Disease relevance of SCT

• To unravel the mechanisms that regulate the human secretin gene expression, in this study, we have used secretin-expressing (HuTu-80 cells, human duodenal adenocarcinoma) and non-secretin-expressing [PANC-1 (human pancreatic ductile carcinoma) and HepG2 (human hepatocellular carcinoma) cells] cell models for in vitro and in vivo analyses [1].
• Specific receptors for secretin have been previously characterized on neuroblastoma cells, pancreatic acini, gastric glands, and liver cholangiocytes [2].
• Twenty-two (63%) cholangiocarcinomas were positive for secretin receptors, while hepatocellular carcinomas were negative [3].
• The secretin receptor expression was investigated in the human liver because the liver is a physiological secretin target and because novel diagnostic and treatment modalities are needed for liver cancer [3].
• Peripheral blood lymphocyte (PBL) chemotaxis to VIP, SEC, HEL and PHI was reduced by inhibition of tyrosine kinase and pertussis or cholera toxin, whereas inhibition of protein kinase C only affected SEC-induced chemotaxis of PBL significantly [4].

Psychiatry related information on SCT

• This reduced-intensity conditioning regimen is the basis of non-myeloablative allo-SCT (also referred to as mini SCT), a new treatment modality that relies more heavily on the antitumour effect exerted by the donor cells than on the antitumour effect of the conditioning therapy [5].
• The patients did not have a normal increase in duodenal spike or motor activity after intestinal distension, but duodenal activity increased after stimulation with intravenous secretin [6].
• Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4 [7].
• By evaluating the pattern of time-response curves obtained from serial T2-weighted EPI after secretin injection, pancreatic exocrine function may be directly assessed at the level of the head, body, and tail [8].
• The plasma concentration of secretin was measured during a 5-day military training course comprising prolonged physical exercise (35% of max O2 uptake), severe caloric deficiency (approx. 35700 kJ/24 h) and sleep deprivation (only 2 h of sleep as a total during 5 days) [9].

High impact information on SCT

• The children were randomly assigned to treatment with an intravenous infusion of synthetic human secretin (0.4 microg per kilogram of body weight) or saline placebo [10].
• Secretin-producing enteroendocrine cells represent a nondividing subpopulation of intestinal epithelial cells, suggesting that expression of the hormone is coordinated with cell cycle arrest during the differentiation of this cell lineage [11].
• Thus, BETA2 may function to coordinate transcriptional activation of the secretin gene, cell cycle arrest, and cell number regulation, providing one of the first examples of a transcription factor that controls terminal differentiation of cells in the intestinal epithelium [11].
• The phage, of the filamentous family, excises from the chromosome and is secreted from the bacteria via the type IV pilin secretin [12].
• Electrogenic anion secretion across intact gallbladder mucosa was stimulated by forskolin, secretin, and exogenous ATP, as assessed by short-circuit current (Isc) increases in Ussing-type chambers [13].

Chemical compound and disease context of SCT

• Secretin did not stimulate adenylate cyclase activity above basal (21.73 +/- 4.07 and 2.29 +/- 1.2 pmol cAMP/mg protein/min) for frozen and cultured gastrinoma, respectively [14].
• Hypothyroidism, provoked in rat by thyroidectomy or propylthiouracil treatment, again induced a marked decrease in secretin-stimulated cardiac adenylate cyclase activity [15].
• Recently, protocols using high-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) have been developed for the treatment of patients with immunoglobulin light chain (AL) amyloidosis [16].
• The study assessed the prognostic value of fluorine 18-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) after salvage chemotherapy before high-dose chemotherapy with stem cell transplantation (HDT/SCT) in patients with induction failure or relapsing chemosensitive lymphoma [17].
• OBJECTIVE: To evaluate the efficacy of surgical-cidofovir (SCT), surgical (ST) and cidofovir (CT) treatment of genital warts in HIV-infected patients [18].

Biological context of SCT

• Although imprinting is a characteristic of some genes in the vicinity, we could find no evidence for methylation of SCT in lymphoblast cells from patients or control individuals [19].
• We also investigated length variation in a variable number of tandem repeats (VNTR) immediately upstream of SCT and found no significant differences in length between patients with autism and normal controls [19].
• Radiation hybrid mapping places the SCT locus on chromosome 11p15.5 [20].
• SCT contains four exons, with the protein coding regions spanning 713 bp of genomic DNA [20].
• Secretin evoked concurrent dose-dependent increases in intracellular cAMP and calcium levels in 293S12 cells and stimulated a 4-fold increase in phosphatidylinositol hydrolysis [2].

