A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate
A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate
复制标题
DOI：
10.4161/cc.5.14.2913
复制
发表时间：
2006-07-15
期刊：
影响因子：
4.3
通讯作者：
Gottesfeld, Joel M.
中科院分区：
文献类型：
--
作者：
Alvarez, David;Chou, C. James;Gottesfeld, Joel M.
一种聚酰胺-氯苯丁腈偶联物(1R-Chl)可将多种人类癌细胞株阻断在细胞周期的G(2)/M期，并下调组蛋白H4c基因的表达。然而，针对H4c基因的siRNA导致G(1)/S阻滞。在这里，我们报告1R-Chl在G(2)/M阻滞之前下调H4c。G(2)/M停滞是1R-Ch1广泛DNA损伤的结果，导致丝氨酸139处的H_2A.X的磷酸化，Nbs1修复蛋白的募集，以及一系列未知事件的级联，最终导致酪氨酸15处的cdc2磷酸化和cdc2激酶活性的丧失。对照聚酰胺-Chl结合物既不与H4c基因结合，也不本身具有抗增殖作用，当细胞用针对H3或H4c的siRNA处理时，它会导致G(2)/M停滞。
A polyamide-chlorambucil conjugate (1R-Chl) arrests a wide range of human cancer cell lines at the G(2)/M phase of the cell cycle and downregulates histone H4c gene expression. However, an siRNA against H4c mRNA causes G(1)/S arrest. Here, we report that 1R-Chl downregulates H4c prior to G(2)/M arrest. G(2)/M arrest is the result of extensive DNA damage by 1R-Chl, which leads to phosphorylation of H2A.X at serine 139, recruitment of the Nbs1 repair protein, and a cascade of unknown events culminating with cdc2 phosphorylation at tyrosine 15 and abolishment of cdc2 kinase activity. A control polyamide-Chl conjugate, which neither binds to the H4c gene nor has an anti-proliferative effect by itself, causes G(2)/M arrest when cells are treated with siRNAs specific for H3 or H4c.