title: Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats.
abstract: We show that the gastric hormone gastrin induces the expression of the prosurvival secretory clusterin (sCLU) in rat adenocarcinoma cells. Clusterin mRNA was still upregulated in the presence of the protein synthesis inhibitor cycloheximide, although at a lower level. This indicates that gastrin induces clusterin transcription independently of de novo protein synthesis but requires de novo protein synthesis of signal transduction pathway components to achieve maximal expression level. Luciferase reporter assay indicates that the AP-1 transcription factor complex is involved in gastrin-mediated activation of the clusterin promoter. Gastrin-induced clusterin expression and subsequent secretion is dependent on sustained treatment, because removal of gastrin after 1-2 h abolished the response. Neutralization of secreted clusterin by a specific antibody abolished the antiapoptotic effect of gastrin on serum starvation-induced apoptosis, suggesting that extracellular clusterin is involved in gastrin-mediated inhibition of apoptosis. The clusterin response to gastrin was validated in vivo in hypergastrinemic rats, showing increased clusterin expression in the oxyntic mucosa, as well as higher levels of clusterin in plasma. In normal rat oxyntic mucosa, clusterin protein was strongly expressed in chromogranin A-immunoreactive neuroendocrine cells, of which the main cell type was the histidine decarboxylase-immunoreactive enterochromaffin-like (ECL) cell. The association of clusterin with neuroendocrine differentiation was further confirmed in human gastric ECL carcinoids. Interestingly, in hypergastrinemic rats, clusterin-immunoreactive cells formed distinct groups of diverse cells at the base of many glands. Our results suggest that clusterin may contribute to gastrin's growth-promoting effect on the oxyntic mucosa.
authors: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors: Christina Sæten
authors: CS
authors: Fjeldbo
authors: Ingunn
authors: I
authors: Bakke
authors: Sten Even
authors: SE
authors: Erlandsen
authors: Jannicke
authors: J
authors: Holmseth
authors: Astrid
authors: A
authors: Lægreid
authors: Arne K
authors: AK
authors: Sandvik
authors: Liv
authors: L
authors: Thommesen
authors: Torunn
authors: T
authors: Bruland
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002276:Carcinoid Tumor / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000032:analysis; D051152:Clusterin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004759:Enterochromaffin Cells / Q000187:drug effects; D005260:Female; D005755:Gastrins / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000378:metabolism; D006801:Humans; D055099:Neuroendocrine Cells / Q000737:chemistry / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010295:Parietal Cells, Gastric / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053379:Chromogranin A; D051152:Clusterin; D005755:Gastrins; D018808:Transcription Factor AP-1; D006640:Histidine Decarboxylase