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

Andrea Balogh, Yoshibumi Shimizu, Sue Chin Lee, Derek D. Norman, Ruchika Gangwar, Mitul Bavaria, Chang Suk Moon, Pradeep Shukla, Radakrishna Rao, Ramesh Ray, Anjaparavanda P. Naren, Souvik Banerje, Duane D. Miller, Louisa Balazs, Louis Pelus, Gabor Tigyi

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA<inf>2</inf> 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 LPA<inf>2</inf> delayed the resolution of γ-H2AX. In LPA<inf>2</inf>-reconstituted MEF cells lacking LPA<inf>1&3</inf> 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 C<inf>311</inf>A/C<inf>314</inf>A/L<inf>351</inf>A mutation in the C-terminus of LPA<inf>2</inf> abrogated the effect of LPA on DNA repair. LPA<inf>2</inf> transcripts in Lin<sup>-</sup>Sca-1<sup>+</sup>c-Kit<sup>+</sup> 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 LPA<inf>2</inf>-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 LPA<inf>2</inf> as radiation-regulated genes that appear to play a physiological role in DNA repair.

Original languageEnglish (US)
Pages (from-to)1751-1762
Number of pages12
JournalCellular Signalling
Volume27
Issue number9
DOIs
StatePublished - Sep 1 2015

Keywords

  • ATX
  • DNA damage repair
  • LPA<inf>2</inf>
  • Lysophosphatidic acid
  • NF-κB
  • γ-H2AX

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Balogh, A., Shimizu, Y., Lee, S. C., Norman, D. D., Gangwar, R., Bavaria, M., Moon, C. S., Shukla, P., Rao, R., Ray, R., Naren, A. P., Banerje, S., Miller, D. D., Balazs, L., Pelus, L., & Tigyi, G. (2015). The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. Cellular Signalling, 27(9), 1751-1762. https://doi.org/10.1016/j.cellsig.2015.05.015