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.
Keywords:
ATM; Apoptosis; Base Excision Repair; Cancer Biology; Cell Signaling; DNA Damage Response; E2F-1; PIM-2.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Ataxia Telangiectasia Mutated Proteins
-
Blotting, Western
-
Cell Cycle Proteins / antagonists & inhibitors
-
Cell Cycle Proteins / metabolism*
-
Cell Line, Tumor
-
DNA Damage*
-
DNA Repair
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / metabolism*
-
E2F1 Transcription Factor / genetics
-
E2F1 Transcription Factor / metabolism*
-
Enzyme Activation
-
Gene Expression Regulation, Neoplastic / drug effects
-
Histones / metabolism
-
Humans
-
Immunohistochemistry
-
Morpholines / pharmacology
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
RNA Interference
-
Reverse Transcriptase Polymerase Chain Reaction
-
Thioxanthenes / pharmacology
-
Time Factors
-
Tumor Suppressor Proteins / antagonists & inhibitors
-
Tumor Suppressor Proteins / metabolism*
-
Ultraviolet Rays*
Substances
-
2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
E2F1 Transcription Factor
-
E2F1 protein, human
-
H2AX protein, human
-
Histones
-
Morpholines
-
PIM2 protein, human
-
Proto-Oncogene Proteins
-
Thioxanthenes
-
Tumor Suppressor Proteins
-
ATM protein, human
-
ATR protein, human
-
Ataxia Telangiectasia Mutated Proteins
-
Protein Serine-Threonine Kinases