Balogh, AndreaShimizu, YoshibumiLee, Sue ChinNorman, Derek D.Gangwar, RuchikaBavaria, MitulMoon, ChangSukShukla, PradeepRao, RadakrishnaRay, RameshNaren, Anjaparavanda P.Banerje, SouvikMiller, Duane D.Balazs, LouisaPelus, LouisTigyi, Gabor2017-05-162017-05-162015-09Balogh, A., Shimizu, Y., Lee, S. C., Norman, D. D., Gangwar, R., Bavaria, M., … Tigyi, G. (2015). The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. Cellular Signalling, 27(9), 1751–1762. http://doi.org/10.1016/j.cellsig.2015.05.015https://hdl.handle.net/1805/12548In 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.en-USPublisher PolicyDNA damage repairLysophosphatidic acidATXLPA2γH2AXNF-κBArticle