The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair.
The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair.
复制标题
DOI：
10.1016/j.cellsig.2015.05.015
复制
发表时间：
2015-09
影响因子：
4.8
通讯作者：
Tigyi G
中科院分区：
文献类型：
--
作者：
Balogh A;Shimizu Y;Lee SC;Norman DD;Gangwar R;Bavaria M;Moon C;Shukla P;Rao R;Ray R;Naren AP;Banerjee S;Miller DD;Balazs L;Pelus L;Tigyi G
在这项研究中，我们表征了辐射损伤对IEC-6加密细胞和空肠肠内RT-PCR中自动蛋白（ATX）-LPA2 GPCR轴的表达和功能的影响。与CGK-733相关，表明LPA2是DNA损伤反应基因通过NF-κB上调。与媒介物相比，在LPA处理的IEC-6细胞中，暴露于LPA的IEC-6细胞中的分辨率γ-H2AX加速了。迅速增加，而矢量MEF却保持较高并保持抑制作用ERK1和2或PI3K/AKT信号传导轴通过百日咳毒素或LPA2的C末端中的C311A/C314A/L351A突变，这使LPA的效果促使LPA对DNA修复的LPA的影响更高。此外，在骨髓或与WT小鼠相比，辐照的LPA2-KO小鼠的空肠会发现γ辐射会增加血浆ATX活性和LPA水平，部分是由于先前确定的辐射诱导的上调TNFα的上调。
In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to γ-irradiation that was abolished by mutation of the NF-κB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-κB. The resolution kinetics of the DNA damage marker γ-H2AX in LPA-treated IEC-6 cells exposed to γ-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of γ-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of γ-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin−Sca-1+c-Kit+ enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual γ-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that γ-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFα. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair.