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Lung tissue regeneration after induced injury in Runx3 KO mice

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Abstract

Runx3 is essential for normal murine lung development, and Runx3 knockout (KO) mice, which die soon after birth, exhibit alveolar hyperplasia. Wound healing, tissue repair, and regeneration mechanisms are necessary in humans for proper early lung development. Previous studies have reported that various signaling molecules, such as pErk, Tgf-ß1, CCSP, pJnk, Smad3, and HSP70 are closely related to wound healing. In order to confirm the relationship between lung defects caused by the loss of function of Runx3 and wound healing, we have localized various wound-healing markers after laser irradiation in wild-type and in Runx3 KO mouse lungs at post-natal day 1. Our results indicate that pERK, Tgf-β1, CCSP, pJnk, and HSP70 are dramatically down-regulated by loss of Runx3 during lung wound healing. However, Smad3 is up-regulated in the Runx3 KO laser-irradiated lung region. Therefore, the lung wound-healing mechanism is inhibited in the Runx3 KO mouse, which shows abnormal lung architecture, by reduced pErk, Tgf-β1, CCSP, pJnk, and HSP70 and by induced Smad3.

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References

  • Ashcroft GS, Roberts AB (2000) Loss of Smad3 modulates wound healing. Cytokine Growth Factor Rev 11:125–131

    Article  CAS  PubMed  Google Scholar 

  • Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260–266

    Article  CAS  PubMed  Google Scholar 

  • Bae SC, Lee YH (2006) Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. Gene 366:58–66

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Karin M (2001) Mammalian MAP kinase signaling cascades. Nature 410:37–40

    Article  CAS  PubMed  Google Scholar 

  • Chi XZ, Kim J, Lee YH, Lee JW, Lee KS, Wee H, Kim WJ, Park WY, Oh BC, Stein GS, Ito Y, Wijnen AJ van, Bae SC (2009) Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res 69:8111–8119

    Article  CAS  PubMed  Google Scholar 

  • Eggers JH, Stock M, Fliegauf M, Vonderstrass B, Otto F (2002) Genomic characterization of the RUNX2 gene of Fugu rubripes. Gene 291:159–167

    Article  CAS  PubMed  Google Scholar 

  • Geiser T (2003) Idiopathic pulmonary fibrosis—a disorder of alveolar wound repair? Swiss Med Wkly 133:405–411

    PubMed  Google Scholar 

  • Guo WH, Weng LQ, Ito K, Chen LF, Nakanishi H, Tatematsu M, Ito Y (2002) Oncogene 21:8351–8355

    Article  CAS  PubMed  Google Scholar 

  • Hislop A (2002) Airway and blood vessel interaction during lung growth and postnatal adaptation. J Anat 201:325–334

    Article  PubMed  Google Scholar 

  • Inoue K, Ozaki S, Shiga T, Ito K, Masuda T, Okado N, Iseda T, Kawaguchi S, Ogawa M, Bae SC, Yamashita N, Itohara S, Kudo N, Ito Y (2002) Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nat Neurosci 5:946–954

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS, Lee CW, Voon DC, Koo JK, Wang H, Fukamachi H, Ito Y (2008) RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 14:226–237

    Article  CAS  PubMed  Google Scholar 

  • Kalev-Zylinska ML, Horsfield JA, Flores MV, Postlethwait JH, Vitas MR, Baas AM, Crosier PS, Crosier KE (2002) Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1-CBF2T1 transgene advances a model for studies of leukemogenesis. Development 129:2015–2030

    CAS  PubMed  Google Scholar 

  • Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL, Yang JO, Ito Y, Bae SC (2005) RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res 65:9347–9354

    Article  CAS  PubMed  Google Scholar 

  • Lee KS, Lee YS, Lee JM, Ito K, Cinghu S, Kim JH, Jang JW, Li YH, Goh YM, Chi XZ, Wee H, Lee HW, Hosoya A, Chung JH, Jang JJ, Kundu JK, Surh YJ, Kim WJ, Ito Y, Jung HS, Bae SC (2010) Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer. Oncogene 29:3349–3361

    Article  CAS  PubMed  Google Scholar 

  • Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu V, Eilam R, Bernstein Y, Goldenberg D, Xiao C, Fliegauf M (2002) The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J 21:3454–3463

    Article  CAS  PubMed  Google Scholar 

  • Levanon D, Brenner O, Otto F, Groner Y (2003) Runx3 knockouts and stomach cancer. EMBO Rep 4:560–564

