School of Medicine, University of Toyama, Toyama 930-0194, Japan.
Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 930-0194, Japan.
Int J Mol Sci. 2021 Oct 27;22(21):11623. doi: 10.3390/ijms222111623.
The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by and its C-terminal truncated form, namely p27*, which is translated from pre-mRNA, is one of the causes of G1 phase arrest caused by SSA treatment. However, the detailed molecular mechanism underlying G1 phase arrest caused by SSA treatment remains to be elucidated. In this study, we found that SSA treatment caused the downregulation of cell cycle regulators, including , , and , at both the mRNA and protein levels. We also found that transcription elongation of the genes was deficient in SSA-treated cells. The overexpression of and in combination with knockout partially suppressed G1 phase arrest caused by SSA treatment. These results suggest that the downregulation of and contribute to the G1 phase arrest induced by SSA treatment, although they do not exclude the involvement of other factors in SSA-induced G1 phase arrest.
强效剪接抑制剂剪接体抑制剂 A(SSA)可抑制 G1 和 G2/M 期的细胞周期进程。我们之前曾报道过,上调由 编码的 p27 细胞周期蛋白依赖性激酶抑制剂及其 C 端截断形式 p27*(由 前体 mRNA 翻译而来)是 SSA 处理引起 G1 期阻滞的原因之一。然而,SSA 处理引起 G1 期阻滞的详细分子机制仍有待阐明。在这项研究中,我们发现 SSA 处理导致细胞周期调节剂,包括 、 、 和 ,在 mRNA 和蛋白质水平上的下调。我们还发现,在 SSA 处理的细胞中,基因的转录延伸存在缺陷。 和 的过表达与 基因敲除相结合,部分抑制了 SSA 处理引起的 G1 期阻滞。这些结果表明, 和 的下调导致 SSA 处理诱导的 G1 期阻滞,但它们不能排除 SSA 诱导的 G1 期阻滞涉及其他因素。