a Geisel School of Medicine at Dartmouth, Department of Molecular and Systems Biology , Hanover , NH , USA.
Cell Cycle. 2017;16(21):2058-2072. doi: 10.1080/15384101.2017.1338221. Epub 2017 Sep 28.
The regulation of cell cycle progression by steroid hormones and growth factors is important for maintaining normal cellular processes including development and cell proliferation. Deregulated progression through the G1/S and G2/M cell cycle transitions can lead to uncontrolled cell proliferation and cancer. The transcription factor E2F1, a key cell cycle regulator, targets genes encoding proteins that regulate cell cycle progression through the G1/S transition as well as proteins important in DNA repair and apoptosis. E2F1 expression and activity is inhibited by inorganic arsenic (iAs) that has a dual role as a cancer therapeutic and as a toxin that leads to diseases including cancer. An understanding of what underlies this dichotomy will contribute to understanding how to use iAs as a more effective therapeutic and also how to treat cancers that iAs promotes. Here, we show that quiescent breast adenocarcinoma MCF-7 cells treated with 17-β estradiol (E2) progress through the cell cycle, but few cells treated with E2 + iAs progress from G1 into S-phase due to a block in cell cycle progression. Our data support a model in which iAs inhibits the dissociation of E2F1 from the tumor suppressor, retinoblastoma protein (pRB) due to changes in pRB phosphorylation which leads to decreased E2F1 transcriptional activity. These findings present an explanation for how iAs can disrupt cell cycle progression through E2F1-pRB and has implications for how iAs acts as a cancer therapeutic as well as how it may promote tumorigenesis through decreased DNA repair.
甾体激素和生长因子对细胞周期进程的调节对于维持正常细胞过程（包括发育和细胞增殖）非常重要。细胞周期在 G1/S 和 G2/M 转换点的异常进展可导致不受控制的细胞增殖和癌症。转录因子 E2F1 是一种关键的细胞周期调节剂，它靶向编码调节细胞周期在 G1/S 转换点进展的蛋白质的基因，以及在 DNA 修复和细胞凋亡中起重要作用的蛋白质。无机砷（iAs）具有作为癌症治疗剂和导致癌症等疾病的毒素的双重作用，可抑制 E2F1 的表达和活性。了解这种二分法的基础将有助于理解如何更有效地利用 iAs 作为治疗剂，以及如何治疗 iAs 促进的癌症。在这里，我们表明，用 17-β 雌二醇（E2）处理静止的乳腺腺癌 MCF-7 细胞会使其通过细胞周期，但由于细胞周期进展受阻，很少有细胞从 G1 进入 S 期。我们的数据支持这样一种模型，即 iAs 抑制 E2F1 从肿瘤抑制因子视网膜母细胞瘤蛋白（pRB）上解离，这是由于 pRB 磷酸化的变化导致 E2F1 转录活性降低。这些发现为 iAs 如何通过 E2F1-pRB 破坏细胞周期进程提供了一个解释，并对 iAs 如何作为癌症治疗剂以及如何通过降低 DNA 修复来促进肿瘤发生具有重要意义。
