Arora T, Jelinek D F
Department of Immunology, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA.
J Biol Chem. 1998 May 8;273(19):11799-805. doi: 10.1074/jbc.273.19.11799.
Interferon-alpha (IFN-alpha) has been used as therapy for the treatment of a variety of viral diseases and malignancies including multiple myeloma. The effectiveness of interferon-alpha in treating multiple myeloma, however, has been somewhat variable, and the mechanism(s) accounting for this is not well understood. As a means to examine the basis for the differential effectiveness of this cytokine, we have analyzed IFN-alpha-mediated modulation of the cell cycle in two human myeloma cell lines. These two cell lines, ANBL-6 and KAS-6/1, display dramatically different outcomes in response to this cytokine. Although IFN-alpha inhibited the growth of ANBL-6 cells by blocking cell cycle progression from G0/G1 to S phase, IFN-alpha stimulated cell cycle progression in KAS-6/1 cells. Moreover, the effects of IFN-alpha on cell cycle progression correlated with the phosphorylation status of the retinoblastoma protein. Of interest, IFN-alpha increased cyclin D2 expression and cyclin-dependent kinase activity in the KAS-6/1 cells but not in the ANBL-6 cells. To determine whether the differential effects of IFN-alpha on myeloma cell cycle progression could also result from differences in the expression of cyclin-dependent kinase inhibitors, we examined the effects of IFN-alpha on the induction of cyclin-dependent kinase inhibitors with broad regulatory function (p21 and p27) and those with specificity for G1-associated cyclin-cyclin-dependent kinase complexes (p15, p16, p18, and p19). Although we failed to detect an effect of IFN-alpha on expression levels of p21, p15, p16, or p18, IFN-alpha treatment of the ANBL-6 cell line resulted in induction of p19 expression, whereas it was without effect on the KAS-6/1 cell line. These results suggest that heterogeneity in IFN-alpha-mediated growth effects in myeloma cells correlates with differential induction of cyclin D2 and p19(INK4d) expression.
α干扰素（IFN-α）已被用作治疗多种病毒性疾病和恶性肿瘤（包括多发性骨髓瘤）的疗法。然而，α干扰素治疗多发性骨髓瘤的有效性存在一定差异，其背后的机制尚未完全明确。为了探究这种细胞因子疗效差异的基础，我们分析了α干扰素对两个人骨髓瘤细胞系细胞周期的调节作用。这两个细胞系，ANBL-6和KAS-6/1，对这种细胞因子的反应呈现出显著不同的结果。虽然α干扰素通过阻断细胞周期从G0/G1期向S期的进展来抑制ANBL-6细胞的生长，但α干扰素却刺激了KAS-6/1细胞的细胞周期进程。此外，α干扰素对细胞周期进程的影响与视网膜母细胞瘤蛋白的磷酸化状态相关。有趣的是，α干扰素增加了KAS-6/1细胞中细胞周期蛋白D2的表达和细胞周期蛋白依赖性激酶活性，但在ANBL-6细胞中却没有。为了确定α干扰素对骨髓瘤细胞周期进程的不同影响是否也源于细胞周期蛋白依赖性激酶抑制剂表达的差异，我们研究了α干扰素对具有广泛调节功能的细胞周期蛋白依赖性激酶抑制剂（p21和p27）以及对G1相关细胞周期蛋白 - 细胞周期蛋白依赖性激酶复合物具有特异性的抑制剂（p15、p16、p18和p19）诱导的影响。虽然我们未能检测到α干扰素对p21、p15、p16或p18表达水平的影响，但α干扰素处理ANBL-6细胞系会导致p19表达的诱导，而对KAS-6/1细胞系则无影响。这些结果表明，α干扰素介导的骨髓瘤细胞生长效应的异质性与细胞周期蛋白D2和p19（INK4d）表达的差异诱导相关。
