The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-γ growth inhibition of human breast carcinoma cell lines
The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-γ growth inhibition of human breast carcinoma cell lines
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DOI：
10.1089/10799900360708623
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发表时间：
2003-09-01
影响因子：
2.3
通讯作者：
Doherty, GM
中科院分区：
文献类型：
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作者：
Yim, JH;Ro, SH;Doherty, GM
干扰素（IFN）调控因子-1 （IRF-1）和IRF-2在许多IFN- γ诱导基因的调控中发挥相反的作用。为了研究ifn - γ对生长影响差异的信号转导途径，我们根据ifn - γ对生长抑制的谱选择了四种人乳腺癌细胞系。ifn - γ显著抑制MDA468的生长，对IRF-1 mRNA有明显的诱导作用，但对IRF-2的诱导作用很小。SKBR3对IRF-1 mRNA的诱导作用较弱，但对IRF-2 mRNA的诱导作用较强。HS578T和MDA436的生长抑制作用和IRF-1/IRF-2诱导作用为中等。免疫染色显示4种细胞系表面受体完整，Stat1易位至细胞核。通过EMSA检测，与生长抑制相关的细胞系间IRF-1和IRF-2结合活性的诱导比值存在显著差异。最后，IRF-1特异性的反义寡核苷酸减弱了MDA436和MDA468中IFN-gamma生长抑制，证实了IRF-1在IFN-gamma生长抑制中的直接作用。诱导IRF-1可以抑制人乳腺癌细胞系的生长，而诱导IRF-2可以相反。IRF-1对IRF-2的相对诱导是ifn - γ反应的关键控制点。
Interferon (IFN) regulatory factor-1 (IRF-1) and IRF-2 play opposing roles in the regulation of many IFN-gamma-inducible genes. To investigate the signal transduction pathway in response to IFN-gamma in light of differences in growth effects, we selected four human breast carcinoma cell lines based on a spectrum of growth inhibition by IFN-gamma. MDA468 growth was markedly inhibited by IFN-gamma, and it showed substantial induction of IRF-1 mRNA but little IRF-2 induction. SKBR3 showed little growth inhibition and little induction of IRF-1 mRNA but significant induction of IRF-2 mRNA. HS578T and MDA436 growth inhibition and IRF-1/IRF-2 induction were intermediate. All four cell lines showed intact receptor at the cell surface and Stat1 translocation to the nucleus by immunostaining. By EMSA, there were marked differences in the induced ratio of IRF-1 and IRF-2 binding activity between the cell lines that correlated with growth inhibition. Finally, antisense oligonucleotides specific for IRF-1 attenuated IFN-gamma growth inhibition in MDA436 and MDA468, confirming the direct role of IRF-1 in IFN-gamma growth inhibition. Induction of IRF-1 causes growth inhibition in human breast cancer cell lines, and induction of IRF-2 can oppose this. The relative induction of IRF-1 to IRF-2 is a critical control point in IFN-gamma response.