AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells
AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells
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DOI：
10.4161/cc.8.10.8547
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发表时间：
2009-05-15
期刊：
影响因子：
4.3
通讯作者：
Ceryak, Susan
中科院分区：
文献类型：
--
作者：
Lal, Madhu A.;Bae, Dongsoon;Ceryak, Susan
某些形式的六价铬[Cr（VI）]是人类致癌物。我们最近的工作表明，广泛的蛋白酪氨酸磷酸酶（PTP）抑制剂，原钒酸钠（SOV），废除铬（VI）诱导的生长停滞和克隆致死。值得注意的是，SOV增强了Cr（VI）突变频率，表面上是通过强迫遗传受损细胞存活。在本研究中，与这种PTP抑制剂的共同治疗绕过了Cr（VI）诱导的二倍体人肺成纤维细胞（HLF）的G（1）/S检查点阻滞。此外，PTP抑制剂消除了Cr（VI）诱导的G（1）/S检查点关键效应物表达的降低[细胞周期蛋白D1，磷酸化Ser 807/811 Rb（pRB），p27]。Cr（VI）诱导的G（1）阻滞与pRb的胞质外观和p27的核定位有关，这两者都被PTP抑制剂逆转。PTP抑制剂对Cr暴露后G（1）/S检查点效应子定位的逆转被发现是Akt 1依赖性的，因为这被Akt 1 siRNA或Akt 1激酶死亡质粒转染所废除。此外，单独激活Akt 1足以诱导G（1）/S检查点旁路，并阻止Cr（VI）诱导的pRb和p27定位变化。总之，这项工作建立了Akt 1激活，足以绕过Cr（VI）诱导的G（1）/S检查点，以及所观察到的PTP抑制剂对G1/S转换的关键介质的影响。Akt在面对基因毒性损伤时绕过G（1）/S检查点阻滞的可能性可能会增加基因组不稳定性，这是肿瘤进展的标志。
Certain forms of hexavalent chromium [Cr(VI)] are human carcinogens. Our recent work has shown that a broad range protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SOV), abrogated both Cr(VI)-induced growth arrest and clonogenic lethality. Notably, SOV enhanced Cr(VI) mutation frequency, ostensibly through forced survival of genetically damaged cells. In the present study, co-treatment with this PTP inhibitor bypassed the Cr(VI)- induced G(1)/S checkpoint arrest in diploid human lung fibroblasts (HLF). Moreover, the PTP inhibitor abrogated the Cr(VI)- induced decrease in the expression of key effectors of the G(1)/S checkpoint [Cyclin D1, phospho Ser 807/811 Rb (pRB), p27]. Cr(VI)- induced G(1) arrest was associated with the cytoplasmic appearance of pRb and the nuclear localization of p27, both of which were reversed by the PTP inhibitor. The PTP inhibitor's reversal of G(1)/S checkpoint effector localization after Cr exposure was found to be Akt1-dependent, as this was abrogated by transfection with either akt1 siRNA or an Akt1-kinase dead plasmid. Furthermore, Akt1 activation alone was sufficient to induce G(1)/S checkpoint bypass and to prevent Cr(VI)- induced changes in pRb and p27 localization. In conclusion, this work establishes Akt1 activation to be both sufficient to bypass the Cr(VI)- induced G(1)/S checkpoint, as well as necessary for the observed PTP inhibitor effects on key mediators of the G1/S transition. The potential for Akt to bypass G(1)/S checkpoint arrest in the face of genotoxic damage could increase genomic instability, which is a hallmark of neoplastic progression.