Inhibition of ornithine decarboxylase induces STAT3 tyrosine phosphorylation and DNA binding in IEC-6 cells

Polyamines are required for the proliferation of the rat intestinal mucosal IEC-6 cell line. Ornithine decarboxylase (ODC) is the enzyme that catalyze s the first step in polyamine synthesis. ODC inhibition not only leads to p oly amine depletion but also leads to inhibition of cell proliferation and regulates the expression of the immediate-early genes c-fos, c-myc, and c-j un. Members of the signal transducers and activators of transcription (STAT ) transcription factor family bind to the sis-inducible element (SIE) prese nt in the promoters to regulate the expression of a variety of important ge nes. In the present study, we tested the hypothesis that the STAT3 transcri ption factor, which is responsible for activation of the acute phase respon se genes, is activated after inhibition of ODC. We found that inhibition of ODC rapidly induces STAT3 activation as determined by STAT3 tyrosine phosp horylation, translocation of STAT3 from the cytoplasm into the nucleus, and the presence of STAT3 in SIE-dependent DNA-protein complexes. STAT3 activa tion upon inhibition of ODC was accompanied by the activation of a STAT3-de pendent reporter construct. Moreover, prolonged polyamine depletion resulte d in downregulation of cellular STAT3 levels.