title: STAT3 and importins are novel mediators of early molecular and cellular responses in experimental duodenal ulceration.
abstract: OBJECTIVE
  Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers.
  
  
  METHODS
  We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses.
  
  
  RESULTS
  We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and β in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or β, and STAT3/DNA binding than wild-type mice in response to cysteamine.
  
  
  CONCLUSIONS
  Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.
authors.affiliation: VA Medical Center, (05/113) 5901 East 7th Street, Long Beach, CA, 90822-5201, USA.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Khomenko
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Deng
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
authors.forename: Andrzej
authors.initials: A
authors.lastname: Tarnawski
authors.forename: Khushin N
authors.initials: KN
authors.lastname: Patel
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Sandor
authors.forename: Sandor
authors.initials: S
authors.lastname: Szabo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D003543:Cysteamine; D004195:Disease Models, Animal; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics; D004840:Epirizole; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine; D028901:alpha Karyopherins / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C510005:GQ-ODN T40214; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D028901:alpha Karyopherins; D028961:beta Karyopherins; D004840:Epirizole; D014443:Tyrosine; D003543:Cysteamine