Towards Understanding of Gastric Cancer Based upon Physiological Role of Gastrin and ECL Cells

The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer.

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A Role for the DnaJ Homologue Scj1p in Protein Folding in the Yeast Endoplasmic Reticulum

The Journal of Cell Biology ◽

10.1083/jcb.143.4.921 ◽

1998 ◽

Vol 143 (4) ◽

pp. 921-933 ◽

Cited By ~ 67

Author(s):

Susana Silberstein ◽

Gabriel Schlenstedt ◽

Pam A. Silver ◽

Reid Gilmore

Keyword(s):

Endoplasmic Reticulum ◽

Unfolded Protein Response ◽

Physiological Role ◽

Carboxypeptidase Y ◽

Reporter Protein ◽

Unfolded Protein ◽

A Cell ◽

The Unfolded Protein Response ◽

Protein Response

Members of the eukaryotic heat shock protein 70 family (Hsp70s) are regulated by protein cofactors that contain domains homologous to bacterial DnaJ. Of the three DnaJ homologues in the yeast rough endoplasmic reticulum (RER; Scj1p, Sec63p, and Jem1p), Scj1p is most closely related to DnaJ, hence it is a probable cofactor for Kar2p, the major Hsp70 in the yeast RER. However, the physiological role of Scj1p has remained obscure due to the lack of an obvious defect in Kar2p-mediated pathways in scj1 null mutants. Here, we show that the Δscj1 mutant is hypersensitive to tunicamycin or mutations that reduce N-linked glycosylation of proteins. Although maturation of glycosylated carboxypeptidase Y occurs with wild-type kinetics in Δscj1 cells, the transport rate for an unglycosylated mutant carboxypeptidase Y (CPY) is markedly reduced. Loss of Scj1p induces the unfolded protein response pathway, and results in a cell wall defect when combined with an oligosaccharyltransferase mutation. The combined loss of both Scj1p and Jem1p exaggerates the sensitivity to hypoglycosylation stress, leads to further induction of the unfolded protein response pathway, and drastically delays maturation of an unglycosylated reporter protein in the RER. We propose that the major role for Scj1p is to cooperate with Kar2p to mediate maturation of proteins in the RER lumen.

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Differentiation of the Gastric Mucosa I. Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00178.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. G539-G544 ◽

Cited By ~ 29

Author(s):

Duan Chen ◽

Takeshi Aihara ◽

Chun-Mei Zhao ◽

Rolf Håkanson ◽

Susumu Okabe

Keyword(s):

Gastric Mucosa ◽

Histidine Decarboxylase ◽

Parietal Cells ◽

Oxyntic Mucosa ◽

Mucosal Integrity ◽

Ecl Cells ◽

Gastric Physiology ◽

Ecl Cell ◽

Insight Into

Many physiological functions of the stomach depend on an intact mucosal integrity; function reflects structure and vice versa. Histamine in the stomach is synthesized by histidine decarboxylase (HDC), stored in enterochromaffin-like (ECL) cells, and released in response to gastrin, acting on CCK2 receptors on the ECL cells. Mobilized ECL cell histamine stimulates histamine H2 receptors on the parietal cells, resulting in acid secretion. The parietal cells express H2, M3, and CCK2 receptors and somatostatin sst2 receptors. This review discusses the consequences of disrupting genes that are important for ECL cell histamine release and synthesis (HDC, gastrin, and CCK2 receptor genes) and genes that are important for “cross-talk” between H2 receptors and other receptors on the parietal cell (CCK2, M3, and sst2 receptors). Such analysis may provide insight into the functional significance of gastric histamine.

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Differentiation of the Gastric Mucosa II. Role of gastrin in gastric epithelial cell proliferation and maturation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00172.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. G762-G765 ◽

Cited By ~ 37

Author(s):

Renu N. Jain ◽

Linda C. Samuelson

Keyword(s):

Genetically Engineered ◽

Gastric Epithelial Cells ◽

Balanced Growth ◽

Cellular Targets ◽

Genetically Engineered Mouse Models ◽

Gastric Physiology ◽

Ecl Cell ◽

Acid Secreting ◽

And Function

Gastrin is the principal hormonal inducer of gastric acid secretion. The cellular targets for gastrin in the stomach are the acid-secreting parietal cell and histamine-producing enterochromaffin-like (ECL) cell. Gastrin is also a growth factor, with hypergastrinemia resulting in increased proliferation of gastric progenitor cells and a thickened mucosa. This review presents insights into gastrin function revealed by genetically engineered mouse models, demonstrating a new role for gastrin in the maturation of parietal and ECL cells. Thus, gastrin regulates many aspects of gastric physiology, with tight regulation of gastrin levels required to maintain balanced growth and function of gastric epithelial cells.

