Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.

• MeSH
• gastrointestinální nádory * genetika   MeSH
• karcinogeneze genetika   MeSH
• mukoproteiny genetika   MeSH
• myši MeSH
• nádorové mikroprostředí MeSH
• onkogenní proteiny * genetika   MeSH
• proteindisulfidisomerasy MeSH
• zánět genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• mukoproteiny MeSH
• onkogenní proteiny * MeSH
• proteindisulfidisomerasy MeSH

Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses.

• Klíčová slova
• AGR2, TMED2, endoplasmic reticulum, inflammation, proteostasis,
• MeSH
• endoplazmatické retikulum genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• homeostáze proteinů * MeSH
• lidé MeSH
• mukoproteiny genetika   metabolismus   MeSH
• multimerizace proteinu * MeSH
• myši MeSH
• onkogenní proteiny genetika   metabolismus   MeSH
• stres endoplazmatického retikula * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AGR2 protein, human MeSH Prohlížeč
• Agr2 protein, mouse MeSH Prohlížeč
• mukoproteiny MeSH
• onkogenní proteiny MeSH

Banana Fusarium wilt caused by Fusarium oxysporum f. sp. cubense (Foc) is soil-borne disease of banana (Musa spp.) causing significant economic losses. Extensins and arabinogalactan proteins (AGPs) are cell wall components important for pathogen defence. Their significance for Foc resistance in banana was not reported so far. In this study, two banana cultivars differing in Foc sensitivity were used to monitor the changes in transcript levels, abundance and distribution of extensins and AGPs after wounding and Foc inoculation. Extensins mainly appeared in the root cap and meristematic cells. AGPs recognized by JIM13, JIM8, PN16.4B4 and CCRC-M134 antibodies located in root hairs, xylem and root cap. Individual AGPs and extensins showed specific radial distribution in banana roots. At the transcript level, seven extensins and 23 AGPs were differentially expressed between two banana cultivars before and after treatments. Two extensins and five AGPs responded to the treatments at the protein level. Most extensins and AGPs were up-regulated by wounding and pathogen inoculation of intact plants but down-regulated by pathogen attack of wounded plants. Main components responsible for the resistance of banana were MaELP-2 and MaPELP-2. Our data revealed that AGPs and extensins represent dynamic cell wall components involved in wounding and Foc resistance.

• MeSH
• banánovník mikrobiologie   fyziologie   MeSH
• epitopy imunologie   MeSH
• Fusarium * MeSH
• glykoproteiny genetika   metabolismus   MeSH
• interakce hostitele a patogenu genetika   MeSH
• kořeny rostlin genetika   metabolismus   mikrobiologie   MeSH
• mukoproteiny genetika   metabolismus   MeSH
• nemoci rostlin genetika   mikrobiologie   MeSH
• odolnost vůči nemocem genetika   MeSH
• regulace genové exprese u rostlin * MeSH
• rostlinné proteiny genetika   imunologie   metabolismus   MeSH
• transport proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• arabinogalactan proteins MeSH Prohlížeč
• epitopy MeSH
• extensin protein, plant MeSH Prohlížeč
• glykoproteiny MeSH
• mukoproteiny MeSH
• rostlinné proteiny MeSH

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) contributes to the recruitment of donor T cells into the mucosal tissues of the recipient after allogeneic hematopoietic stem cell transplantation (aHSCT). The aim of our study was to determine whether selected single nucleotide polymorphisms (SNPs) of the MADCAM1 gene are associated with development of serious complications after aHSCT. Three MADCAM1 gene single nucleotide polymorphisms (rs758502 C/T, rs2302217 A/G, rs3745925 G/T) were genotyped by polymerase chain reaction with sequence-specific primers in 87 Czech, HLA-identical donor-recipient aHSCT pairs. MADCAM1 rs2302217 AA homozygous recipients developed chronic GVHD more frequently than patients with other genotypes (65% vs. 34%; p = 0.025). Furthermore, multivariate analysis revealed the MADCAM1 rs2302217 AA genotype in recipient being also an independent factor associated with development of acute GVHD (p = 0.036) and decreased overall survival (p = 0.001). These data suggest that MADCAM1 gene polymorphisms may be associated with the risk of chronic GVHD and may, also, affect mortality related to aHSCT.

• MeSH
• dospělí MeSH
• homologní transplantace MeSH
• imunoglobuliny genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• molekuly buněčné adheze MeSH
• mukoproteiny genetika   MeSH
• multivariační analýza MeSH
• nemoc štěpu proti hostiteli genetika   mortalita   MeSH
• transplantace hematopoetických kmenových buněk škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imunoglobuliny MeSH
• MADCAM1 protein, human MeSH Prohlížeč
• molekuly buněčné adheze MeSH
• mukoproteiny MeSH

Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.

