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

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

Research output: Contribution to journalArticle

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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 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.

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

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DNA Repair
DNA Damage
Jejunum
Up-Regulation
Lymphoid Progenitor Cells
Radiation
Myeloid Progenitor Cells
Radiation Injuries
Mutation
Pertussis Toxin
Phosphatidylinositol 3-Kinases
Genetic Markers
Bone Marrow Cells
Genes
Phosphotransferases
Stem Cells
Bone Marrow
Pharmacology
Polymerase Chain Reaction
CGK 733

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. / Balogh, Andrea; Shimizu, Yoshibumi; Lee, Sue; Norman, Derek D.; Gangwar, Ruchika; Bavaria, Mitul; Moon, Chang Suk; Shukla, Pradeep Kumar; Rao, Radhakrishna; Ray, Ramesh; Naren, Anjaparavanda P.; Banerje, Souvik; Miller, Duane; Balazs, Louisa; Pelus, Louis; Tigyi, Gabor.

In: Cellular Signalling, Vol. 27, No. 9, 01.09.2015, p. 1751-1762.

Research output: Contribution to journalArticle

Balogh, A, Shimizu, Y, Lee, S, Norman, DD, Gangwar, R, Bavaria, M, Moon, CS, Shukla, PK, Rao, R, Ray, R, Naren, AP, Banerje, S, Miller, 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, vol. 27, no. 9, pp. 1751-1762. https://doi.org/10.1016/j.cellsig.2015.05.015
Balogh, Andrea ; Shimizu, Yoshibumi ; Lee, Sue ; Norman, Derek D. ; Gangwar, Ruchika ; Bavaria, Mitul ; Moon, Chang Suk ; Shukla, Pradeep Kumar ; Rao, Radhakrishna ; Ray, Ramesh ; Naren, Anjaparavanda P. ; Banerje, Souvik ; Miller, Duane ; Balazs, Louisa ; Pelus, Louis ; Tigyi, Gabor. / The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. In: Cellular Signalling. 2015 ; Vol. 27, No. 9. pp. 1751-1762.
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AU - Gangwar, Ruchika

AU - Bavaria, Mitul

AU - Moon, Chang Suk

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AU - Ray, Ramesh

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