Submitted on December 19, 2002
Accepted on March 28, 2003
REGULATION OF TGF-
-INDUCED ACTIVATION OF AP-1 IN THE AGING GASTRIC MUCOSA
Zhi-Qiang Xiao1, Jianling Li1, and Adhip P. N. Majumdar2*
1 Department of Internal Medicine, Wayne State University, Detroit, MI, USA
2 Veterans Affairs Medical Center, Wayne State University, Detroit, MI, USA; Department of Internal Medicine, Wayne State University, Detroit, MI, USA; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: a.majumdar{at}wayne.edu.
Although the age-related activation of EGFR in the gastric mucosa of Fischer-344 rats is associated with increased DNA binding activity of AP-1, little is known about the EGFR signaling cascades that regulate this process. The primary objective of this investigation is to determine the role of signaling pathways initiated by EGFR in regulating the TGF-
-induced activation of AP-1 in the gastric mucosa in aged rats. Freshly isolated gastric mucosal cells from male young (4-5-month) and aged (22-24-month) were used. We have observed that although exposure of mucosal cells from young (4-5 months) and old (22-24 months) rats to 1 nM TGF- 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- induction of AP-1 transcriptional activity in gastric mucosal cells from aged rats to 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 PI-3 kinase. PP2, a specific inhibitor of Src kinase, produces a 50% inhibition of the TGF--induced activation of AP-1 transcriptional activity. Our results suggest that the TGF--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, while Src-kinase pathways plays a minor role.
