p14(ARF) undergo apoptosis in response to IFNbeta treatment, and this effect was not inhibited by expression of dominant negative p53. These data suggest that (i) at least in specific cell types, the induction of apoptosis by type I IFNs requires an ARF pathway that is p53-independent and (ii) the cytostatic and pro-apoptotic effects of type I IFNs employ different pathways.