Parathyroid Hormone-Like Hormone (PTHLH): A Novel Parietal Cell Growth Factor Regulated by Gastrin.

Parietal cells play a fundamental role in stomach physiology, not only by creating a pathogen free environment through the production of gastric acid, but also by secreting essential growth factors thought to be important for cellular homeostasis of the gastric glands. The gastrointestinal hormone gastrin is known to be a critical regulator of parietal cell function as well as proliferation and differentiation of the gastric glands. High gastrin levels in the body are frequently associated with gastric hyperplasia, yet the mechanism has not been defined. Since parietal cells contain gastrin receptors, one hypothesis is that the proliferation effect of hypergastrinemia is due to gastrin stimulation of growth factor(s) from parietal cells. Recent gene expression microarray studies of mouse stomach mucosa identified parathyroid hormone-like hormone (Pthlh) as a potential new gastric growth factor. Pthlh is expressed widely and has been described to orchestrate key cellular events in different tissues, such as cell proliferation and differentiation. Although Pthlh is highly expressed in gastric tumors, its normal expression, function and regulation in the stomach have not been studied. In this dissertation I examined the physiological importance of Pthlh in the mouse stomach. I used pharmacologic and genetic mouse models as well as human gastric cancer cell lines to determine the cellular localization and regulation of this growth factor by the hormone gastrin. Analysis of PthlhLacZ/+ reporter mice localized Pthlh to parietal cells in the gastric corpus. Acute treatment of mice with gastrin rapidly and transiently increased Pthlh mRNA abundance. Accordingly, Pthlh expression was significantly reduced in gastrin-deficient mice. Together these data suggested that gastrin is a physiologic regulator of Pthlh in the gastric mucosa. To examine the mechanism, human gastric AGS-E cells treated with gastrin exhibited a robust induction of endogenous Pthlh mRNA via stimulation of the gastrin receptor (Cckbr). Furthermore, gastrin induced Pthlh mRNA isoforms that arose from different promoters. Moreover, measurement of mRNA half-life confirmed that gastrin slowed the degradation of Pthlh transcripts. Collectively, this dissertation identified Pthlh as a novel parietal cell growth factor. It also identified Pthlh as a potential mediator of gastrin growth factor activity in the stomach.Ph.D.Molecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91456/1/asmaaa_1.pd