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Cre-mediated stress affects sirtuin expression levels, Peroxisome biogenesis and metabolism, antioxidant and proinflammatory signaling pathways

Xiao, Yu ; Karnati, Srikanth ; Qian, Guofeng ; Nenicu, Anca ; Fan, Wei ; Tchatalbachev, Svetlin ; Höland, Anita ; Hossain, Hamid ; Guillou, Florian ; Lüers, Georg H. ; Baumgart-Vogt, Eveline

Originalveröffentlichung: (2012) PLoS ONE, 7(7), e41097, 1-21 doi:10.1371/journal.pone.0041097
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URN: urn:nbn:de:hebis:26-opus-89487

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Freie Schlagwörter (Englisch): Cre-expression , AMH-Cre-transgenic mice , Sertoli cells , stress-related signaling pathways , DNA damage
Sammlung: Open Access - Publikationsfonds
Universität Justus-Liebig-Universität Gießen
Institut: Institute for Anatomy and Cell Biology II; Institute for Medical Microbiology
Fachgebiet 1: Universität, Präsident der JLU
Fachgebiet 2: Medizin
DDC-Sachgruppe: Medizin
Dokumentart: Aufsatz
Sprache: Englisch
Erstellungsjahr: 2012
Publikationsdatum: 30.08.2012
Kurzfassung auf Englisch: Cre-mediated excision of loxP sites is widely used in mice to manipulate gene function in a tissue-specific manner. To analyze phenotypic alterations related to Cre-expression, we have used AMH-Cre-transgenic mice as a model system. Different Cre expression levels were obtained by investigation of C57BL/6J wild type as well as heterozygous and homozygous AMH-Cre-mice. Our results indicate that Cre-expression itself in Sertoli cells already has led to oxidative stress and lipid peroxidation (4-HNE lysine adducts), inducing PPAR-alpa/gamma, peroxisome proliferation and alterations of peroxisome biogenesis (PEX5, PEX13 and PEX14) as well as metabolic proteins (ABCD1, ABCD3, MFP1, thiolase B, catalase). In addition to the strong catalase increase, a NRF2- and FOXO3-mediated antioxidative response (HMOX1 of the endoplasmic reticulum and mitochondrial SOD2) and a NF-?B activation were noted. TGFß1 and proinflammatory cytokines like IL1, IL6 and TNFa were upregulated and stress-related signaling pathways were induced. Sertoli cell mRNA-microarray analysis revealed an increase of TNFR2-signaling components. 53BP1 recruitment and expression levels for DNA repair genes as well as for p53 were elevated and the ones for related sirtuin deacetylases affected (SIRT 1, 3-7) in Sertoli cells. Under chronic Cre-mediated DNA damage conditions a strong downregulation of Sirt1 was observed, suggesting that the decrease of this important coordinator between DNA repair and metabolic signaling might induce the repression release of major transcription factors regulating metabolic and cytokine-mediated stress pathways. Indeed, caspase-3 was activated and increased germ cell apoptosis was observed, suggesting paracrine effects. In conclusion, the observed wide stress-induced effects and metabolic alterations suggest that it is essential to use the correct control animals (Cre/Wt) with matched Cre expression levels to differentiate between Cre-mediated and specific gene-knock out-mediated effects.
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