    Article  CAS  PubMed  Google Scholar 

  • Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109:113–124

    Article  CAS  PubMed  Google Scholar 

  • Metzger RJ, Klein OD, Martin GR, Krasnow MA (2008) The branching programme of mouse lung development. Nature 453:745–750

    Article  CAS  PubMed  Google Scholar 

  • Mushtaq S, Naqvi ZA, Siddiqui AA, Palmberg C, Shafqat J, Ahmed N (2007) Changes in albumin precursor and heat shock protein 70 expression and their potential role in response to corneal epithelial wound repair. Proteomics 7:463–468

    Article  CAS  PubMed  Google Scholar 

  • Mushtaq S, Naqvi ZA, Siddiqui AA, Ahmed N (2009) Albumin precursor and Hsp70 modulate corneal wound healing in an organ culture model. Acta Histochem (in press)

  • Odashima M, Otaka M, Matsuhashi T, Jin M, Horikawa Y, Ohba R, Itoh H, Watanabe S (2007) Mechanical strain stress suppresses expression of HSP70 and wound restoration in gastric mucosal cells. Dig Dis Sci 52:3087–3091

    Article  CAS  PubMed  Google Scholar 

  • Okuda T, Fisher R, Downing JR (1996) Molecular diagnostics in pediatric acute lymphoblastic leukemia. Mol Diagn 1:139–151

    Article  CAS  PubMed  Google Scholar 

  • Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771

    Article  CAS  PubMed  Google Scholar 

  • Parrish AR, Gandolfi AJ, Brendel K (1995) Precision-cut tissue slices: applications in pharmacology and toxicology. Life Sci 57:1887–1901

    Article  CAS  PubMed  Google Scholar 

  • Rämet M, Lanot R, Zachary D, Manfruelli P (2002) JNK signaling pathway is required for efficient wound healing in Drosophila. Dev Biol 241:145–156

    Article  PubMed  Google Scholar 

  • Ravikumar P, Bellotto DJ, Johnson RL Jr, Hsia CC (2009) Permanent alveolar remodeling in canine lung induced by high-altitude residence during maturation. J Appl Physiol 107:1911–1917

    Article  PubMed  Google Scholar 

  • Reynolds LE, Conti FJ, Lucas M, Grose R, Robinson S, Stone M, Saunders G, Dickson C, Hynes RO, Lacy-Hulbert A, Hodivala-Dilke K (2005) Accelerated re-epithelialization in beta3-integrin-deficient mice is associated with enhanced TGF-beta1 signaling. Nat Med 11:167–174

    Article  CAS  PubMed  Google Scholar 

  • Sandra F, Haradab H, Nakamurac N, Ohishic M (2004) Midkine induced growth of ameloblastoma through MAPK and Akt pathways. Oral Oncol 40:274–280

    Article  CAS  PubMed  Google Scholar 

  • Selman M, King TE, Pardo A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134:136–151

    CAS  PubMed  Google Scholar 

  • Taniuchi I, Sunshine MJ, Festenstein R, Littman DR (2002) Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol Cell 10:1083–1096

    Article  CAS  PubMed  Google Scholar 

  • Teranishi S, Kimura K, Nishida T (2009) Role of formation of an ERK-FAK-paxillin complex in migration of human corneal epithelial cells during wound closure in vitro. Invest Ophthalmol Vis Sci 50:5646–5652

    Article  PubMed  Google Scholar 

  • Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V, Bernstein Y, Goldenberg D, Brenner O, Berke G, Levanon D, Groner Y (2003) Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc Natl Acad Sci USA 100:7731–7736

    Article  CAS  PubMed  Google Scholar 

  • Xing Y, Li C, Li A, Sridurongrit S, Tiozzo C, Bellusci S, Borok Z, Kaartinen V, Minoo P (2010) Signaling via Alk5 controls the ontogeny of lung Clara cells. Development 137:825–833

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Dey CR, Wert SE, Whitsett JA (1996) Arrested lung morphogenesis in transgenic mice bearing an SP-C-TGF-beta 1 chimeric gene. Dev Biol 175:227–238

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Han-Sung Jung.

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This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (R13-2003-013-05001-0).

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Lee, JM., Kwon, HJ., Bae, SC. et al. Lung tissue regeneration after induced injury in Runx3 KO mice. Cell Tissue Res 341, 465–470 (2010). https://doi.org/10.1007/s00441-010-1011-7

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  • DOI: https://doi.org/10.1007/s00441-010-1011-7

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