Abstract
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.
Highlights
The Pim-2-silenced cells (PIM-2) kinase is a potent survival factor; its role in the DNA damage response has never been addressed
To determine whether the increased expression of PIM-2 was due to the rather high UV radiation intensity of 50 mJ/cm2, we repeated these experiments with various intensities from 2 to 50 mJ/cm2 and found that UV radiation-dependent elevation in PIM-2 levels was evident at all intensities, with a more prominent increase at 8, 15, and 50 mJ/cm2
The oncogenic nature ascribed to PIM-2 relies mostly on the pro-survival effect exerted by phosphorylation of substrates that upon phosphorylation act as pro-survival/anti-apoptotic factors
Summary
The PIM-2 kinase is a potent survival factor; its role in the DNA damage response has never been addressed. Results: PIM-2 promotes DNA lesions repair in an E2F-1 and ATM-dependent manner; Pim-2-silenced cells are more susceptible to UV damage. Conclusion: PIM-2 is an upstream activator of E2F-1 and ATM in the UV damage response. Pro-survival effects can result from activating DNA repair mechanisms following damage. 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. Overexpression of PIM-2 accelerated removal of UV-induced DNA lesions over time, reduced ␥H2AX accumulation in damaged cells, and rendered these cells significantly more viable following UV radiation. The results obtained in this study place PIM-2 upstream to E2F-1 and ATM in the UV-induced DNA damage response
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