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Gastrin regulation of parathyroid hormone like‐hormone (Pthlh) in gastric parietal cells

Although Pthlh is highly expressed in gastric tumors, its normal expression, function and regulation in the stomach are unknown. In this study we used pharmacologic and genetic mouse models and human gastric cancer cell lines to determine the cellular localization and regulation of this growth factor by the hormone gastrin. Analysis of Pthlh‐LacZ reporter mice localized Pthlh to parietal cells in the gastric corpus. Acute treatment of mice with gastrin (0.25 mg/kg i.p.) increased Pthlh mRNA abundance within 1 hour. Accordingly, Pthlh expression was reduced 5‐fold in gastrin‐deficient mice. Together these data suggested that gastrin is a physiologic regulator of Pthlh in the gastric mucosa. To examine the mechanism, we treated human gastric AGS‐E cells with gastrin (10−7M), observing a robust induction of endogenous Pthlh mRNA within 2 hours. Pharmacologic inhibitor studies demonstrated that PI3K, PKC, Erk1/2 and P38 MAPK signaling were required for this induction. Furthermore, gastrin induced Pthlh mRNA isoforms that arose from different promoters. The rapid response and co‐regulation of numerous molecular forms suggested that gastrin signaling targets the Pthlh mRNA stability elements in the 3′‐untranslated region. These studies identify Pthlh as a potential mediator of gastrin growth factor activity in the stomach.