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Genetic Characterization of a Cell Envelope-Associated Proteinase from Lactobacillus helveticus CNRZ32

Journal of Bacteriology ◽

10.1128/jb.181.15.4592-4597.1999 ◽

1999 ◽

Vol 181 (15) ◽

pp. 4592-4597 ◽

Cited By ~ 59

Author(s):

Jeffrey A. Pederson ◽

Gerald J. Mileski ◽

Bart C. Weimer ◽

James L. Steele

Keyword(s):

Cell Surface ◽

Deletion Mutant ◽

Cell Envelope ◽

Physiological Role ◽

Lactobacillus Helveticus ◽

Whole Cells ◽

A Cell ◽

Hydrolysis Of

ABSTRACT A cell envelope-associated proteinase gene (prtH) was identified in Lactobacillus helveticus CNRZ32. TheprtH gene encodes a protein of 1,849 amino acids and with a predicted molecular mass of 204 kDa. The deduced amino acid sequence of the prtH product has significant identity (45%) to that of the lactococcal PrtP proteinases. Southern blot analysis indicates thatprtH is not broadly distributed within L. helveticus. A prtH deletion mutant of CNRZ32 was constructed to evaluate the physiological role of PrtH. PrtH is not required for rapid growth or fast acid production in milk by CNRZ32. Cell surface proteinase activity and specificity were determined by hydrolysis of αs1-casein fragment 1-23 by whole cells. A comparison of CNRZ32 and its prtH deletion mutant indicates that CNRZ32 has at least two cell surface proteinases that differ in substrate specificity.

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Regulation of insulin secretion by uncoupling protein

Biochemical Society Transactions ◽

10.1042/bst0340802 ◽

2006 ◽

Vol 34 (5) ◽

pp. 802-805 ◽

Cited By ~ 29

Author(s):

C.B. Chan ◽

N. Kashemsant

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Uncoupling Protein ◽

Physiological Role ◽

Atp Production ◽

Ucp2 Expression ◽

Increased Sensitivity ◽

Glucose Stimulated Insulin Secretion

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet β-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.

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Analysis of the role of ICAM-3 as a costimulatory molecule through a cell model: CAMY-1 and CAMY-2 (two CD50-negative Jurkat-T cell clones)

Immunology Letters ◽

10.1016/s0165-2478(97)87030-7 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 52

Author(s):

C Vilardell

Keyword(s):

T Cell ◽

Cell Model ◽

Costimulatory Molecule ◽

T Cell Clones ◽

Cell Clones ◽

Jurkat T Cell ◽

A Cell

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Role of vitamin C in gastric cancer

10.33118/oap.radiol/01.001 ◽

2018 ◽

Vol 01 (1) ◽

Author(s):

Takalkar U Vidyadhar

Keyword(s):

Gastric Cancer ◽

Vitamin C ◽

Gastric Juice ◽

Oxidative Dna Damage ◽

Preventive Measure ◽

Dietary Factors ◽

Preventive Strategy ◽

H Pylori

Gastric cancer is a multifactorial disease with complex interplay of environmental and genetic factors. Helicobacter pylori (H. pylori) infestation has been identified as the most important etiological agent in the pathogenesis of gastric cancer. Also, the role of dietary factors that is low consumption of fruits and vegetables have been found to be associated with gastric cancer. Among the dietary factors, antioxidants especially vitamin C has been found to confer the strongest protection against gastric cancer. Its anti-proliferative and pro-apoptotic action has been suggested in vitro. Because of its antioxidant activity, it protects cells against oxidative DNA damage caused by toxic effects of reactive oxygen species. It also inhibits production of carcinogenic N-nitroso compound in the stomach. The person with H. pylori infection has low levels of vitamin C in their gastric juice and levels of vitamin C normalizes on eradication of H. pylori. Vitamin C levels are high in gastric mucosa and gastric juice, sometimes more than that of in plasma. But gastric pathological conditions cause lowered secretion of vitamin C into gastric juice. Effect of H. pylori on vitamin C in gastric juice is reversible and on eradication of H. pylori, it returns to normal level. Hence, eradication of H. pylori and chemoprevention with antioxidant supplementation will be an effective preventive strategy to reduce the incidence of gastric cancer and related mortality. Vitamin C and gastric cancer is an area of potential interest for researchers as a preventive measure. Keywords: Vitamin C, H. pylori, gastric cancer.

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