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Regulation of TGF-alpha-induced activation of AP-1 in the aging gastric mucosa.

Although the age-related activation of EGF receptor (EGFR) in the gastric mucosa of Fischer 344 rats is associated with increased DNA binding activity of activator protein-1 (AP-1), little is known about the EGFR signaling cascades that regulate this process. The primary objective of this investigation was to determine the role of signaling pathways initiated by EGFR in regulating the transforming growth factor-alpha (TGF-alpha)-induced activation of AP-1 in the gastric mucosa in aged rats. Freshly isolated gastric mucosal cells from male young (4-5 mo) and aged (22-24 mo) rats were used. We have observed that although exposure of mucosal cells from young (4-5 mo) and old (22-24 mo) rats to 1 nM TGF-alpha for 20 min stimulates the DNA binding activity of AP-1 in both age groups, the magnitude of stimulation is substantially higher in aged (131%) than in young (35%) rats. This stimulation in the aged is associated with a concomitant activation of MEKs and ERKs, but not JNKs and p38. The TGF-alpha induction of AP-1 transcriptional activity in gastric mucosal cells from aged rats could be totally abrogated by either PD153035, a specific inhibitor of EGFR tyrosine kinase, or PD98059, a specific inhibitor of MEKs, but not by Wortmannin, which inhibits phosphatidylinositol kinase. PP2, a specific inhibitor of Src kinase, produces a 50% inhibition of the TGF-alpha-induced activation of AP-1 transcriptional activity. Our results suggest that the TGF-alpha-induced stimulation of DNA binding activity of AP-1 in the gastric mucosa of aged rats is primarily through a signaling pathway involving MEKs and ERKs, whereas Src kinase pathways play a minor role.