Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic changes associated with some forms of chronic pancreatitis have been recently defined. There are three genes that play a role, each with a variety of genotypes and different pathologic mechanisms and clinical correlations. Selection of the appropriate diagnostic tests requires integration of the clinical and family history and the interpretation of results has a significant impact on genetic counseling for the patient and family. The relative significance of some variant alleles is still under investigation as they are common in the population and show low penetrance. Knowledge of the pathophysiology of each abnormal allele could lead the way towards more specific therapeutic options in the future.
Expert Rev Mol Diagn 2003 Nov
PMID:Genetic testing in chronic pancreatitis. 1462 7

Formation of fatty acid ethyl esters (FAEEs, catalyzed by FAEE synthase) has been implicated in the pathogenesis of chronic pancreatitis. In previous studies, we demonstrated that FAEE synthase, purified from rat liver microsomes, is identical to rat liver carboxylesterase (pI 6.1), and structurally and functionally different than that from pancreas. In this study, we purified and characterized rat pancreatic microsomal FAEE synthase, and determined its relationship with rat pancreatic cholesterol esterase (ChE). Since most of the serine esterases express p-nitrophenyl acetate (PNPA)-hydrolyzing activity as well as synthetic activity to form fatty acid esters or amides with a wide spectrum of alcohols and amines, respectively, we used PNPA-hydrolyzing activity to monitor the purification of FAEE synthase during various chromatographic purification steps. Synthesizing activity towards FAEEs, fatty acid methyl esters, and fatty acid anilides was measured only in the pooled fractions. At each step of purification (ammonium sulfate saturation, Q Sepharose XL, and heparin-agarose column chromatographies, and high performance liquid chromatography (anion exchange and gel filtration)) synthetic as well as hydrolytic activities copurified. Using ethanol, methanol, or aniline as substrates, the ester or anilide synthesizing activity of the purified protein was found to be 8709, 13000, and 2201 nmol/h/mg protein, respectively. The purified protein displayed a single band with an estimated molecular mass of approximately 68 kD upon SDS-PAGE under reduced denaturing conditions, cross-reacted with antisera against rat pancreatic ChE and showed 100% N-terminal sequence homology of the first 15 amino acids to that of rat pancreatic ChE. These results suggest that the purified protein has broad substrate specificity towards the conjugation of endogenous long chain fatty acids with substrates having hydroxyl and amino groups and is identical to ChE.
J Biochem Mol Toxicol 2003
PMID:Purification and characterization of rat pancreatic fatty acid ethyl ester synthase and its structural and functional relationship to pancreatic cholesterol esterase. 1470 89

Until now, no specific therapies are available to inhibit pancreatic fibrosis, a constant pathological feature of chronic pancreatitis and pancreatic cancer. One major reason is the incomplete knowledge of the molecular principles underlying fibrogenesis in the pancreas. In the past few years, evidence has been accumulated that activated pancreatic stellate cells (PSCs) are the predominant source of extracellular matrix (ECM) proteins in the diseased organ. PSCs are vitamin A-storing, fibroblast-like cells with close morphological and biochemical similarities to hepatic stellate cells (also known as Ito-cells). In response to profibrogenic mediators such as various cytokines, PSCs undergo an activation process that involves proliferation, exhibition of a myofibroblastic phenotype and enhanced production of ECM proteins. The intracellular mediators of activation signals, and their antagonists, are only partially known so far. Recent data suggest an important role of enzymes of the mitogen-activated protein kinase family in PSC activation. On the other hand, ligands of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma) stimulate maintenance of a quiescent PSC phenotype. In the future, targeting regulators of the PSC activation process might become a promising approach for the treatment of pancreatic fibrosis.
Mol Cancer 2004 Oct 06
PMID:Molecular regulation of pancreatic stellate cell function. 1546 5

