The autotaxin-LPA2 GPCR axis is modulated by ?-irradiation and facilitates DNA damage repair.

ABSTRACT: 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 ?-irradiation that was abolished by mutation of the NF-?B 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-?B. The resolution kinetics of the DNA damage marker ?-H2AX in LPA-treated IEC-6 cells exposed to ?-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of ?-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of ?-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 ?-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that ?-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNF?. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair.

SUBMITTER: Balogh A 

PROVIDER: S-EPMC4514920 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature