Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation.
Sonic hedgehog (Shh) is not only essential to the development of the gastrointestinal tract, but is also necessary to maintain the characteristic acid-secreting phenotype of the adult stomach. Gastrin is the only hormone capable of stimulating gastric acid and is thus required to maintain functional parietal cells. We have shown previously that gastrin-null mice display gastric atrophy and metaplasia prior to progression to distal, intestinal-type gastric cancer. Because reduced levels of Shh peptide correlate with gastric atrophy, we examined whether gastrin regulates Shh expression in parietal cells. We show here that gastrin stimulates Shh gene expression and acid-dependent processing of the 45-kDa Shh precursor to the 19-kDa secreted peptide in primary parietal cell cultures. This cleavage was blocked by the proton pump inhibitor omeprazole and mediated by the acid-activated protease pepsin A. Pepsin A was also the protease responsible for processing Shh in tissue extracts from human stomach. By contrast, extracts prepared from neoplastic gastric mucosa had reduced levels of pepsin A and did not process Shh. Therefore processing of Shh in the normal stomach is hormonally regulated, acid-dependent, and mediated by the aspartic protease pepsin A. Moreover parietal cell atrophy, a known pre-neoplastic lesion, correlates with loss of Shh processing.
Zavros
Yana
Y
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109.
Waghray
Meghna
M
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109.
Tessier
Arthur
A
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109.
Bai
Longchuan
L
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109.
Todisco
Andrea
A
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109.
L Gumucio
Deborah
D
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, 48109.
Samuelson
Linda C
LC
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
Dlugosz
Andrzej
A
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, 48109.
Merchant
Juanita L
JL
Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, 48109; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109. Electronic address: merchanj@umich.edu.
D000818:Animals; D018929:Cell Culture Techniques; D002845:Chromatography; D004285:Dogs; D005757:Gastritis, Atrophic / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010434:Pepsin A / Q000737:chemistry*; D010641:Phenotype; D011485:Protein Binding; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D010434:Pepsin A