title: The autotaxin-LPA2 GPCR axis is modulated by γ-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 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.
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balogh
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Yoshibumi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Sue Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Ruchika
authors.initials: R
authors.lastname: Gangwar
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Mitul
authors.initials: M
authors.lastname: Bavaria
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: ChangSuk
authors.initials: C
authors.lastname: Moon
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Radakrishna
authors.initials: R
authors.lastname: Rao
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerje
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.affiliation: Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, R2-302, Indianapolis, IN 46202, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Pelus
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA. Electronic address: gtigyi@uthsc.edu.
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D005720:Gamma Rays; D007583:Jejunum / Q000378:metabolism / Q000473:pathology; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000528:radiation effects*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D000099189:Lysophospholipase D
chemical_list: D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D010727:Phosphoric Diester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D
keywords: ATX; DNA damage repair; LPA(2); Lysophosphatidic acid; NF-κB; γ-H2AX