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?1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1.

ABSTRACT: This study was carried out to dissect the mechanism by which ?1 integrins promote resistance to radiation. For this purpose, we conditionally ablated ?1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of ?1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to ?1 , AIIB2, in a xenograft model. The role of ?1 integrins and of a ?1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that ?1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, ?1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of ?1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between ?1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate ?1 integrin levels. We report that IGF-IR regulates the expression of ?1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that ?1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation.

SUBMITTER: Goel HL

PROVIDER: S-EPMC3749928 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1.

Goel Hira Lal HL Sayeed Aejaz A Breen Michael M Zarif Matthew J MJ Garlick David S DS Leav Irwin I Davis Roger J RJ Fitzgerald Thomas J TJ Morrione Andrea A Hsieh Chung-Cheng CC Liu Qin Q Dicker Adam P AP Altieri Dario C DC Languino Lucia R LR

Journal of cellular physiology 20130701 7

This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1 , AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating ...[more]

PMID: 23359252

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Project description:UnlabelledKeratins 8 and 18 (K8/K18) are the intermediate filaments proteins of simple-type digestive epithelia and provide important cytoprotective function. K8/K18 variants predispose humans to chronic liver disease progression and poor outcomes in acute acetaminophen (APAP)-related liver failure. Given that K8 G62C and R341H/R341C are common K8 variants in European and North American populations, we studied their biological significance using transgenic mice. Mice that overexpress the human K8 variants, R341H or R341C, were generated and used together with previously described mice that overexpress wild-type K8 or K8 G62C. Mice were injected with 600 mg/kg of APAP or underwent bile duct ligation (BDL). Livers were evaluated by microarray analysis, quantitative real-time polymerase chain reaction, immunoblotting, histological and immunological staining, and biochemical assays. Under basal conditions, the K8 G62C/R341H/R341C variant-expressing mice did not show an obvious liver phenotype or altered keratin filament distribution, whereas K8 G62C/R341C animals had aberrant disulphide cross-linked keratins. Animals carrying the K8 variants displayed limited gene expression changes, but had lower nicotinamide N-methyl transferase (NNMT) levels and were predisposed to APAP-induced hepatotoxicity. NNMT represents a novel K8/K18-associated protein that becomes up-regulated after K8/K18 transfection. The more pronounced liver damage was accompanied by increased and prolonged JNK activation; elevated APAP protein adducts; K8 hyperphosphorylation at S74/S432 with enhanced keratin solubility; and prominent pericentral keratin network disruption. No differences in APAP serum levels, glutathione, or adenosine triphosphate levels were noted. BDL resulted in similar liver injury and biliary fibrosis in all mouse genotypes.ConclusionExpression of human K8 variants G62C, R341H, or R341C in mice predisposes to acute APAP hepatotoxicity, thereby providing direct evidence for the importance of these variants in human acute liver failure.

Dataset Information

?1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1.

Publications

β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1.

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