Tarakanova Vera L, Wold William S M
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
J Virol. 2003 Sep;77(17):9324-36. doi: 10.1128/jvi.77.17.9324-9336.2003.
Transforming growth factor beta1 (TGF-beta1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a "tumor-like" state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-beta1 signaling is inhibited. The levels of TGF-beta1 receptor II (TbetaRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TbetaRII protein was accompanied by a decrease in TbetaRII mRNA. The decrease in TbetaRII protein levels in adenovirus-infected cells was greater than the decrease in TbetaRII mRNA, suggesting that downregulation of the TbetaRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TbetaRII protein in infected and uninfected cells were similar. TGF-beta1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-beta-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TbetaRII downregulation did not inhibit TGF-beta1 signaling. TGF-beta1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-beta signaling pathway. These results raise the possibility that inhibition of TGF-beta signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.
转化生长因子β1（TGF-β1）信号传导在许多肿瘤中受损，从而使肿瘤能够逃避该细胞因子的生长抑制和促凋亡活性。人腺病毒干扰多种参与细胞周期调控和凋亡的细胞途径，最初通过迫使静止细胞进入细胞周期并抑制凋亡，使细胞处于“肿瘤样”状态。我们报告腺病毒感染的细胞类似于肿瘤细胞，因为TGF-β1信号传导受到抑制。腺病毒感染细胞中TGF-β1受体II（TβRII）的水平降低，通过使用病毒突变体将这种降低定位到E1A基因以及E1A蛋白中的第2至36位氨基酸和C末端结合蛋白结合位点。TβRII蛋白的减少伴随着TβRII mRNA的减少。腺病毒感染细胞中TβRII蛋白水平的降低大于TβRII mRNA的降低，这表明TβRII蛋白的下调可能通过多种机制发生。令人惊讶的是，在这种情况下，感染和未感染细胞中TβRII蛋白的半衰期相似。用3TP-lux（一种表达荧光素酶的TGF-β敏感报告质粒）测量，野生型腺病毒感染的细胞中TGF-β1信号传导受损。缺乏TβRII下调的腺病毒突变体不抑制TGF-β1信号传导。TGF-β1预处理降低了感染细胞中腺病毒结构蛋白的相对丰度，当细胞用不能调节TGF-β信号通路的突变体感染时，这种作用会增强。这些结果增加了E1A抑制TGF-β信号传导是腺病毒对抗宿主抗病毒防御的一种手段的可能性。
