Induction of precocious pepsinogen synthesis by glucocorticoids in fetal rat gastric epithelium in organ culture: Importance of mesenchyme for epithelial differentiation

Tsukada, Sachiyuki; Ichinose, Masakazu; Yahagi, Naohisa; Matsubara, Yasuo; Yonezawa, Satoshi; Shiokawa, K.; Furihata, Chie; Fukamachi, Hiroshi

doi:10.1046/j.1432-0436.1998.6250239.x

Cited by 24 publications

(31 citation statements)

References 40 publications

(44 reference statements)

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“…This is consistent with a model, wherein epithelial differentiation defects would be secondary to altered stromal-epithelial signaling necessary for peptic cell differentiation. 28 ϩ/Ϫ polyps also in this regard, they are smaller and occur in only 61% of mice at 11 months, compared with 100% in the Lkb1 ϩ/Ϫ mice. 8 Based on these observations, it is thus possible that in Lkb1 ϩ/Ϫ mice, here undetected stromal alterations precede epithelial differentiation defects, which in turn are even further enhanced by concomitant epithelial Lkb1 heterozygosity, contributing to increased polyp initiation and growth.…”

Section: Discussionmentioning

confidence: 80%

“…25 The development and persistence of pepsinogen-expressing cells, and particularly chief cells, require glucocorticoids, 26,27 whose homeostatic effects are mediated via the mesenchymal stroma. 28 This stroma, the lamina propria, consisting of fibroblasts, endothelial, and immune cells, is located between and underneath the gastric units. The unit bases, the glands, are surrounded by a sheath of smooth muscle ␣-actin (SMA)-expressing intestinal subepithelial myofibroblasts, 29 which, at least in the small intestine, link with the thin muscular sheath under the basal lamina called muscularis mucosae.…”

mentioning

confidence: 99%

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Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Udd

Katajisto

Kyyrönen

et al. 2010

The American Journal of Pathology

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Gastrointestinal hamartomatous polyps in the PeutzJeghers cancer predisposition syndrome and its mouse model (Lkb1؉/؊ ) are presumed to contain all cell types native to the site of their occurrence. This study aimed to explore the pathogenesis of PeutzJeghers syndrome polyposis by characterizing cell types and differentiation of the epithelium of gastric polyps and predisposed mucosa. Both antral and fundic polyps were characterized by a deficit of pepsinogen C-expressing differentiated gland cells (antral gland, mucopeptic, and chief cells); in large fundic polyps, parietal cells were also absent. Gland cell loss was associated with an increase in precursor neck cells, an expansion of the proliferative zone, and an increase in smooth muscle ␣-actin expressing myofibroblasts in the polyp stroma. Lack of pepsinogen C-positive gland cells identified incipient polyps, and even the unaffected mucosa of young predisposed mice displayed an increase in pepsinogen C negative glands (25%; P ‫؍‬ 0045). In addition, in small intestinal polyps, gland cell differentiation was defective, with the absence of Paneth cells. There were no signs of metaplastic differentiation in any of the tissues studied, and both the gastric and small intestinal defects were seen in Lkb1 ؉/؊ mice, as well as polyps from patients with Peutz-Jeghers syndrome. These results identify impaired epithelial differentiation as the earliest pathological sign likely to contribute to tumorigenesis in individuals with inherited Lkb1 mutations. (Am J

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Udd

Katajisto

Kyyrönen

et al. 2010

The American Journal of Pathology

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“…Glucocorticoids also induce the expression of pepsinogen genes, thus acting as important regulators of both function and differentiation of chief cells [127]. Direct actions of the hormones are unknown, but glucocorticoids may act indirectly on pepsinogen genes via other factors, as suggested by the fact that mesenchyme is necessary for enzyme induction [128].…”

mentioning

confidence: 99%

Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development

Kageyama¹

2002

CMLS, Cell. Mol. Life Sci.

230

214

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Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin, and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly, and a stepwise pathway through a pseudo-pepsin(s). The active-site cleft is large enough to accommodate at least seven residues of a substrate, thus forming S4 through S'3 subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P'1 positions. Interactions at additional subsites are important in some cases, for example with cleavage of kappa-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors, including steroid hormones.

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“…Direct actions of hormones on PGC genes are unknown. As suggested by the fact that mesenchyme is necessary for enzyme induction glucocorticoids may act indirectly on PGC genes through other factors (Tsukada et al, 1998). In the other study, it was suggested that glucocorticoids presumably inhibit the proliferation of mucosal cells and in turn enhance the expression of pepsinogen gene (Tsukada et al, 1994b).…”

Section: Gene Structure and Regulationmentioning

confidence: 97%

Progastriscin: Structure, Function, and Its Role in Tumor Progression

Hassan

Toor

Ahmad

2010

Journal of Molecular Cell Biology

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Progastricsin (PGC) is a major seminal plasma protein having aspartyl proteinases-like activity and showing close sequence similarity to pepsins. PGC is also present as zymogen in gastric mucosa. In this article, we have reviewed all important features of PGC. Furthermore, we have compared all features of PGC with those of different aspartyl proteinases. The complete amino acid sequence of PGC reveals that it is composed of 374 residues (gastricsin moiety of 331 residues and the activation segment of 43 residues). The gene of human PGC is located at single locus on chromosome 6, whereas the human pepsinogen genetic locus is polymorphic and codes for at least three distinct polypeptide sequences on chromosome 11. The major useful function of PGC includes production of pro-antimicrobial substance in seminal plasma. The crystal structure of human PGC is known, which shows that it is quite similar to that of porcine pepsinogen. The tertiary structure of PGC is comprised of commonly bilobal structure with a large active-site cleft between the lobes. Two aspartate residues in the center of the cleft, namely Asp32 and Asp215, function as catalytic residues. The sequence and structural features of PGC indicate that it is diverged from its pepsinogen ancestor in the early phase of the evolution of gastric aspartyl proteinases. Our detailed review of PGC structure, function and activation mechanism will also be of interest to cancer biologists as well as gastroenterologists.

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Induction of precocious pepsinogen synthesis by glucocorticoids in fetal rat gastric epithelium in organ culture: Importance of mesenchyme for epithelial differentiation

Cited by 24 publications

References 40 publications

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development

Progastriscin: Structure, Function, and Its Role in Tumor Progression

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