Successful gene profiling studies involve careful experimental design, use of sensitive and accurate technologies, and statistically valid analysis of experimental results. In this chapter we describe our approach to the profiling of pancreatic adenocarcinoma to illustrate the various steps and methods involved in this type of study. Pancreatic adenocarcinoma is a particularly challenging subject for gene profiling, as these tumors have a profound desmoplastic response such that neoplastic epithelium makes up only a small proportion of the tissue mass. We have utilized statistical comparisons of gene expression between adenocarcinoma, normal pancreas, samples of chronic pancreatitis, and pancreatic cancer cell lines that provides a means to deduct the influence of the stromal elements. We utilized oligonucleotide-directed gene chips (Affymetrix), as they allow the simultaneous interrogation of thousands of genes in an efficient, reproducible, sensitive, and highly quantitative manner. The details of the approach we utilized are reported here, including information on experimental design, sample collection, expression level measurements, and data analysis for gene profiling.
Methods Mol Med 2005
PMID:Oligonucleotide-directed microarray gene profiling of pancreatic adenocarcinoma. 1554 6

Telomerase, which ensures the unlimited proliferation by adding TTAGGG repeat at the end of the chromosome, is strongly activated at a very high incidence in a variety of malignant neoplasms including pancreatic cancer. In addition to the acquisition of the immortality, telomerase plays an important role in the aggressive behavior of pancreatic cancer. Invasiveness of human pancreatic cancer cells correlates well with telomerase activity. Exposure of pancreatic cancer to anticancer drugs up-regulates telomerase activity, and the increase in telomerase activity correlates with resistance to the drug-induced apoptosis. More important, diagnositic values of telomerase activity are highly focused because of the lack of other specific genetic markers for pancreatic cancer. Samples of pancreatic juice are obtained at endoscopic retrograde pancreatography using a balloon catheter after intraveneous injection of secretin. Because the pancreatic juice has strong protease and RNase activity, addition of protease inhibitors and RNase inhibitors in the telomerase extraction buffer is necessary for the detection of telomerase activity in the pancreatic juice. A telomeric ladder was detected in 80% patients with carcinoma, whereas only 4.3% patients with adenoma and none with chronic pancreatitis showed positive telomerase activity.
Methods Mol Med 2005
PMID:Detection of telomerase activity in patients with pancreatic cancer. 1554 8

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Previously, it has been shown that Indian hedgehog (Ihh) and its two signaling receptors patched (Ptc) and smoothened (Smo) are involved in the pathogenesis of chronic pancreatitis (CP) and PDAC. In the current study we analyzed the expression, distribution, and function of another component of this signaling pathway, the human hedgehog-interacting protein (Hip), in the normal pancreas, CP and PDAC utilizing real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR), immunohistochemistry, immunofluorescence, Hip siRNA transfection, cell growth assays, and cell cycle analysis. By QRT-PCR, Hip mRNA levels were fifteenfold and fourteenfold increased in CP (n = 22) and PDAC (n = 31) tissues, respectively, compared to normal pancreatic tissues (n=20) and correlated with glioma associated antigen (Gli1) but not Ptc or Protein kinase A (PKA) mRNA levels. Only SU-8686 and BxPC-3 pancreatic cancer cells expressed Hip mRNA, whereas expression was below the level of detection in the other six pancreatic cancer cell lines tested. As shown by immunohistochemistry, Hip was expressed in normal pancreatic tissues mainly in the cytoplasm of islet cells and in smooth muscle cells of blood vessels. In contrast, in CP and PDAC there was a different distribution and staining intensity within the islets. Moreover, Hip immunoreactivity was observed in the tubular complexes, PanIN 1-3 lesions, as well as in pancreatic cancer cells. Incubation of pancreatic cancer cell lines with recombinant Hip revealed a growth inhibitory effect in SU-8686 and Capan-1 pancreatic cancer cells and no effect on cell growth in the other tested cell lines. In addition, silencing of Hip expression using specific siRNA molecules increased the growth of SU-8686 cells. In conclusion, Hip is expressed in the normal pancreas, CP and PDAC tissues. The different pattern of Hip expression and abnormal localization in the diseased pancreas suggest that the enhanced activation of hedgehog signaling in CP and PDAC is-at least in part-due to the aberrant responsiveness and expression of Hip in these diseases.
Mol Carcinog 2005 Apr
PMID:Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. 1575 13

