Cooperative induction of transmembrane prostate androgen induced protein TMEPAI/PMEPA1 by transforming growth factor-β and epidermal growth factor signaling

• EGF and TGF-β signaling cooperatively regulate TMEPAI transcription.
• EGF-responsive elements reside in the first intron of TMEPAI gene.
• ELK-1 mediates the EGF-induced enhancement of TMEPAI expression.

TMEPAI/PMEPA1 (transmembrane prostate androgen induced-RNA/prostate transmembrane protein, androgen induced 1) is a pro-tumorigenic factor induced by TGF-β signaling and constitutive TMEPAI expression in lung cancer cells depends on activated autocrine TGF-β signaling. Here we demonstrate a novel mechanism of TMEPAI transcriptional co-regulation by EGF signaling. Interestingly, we found that ELK-1, downstream of EGFR/Ras/MAPK pathway, modulates TMEPAI expression. ELK-1 binds to the first intron (+1037 to +1294) of the TMEPAI gene together with TGF-β activated Smad3 and enhances the transcription of TMEPAI. Furthermore, TMEPAI gene activation by EGF and TGF-β signaling was reduced by the MEK inhibitor U0126. Together, EGF signaling collaboratively regulates TGF-β-induced TMEPAI expression.