Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
J Biol Chem. 2013 Jul 26;288(30):21770-83. doi: 10.1074/jbc.M113.458851. Epub 2013 Jun 11.
The oncogenic nature ascribed to the PIM-2 kinase relies mostly on phosphorylation of substrates that act as pro-survival/anti-apoptotic factors. Nevertheless, pro-survival effects can also result from activating DNA repair mechanisms following damage. In this study, we addressed the possibility that PIM-2 plays a role in the cellular response to UV damage, an issue that has never been addressed before. We found that in U2OS cells, PIM-2 expression and activity increased upon exposure to UVC radiation (2-50 mJ/cm(2)), and Pim-2-silenced cells were significantly more sensitive to UV radiation. Overexpression of PIM-2 accelerated removal of UV-induced DNA lesions over time, reduced γH2AX accumulation in damaged cells, and rendered these cells significantly more viable following UV radiation. The protective effect of PIM-2 was mediated by increased E2F-1 and activated ATM levels. Silencing E2F-1 reduced the protective effect of PIM-2, whereas inhibiting ATM activity abrogated this protective effect, irrespective of E2F-1 levels. The results obtained in this study place PIM-2 upstream to E2F-1 and ATM in the UV-induced DNA damage response.
PIM-2 激酶的致癌性质主要归因于其对作为生存/抗凋亡因子的底物的磷酸化。然而，生存促进效应也可能源于损伤后激活 DNA 修复机制。在这项研究中，我们探讨了 PIM-2 是否在细胞对 UV 损伤的反应中发挥作用的可能性，这是一个以前从未涉及的问题。我们发现，在 U2OS 细胞中，PIM-2 的表达和活性在暴露于 UVC 辐射（2-50 mJ/cm(2)）时增加，并且 Pim-2 沉默的细胞对 UV 辐射更加敏感。PIM-2 的过表达随时间加速去除 UV 诱导的 DNA 损伤，减少受损细胞中 γH2AX 的积累，并使这些细胞在 UV 辐射后更具活力。PIM-2 的保护作用是通过增加 E2F-1 和激活的 ATM 水平介导的。沉默 E2F-1 降低了 PIM-2 的保护作用，而抑制 ATM 活性则消除了这种保护作用，而与 E2F-1 水平无关。本研究的结果将 PIM-2 置于 UV 诱导的 DNA 损伤反应中的 E2F-1 和 ATM 上游。