Anatomical context of SCT

• They were constructed by overlap PCR, transfected in COS-7 cells, and their ligand selectivity, expressed as the ratio of EC(50) for secretin/EC(50) for VIP (referred to as S/V), in stimulating cAMP production was measured [21].
• Secretin is a 27-amino acid neuroendocrine peptide that stimulates fluid and electrolyte secretion in the gastrointestinal tract, activates tyrosine hydroxylase activity in the central nervous system, and affects cardiac and renal function [2].
• RESULTS: Secretin receptors were present in normal bile ducts and ductules, but not in hepatocytes [3].
• CONCLUSIONS: The expression of secretin receptors in the biliary tract is the molecular basis of the secretin-induced bicarbonate-rich choleresis in man [3].
• Secretin-producing enteroendocrine cells arise from a multipotential endocrine progenitor in the crypts of the small intestine [22].

Associations of SCT with chemical compounds

• The expressions of secretin in PANC-1 and HepG2 cells were subsequently found to be significantly activated by a demethylation agent, 5'-Aza-2' deoxycytidine [1].
• Dose-dependent increases in HCO(3)(-) secretion were observed in response to stimulation of both secretin and VPAC receptors [23].
• Results of this study demonstrated that secretin self-assembles to form micelles in HEPES buffer at 25 degrees C above approximately 0.4 microM [24].
• This variant with an in-frame deletion was shown to be synthesized and to traffic to the cell surface normally, where it could neither bind secretin nor mediate a secretin-stimulated adenosine 3',5'-cyclic monophosphate response [25].
• The ability of 1 microM, but not 1 nM, secretin to stimulate intracellular cyclic AMP generation in these cells was consistent with VIP-1 receptor expression [26].

Physical interactions of SCT

• Constitutive formation of oligomeric complexes between family B G protein-coupled vasoactive intestinal polypeptide and secretin receptors [27].
• Mutational analysis of a proximal enhancer in the secretin gene identified several cis-acting elements in addition to the E-box binding site for BETA2 [28].

Regulatory relationships of SCT

• BETA2 induces cell cycle arrest and apoptosis in addition to activating secretin gene expression [22].
• Secretin induces a bicarbonate rich choleresis by stimulating the activity of the Cl-/HCO3- exchanger by cAMP and protein kinase A mediated phosphorylation of CFTR regulatory domain [29].
• In vivo studies showed that ANF at 0.5 mug.kg(-1).h(-1) enhanced secretion stimulated by 1 U.kg(-1).h(-1) secretin but at 1 and 2 mug.kg(-1).h(-1) it abolished secretin response [30].
• Failure of secretin to stimulate gastrin release and adenylate cyclase activity in gastrinoma in vitro [14].
• It augmented CCK-induced pancreatic protein and secretin-induced HCO3 secretion in vivo but failed to affect basal or stimulated (CCK and urecholine) amylase release by the in vitro dispersed pancreatic acini [31].

Other interactions of SCT

• Human VPAC1 receptor selectivity filter. Identification of a critical domain for restricting secretin binding [21].
• Consistent with this idea, we found a putative CpG island (-336 to 262 from ATG) that overlaps with the human secretin gene promoter [1].
• Vasoactive intestinal peptide, pituitary adenylyl cyclase-activating peptide-38, and glucagon were less potent (by 3 orders of magnitude) than secretin in competitively inhibiting 125I-secretin binding to 293S12 cells [2].
• Secretin receptors in the human liver: Expression in biliary tract and cholangiocarcinoma, but not in hepatocytes or hepatocellular carcinoma [3].
• Thus BETA2 may function as a master regulatory gene to coordinate terminal differentiation of secretin cells [22].

Analytical, diagnostic and therapeutic context of SCT

• Northern blot analysis shows that human SCT transcripts are located in the spleen, intestinal tract, and brain [20].
• METHODS: Nineteen normal livers, 10 cirrhotic livers, 35 cholangiocarcinomas, and 45 hepatocellular carcinomas were investigated for secretin receptor expression by in vitro receptor autoradiography using (125)I-[Tyr(10)] rat secretin and, in selected cases, for secretin receptor mRNA by RT-PCR [3].
• The expression and spatial distribution of secretin and its receptor in human cerebellum were investigated by in situ hybridization and immunohistochemical techniques [32].
• The His-tagged recombinant HSR ectodomain may also be used for screening secretin-specific agonists and antagonists by affinity chromatography in the future [33].
• METHODS: One of the rare patients with this histologically proven tumor who had a normal serum gastrin level and a negative secretin-stimulation test result, and 2 more typical patients with this syndrome were investigated using immunohistochemistry, reverse-transcription polymerase chain reaction, receptor binding, and signaling assays [25].

References