Document Detail


Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation.
MedLine Citation:
PMID:  17872943     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yana Zavros; Meghna Waghray; Arthur Tessier; Longchuan Bai; Andrea Todisco; Deborah L Gumucio; Linda C Samuelson; Andrzej Dlugosz; Juanita L Merchant
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-09-14
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-11-12     Completed Date:  2008-01-03     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33265-74     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Culture Techniques
Chromatography
Dogs
Gastritis, Atrophic / metabolism*
Hedgehog Proteins / metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pepsin A / chemistry*
Phenotype
Protein Binding
Radioimmunoassay
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
P01 DK062041/DK/NIDDK NIH HHS; P01 DK062041-05S1/DK/NIDDK NIH HHS; P01-DK62041/DK/NIDDK NIH HHS; P30 DK034933/DK/NIDDK NIH HHS; P30 DK034933-219001/DK/NIDDK NIH HHS; P30-DK32533/DK/NIDDK NIH HHS; P30-DK34933/DK/NIDDK NIH HHS; R01 DK056882/DK/NIDDK NIH HHS; R01 DK061410/DK/NIDDK NIH HHS; R01 DK061410-04/DK/NIDDK NIH HHS; R01-DK61410/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Hedgehog Proteins; 0/Shh protein, mouse; EC 3.4.23.1/Pepsin A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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