Autoimmune pancreatitis, an inflammatory process of the pancreas due to an autoimmune mechanism establishing etiology of chronic pancreatitis, is characterized by the presence of autoantibodies, hypergammaglobulinemia, pancreatic enlargement, pancreatic duct strictures, and pathologic features of fibrotic changes with intense, mainly lymphocytic infiltrations, which may contribute to tissue destruction probably by apoptosis. In almost 60% of the cases, this type of pancreatitis coexists with other autoimmune diseases such as Sjogren's syndrome, sclerosing extrahepatic cholangitis, primary biliary cirrhosis, autoimmune hepatitis, or other extrapancreatic disorders, and recently with gastric peptic ulceration. The diversity of extrapancreatic lesions with similar histopathologic findings suggests general involvement of the digestive system in this disease, although the presence of such involvement has not been fully elucidated. Similarly, Helicobacter pylori (H. pylori) infection, a well known cause of gastric ulcer, has been associated, via molecular mimicry of host structures by its constituents with the same autoimmune conditions, also characterized by fibrotic changes and/or lymphoplasmacytic inflammations, accompanied by aberrations of T cell apoptosis that contribute to hepatobiliary- or extrahepatic-tissue destruction. Considering that H. pylori is involved in the pathogenesis and pathophysiology of these autoimmune disorders, we propose that this organism might trigger autoimmune pancreatitis through induction of autoimmunity and apoptosis.
J Cell Mol Med
PMID:A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis. 1578 77

Pancreatic stellate cells (PSCs) are thought to be the primary source of the extensive fibrotic reaction characteristic of pancreatic cancer and chronic pancreatitis in humans. PSCs share many morphological and functional characteristics with hepatic stellate cells (HSCs), whose central role in liver fibrosis is well established. However, it has remained unclear if hepatic and pancreatic stellate cells are derived from a common cell lineage and if they are completely similar or if they possess organ-specific features. We have analysed the transcriptomes of HSCs, PSCs and skin fibroblasts to assess how the transcriptional phenotype of stellate cells differs from that of a typical fibroblast lineage cell and if there is evidence for a common stellate cell precursor. To this end, we have performed expression profiling of primary cultures of human HSCs, PSCs and skin fibroblasts using 23,000-feature 'whole genome' oligonucleotide micro-arrays. Expression data were verified using real-time PCR. The expression profiles of HSCs and PSCs displayed a great extent of similarity, clearly separating them from the fibroblasts. Predominantly extracellular and cell surface genes, but also signalling molecules, transcription factors and novel neural markers, were concordantly expressed in both stellate cell types. Despite this high degree of similarity, distinct differences in expression patterns were observed between HSCs and PSCs, reflecting organ-specific variations of the common stellate cell-specific phenotype.
J Mol Med (Berl) 2005 Oct
PMID:Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. 1597 18

Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.
J Cell Mol Med
PMID:Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. 1620 14

Autoimmune pancreatitis is a recently defined nosological entity, which accounts for 4.6-6% of all forms of chronic pancreatitis and is often associated with other autoimmune diseases, particularly Sjogren's syndrome. Possession of the HLA DRB1*0405-DQB1*0401 genotype confers a risk for the development of autoimmune pancreatitis. Autoantibodies against carbonic anhydrase II and lactoferrin are frequently present in affected subjects and are suspected to have a pathogenic role. A link between gastric infection by Helicobacter pylori and autoimmune pancreatitis has been hypothesized. We used in silico protein analysis and search for HLA binding motifs to verify this hypothesis. We found a significant homology between human carbonic anhydrase II and alpha-carbonic anhydrase of Helicobacter pylori, an enzyme which is fundamental for the survival and proliferation of the bacterium in the gastric environment. Moreover, the homologous segments contain the binding motif of the HLA molecule DRB1*0405. Our data strengthen the hypothesis that gastric Helicobacter pylori infection can trigger autoimmune pancreatitis in genetically predisposed subjects.
J Cell Mol Med
PMID:Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? 1620 23


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