• MeSH
• bazální membrána patologie   ultrastruktura   MeSH
• biopsie MeSH
• dítě MeSH
• dna (nemoc) MeSH
• dospělí MeSH
• genetická heterogenita * MeSH
• genetická vazba MeSH
• hyperurikemie genetika   metabolismus   MeSH
• hypofýza cytologie   MeSH
• imunohistochemie MeSH
• kultivované buňky MeSH
• ledvinové kanálky patologie   ultrastruktura   MeSH
• ledviny metabolismus   patologie   chirurgie   ultrastruktura   MeSH
• lidé MeSH
• lidské chromozomy, pár 1 MeSH
• lidské chromozomy, pár 16 MeSH
• missense mutace MeSH
• mladiství MeSH
• mukoproteiny genetika   metabolismus   moč   MeSH
• mutační analýza DNA MeSH
• polycystické ledviny autozomálně dominantní genetika   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• rodokmen MeSH
• sekvence nukleotidů MeSH
• syndrom MeSH
• transfekce MeSH
• uromodulin MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• mukoproteiny MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

BACKGROUND: Autosomal-dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are allelic, result from uromodulin (UMOD) mutations and the term uromodulin-associated kidney disease (UAKD) has been proposed for them. Linkage studies also reveal families that do not show linkage to any of the identified loci. To identify additional UAKD loci, we analyzed one of these families, with features suggestive of FJHN. METHODS: Clinical, biochemical, and immunohistochemical investigations were used for phenotype characterization. Genotyping, linkage and haplotype analyses were employed to identify the candidate disease region. Bioinformatics and sequencing were used for candidate gene selection and analyses. RESULTS: We identified a new candidate UAKD locus on chromosome 1q41, bounded by markers D1S3470 and D1S1644. We analyzed and found no linkage to this region in eight additional families, who did not map to the previously established loci. We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD. Immunohistochemical analysis showed that low UMOD excretion resulted from its reduced expression, which is a different mechanism to intracellular UMOD accumulation observed in cases with UMOD mutations. CONCLUSION: We have mapped a new candidate UAKD locus and shown that UAKD may be a consequence of various defects affecting uromodulin biology.

• MeSH
• chronická renální insuficience genetika   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• genetická vazba MeSH
• genotyp MeSH
• hyperurikemie genetika   metabolismus   MeSH
• ledviny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 * MeSH
• mapování chromozomů * MeSH
• mladiství MeSH
• mukoproteiny genetika   metabolismus   MeSH
• rodokmen MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• uromodulin MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mukoproteiny MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

Familial juvenile hyperuricemic nephropathy (FJHN), is an autosomal dominant renal disease characterized by juvenile onset of hyperuricemia, gouty arthritis, and progressive renal failure at an early age. Using a genomewide linkage analysis in three Czech affected families, we have identified, on chromosome 16p11.2, a locus for FJHN and have found evidence for genetic heterogeneity and reduced penetrance of the disease. The maximum two-point LOD score calculated with allowance for heterogeneity (HLOD) was 4.70, obtained at recombination fraction 0, with marker D16S3036; multipoint linkage analysis yielded a maximum HLOD score of 4.76 at the same location. Haplotype analysis defined a 10-cM candidate region between flanking markers D16S501 and D16S3113, exhibiting crossover events with the disease locus. The candidate interval contains several genes expressed in the kidney, two of which-uromodulin and NADP-regulated thyroid-hormone-binding protein-represent promising candidates for further analysis.

• MeSH
• crossing over (genetika) genetika   MeSH
• dítě MeSH
• dna (nemoc) komplikace   genetika   metabolismus   moč   MeSH
• dominantní geny genetika   MeSH
• dospělí MeSH
• genetická heterogenita * MeSH
• haplotypy genetika   MeSH
• hormony štítné žlázy * MeSH
• kyselina močová krev   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 16 genetika   MeSH
• Lod skóre MeSH
• mapování chromozomů MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mukoproteiny genetika   MeSH
• penetrance MeSH
• renální insuficience komplikace   genetika   metabolismus   moč   MeSH
• rodokmen MeSH
• transportní proteiny genetika   MeSH
• uromodulin MeSH
• vazebné proteiny hormonů štítné žlázy MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• hormony štítné žlázy * MeSH
• kyselina močová MeSH
• membránové proteiny MeSH
• mukoproteiny MeSH
• transportní proteiny MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH