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Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acid that is involved in regulating gene expression related to bile acid, fat, glucose, and amino acid metabolism. The activity of FXR is regulated by a variety of post-translational modifications. Common post-translational modifications of FXR include O-GlcNAcylation, phosphorylation, acetylation, sumoylation, methylation, etc. These post-translational modifications may affect FXR binding of DNA and ligand, heterodimerization, and subcellular localization, and may specifically regulate downstream gene transcription and expression. Different post-translational modifications can lead to changes in FXR stability and biological function, which are closely related to the occurrence of diseases. This paper aims to review the post-translational modification of FXR in the past five years and the mechanisms involved in disease regulation, to explore the effects of post-translational modification on the physiological function of FXR and to provide a theoretical basis for mechanism research targeting FXR.
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O⁃glycosylation is a common post⁃translational modification of mucins, widely present in both normal and tumor cells. In colorectal cancer (CRC) cells, there is a varying degree of dysregulation in O ⁃ glycosylation ⁃ related glycosyltransferases, molecular chaperones, and surface Tn antigen, sTn antigen, and T antigen. These dysregulations play a distinctive role in the occurrence and development of CRC, including invasion and metastasis, abnormal apoptosis and proliferation, immune escape, etc. They are extensively studied as novel tumor biomarkers and potential therapeutic targets. This article provides a comprehensive review of progress of research on mucin⁃type O⁃glycosylation and its relevance to the occurrence and development of CRC and its clinical application.
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Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-β (TGF-β). TGF-β bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely, N-glycans, O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-β signaling components regulates TGF-β secretion, bioavailability and TGF-β receptor function. Then, we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-β signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.
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OBJECTIVE: To analyze the glycosylated chains of recombinant interleukin-15 fusion protein using capillary isoelectric focusing-whole column imaging detection (WCID-cIEF) spectrograms. METHODS: Using established corresponding mathematical models and the least square method, the WCID-cIEF spectrograms of whole protein, de-salicylic-acid protein and de-N-glycosylation-chain protein were analyzed. Among the mathematical models, the interval-1-peak model was selected. And according to the model, the relationship between isoform peak-areas and isoelectric points was listed. RESULTS: The rationality of the interval-1-peak model was confirmed and a series of basic data was obtained according to the model as follows:the apparent m value of the protein was 25.53 reference(R), the apparent n value of the protein was 28.83R, the apparent m value of sialic acid was 0.86 (0.855) R, the apparent n value was 0.12 (0.119) R, the apparent n value of N-acetylglucosamine (undifferentiated from N-acetylgalactosamine) was 0.06(0.061) R, and the apparent m value of formed carboxyl after N-chain removal was 0.19 (0.186) R. Some information of protein sugar composition was also obtained: the sialylation degree was about 1.83 mol•mol-1, the percentage of prototype protein was about 8.3%, the percentage of single N-glycosated modification protein was about 19.8%, the percentage of double N-glycosated modification protein was about 28.4%, the percentage of triple N-glycosated modification protein was about 23.7%, and the percentage of O-glycosated modification (with sialic acid) protein was about 19.8%. The main sugar types should be G0 (F), G1 (F), G2 (F), G1A1 (F), and G2A1 (F). CONCLUSION: The structure of sugar chain is complex, but it also has some repeatability and regularity. We hope that through this study, the glycoprotein sugar chain can be quickly outlined, the understanding of glycoprotein and the study of protein interaction can be improved.
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Glycosylation of proteins is an essential process in all eukaryotes. Mucin‑type O‑linked glycosylation is an evolutionarily conserved protein modification as a kind of glycosylation of proteins. The role of O‑glycosylation was well documented in multiple cancers. While in breast cancer, the enzymes that catalyzed the initiation of O‑glycosylation remained elusive. In this review, we briefly introduced the process of the initiation of O‑glycosylation and summarized the roles of enzymes that catalyzed the initiation step of O‑glycosylation in the breast cancer carcinogenesis, development, and progression. Finally, we summarized some attempts exploring the therapy against aberrant O‑glycosylation.
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Objective To study effect of Taxol on protein O-GlcNAcylation levels and investigate whether protein O-GlcNAcylation levels can affect the sensitivity of breast cancer cells to Taxol.Methods Western blot analysis was performed to examine protein O-GlcNAcylation levels and the expression of enzymes related to O-GlcNAcylation biosynthesis in Taxol treated breast cancer cells.RT-qPCR was used to analyze the effects of Taxol on OGA and OGT mRNA expression in cancer cells.The sulforhodamine B colorimetric assay was used to determine the effect of alteration of protein O-GlcNAcylation on the anti-proliferation of Taxol in breast cancer cells by adding OGA inhibitor and OGT inhibitor, respectively.Results Taxol treatment enhanced protein O-GlcNAcylation levels in dose-and time-dependent manners in breast cancer cell MDA-MB-231 ( P <0.05 ) .Taxol increased the mRNA levels of OGT and OGA after MDA-MB-231 cells were treated for 24 h(P<0.05).As OGA inhibitors increased protein O-GlcNAcylation levels, the sensitivity of MDA-MB-231 to Taxol was increased.As OGT inhibitor decreased protein O-GlcNAcylation levels, the sensitivity of MDA-MB-231 to Taxol was reduced.Conclusion Taxol treatment can enhance protein O-GlcNAcylation levels and the changes of O-GlcNAcylation levels alter the sensitivity of breast cancer cell MDA-MB-231 to Taxol.
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Es cada vez mayor la evidencia experimental y clínica de que el sistema inmune interviene activamente en la patogénesis y el control de la progresión tumoral. Una respuesta antitumoral efectiva depende de la correcta interacción de diversos componentes del sistema inmune, como las células presentadoras de antígeno y diferentes sub-poblaciones de células T. Sin embargo, los tumores malignos desarrollan numerosos mecanismos para evadir su reconocimiento y eliminación. Diversos estudios reportan que estructuras asociadas a tumor tales como los antígenos Tn y sialil-Tn se expresan en algunos parásitos protozoarios y helmintos, planteando numerosas interrogantes a nivel de la interacción parásito-hospedador. Considerando que existe una correlación negativa entre ciertas infecciones parasitarias y el desarrollo de cáncer, los antígenos de O-glicosilación incompleta obtenidos de parásitos podrían ser potenciales estructuras miméticas para la inducción de respuestas cruzadas contra antígenos tumorales. Actualmente, el área de la glicobiología del cáncer tiene muchas expectativas para encontrar solución a uno de los grandes problemas de salud que afecta a la población tanto desde el punto de vista económico como social.
There is increasing experimental and clinical evidence that the immune system plays an active role in the pathogenesis and control of tumor progression. An effective antitumor response depends on the correct interaction of the various components of the immune system, such as antigen presenting cells and sub-populations of T cells. However, malignant tumors develop numerous mechanisms to evade recognition and elimination. Several studies report that structures associated with tumors such as Tn and sialyl-Tn antigens are expressed in some protozoan parasites and helminths, thus raising many questions regarding parasite-host interactions. The negative correlation between certain parasite infections and cancer development suggests that antigens from incomplete O-glycosylation obtained from parasites could represent potential mimetic structures for inducing cross responses against tumor antigens. Currently, cancer glycobiology is a promising area in the search for a solution to one of the major health problems affecting the population both from an economic and a social perspective.
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Durante la carcinogénesis ocurren modificaciones importantes en la glicosilación, entre ellas la elongación incompleta de las cadenas sacarídicas con uniones de tipo O y la exposición de antígenos que en condiciones normales estaban ocultos, los cuales son reconocidos por componentes de la respuesta inmune que promueven o limitan el crecimiento tumoral. Diversos estudios reportan que estructuras asociadas a tumor tales como los antígenos Tn y sialil-Tn se expresan en algunos parásitos protozoarios y helmintos, planteando numerosas interrogantes a nivel de la interacción parásito-hospedador. Considerando que existe una correlación negativa entre ciertas infecciones parasitarias y el desarrollo de cáncer, los antígenos de O-glicosilación incompleta obtenidos de parásitos podrían ser potenciales blancos en la inmunoterapia del cáncer.
During carcinogenesis important modifications in glycosylation occur, among them incomplete elongation of the saccharide chains with type O bonds and the exposure of antigens that were hidden under normal conditions, which are recognized by components of the immune system which promote or limit tumor growth. Several studies report that tumor-associated structures, such as Tn and sialil-Tn, are expressed in some parasites protozoa and helminths, and pose many questions regarding parasite-host interaction. Considering the negative correlation between certain parasite infections and cancer development, antigens from incomplete O-glycosylation obtained from parasites could be potential targets in cancer immunotherapy.
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Objective To investigate the effect of glucose metabolism alteration induced by alloxan intraventricular injection on learning and memory abilities of mice, and its role in the development of AD. Methods Mice were randomly divided into high-dose alloxan intraventricular injection group (n=7, 4 mg/kg) and low-dose alloxan intraventricular injection group (n=7, 1.5 mg/kg)and control group (n=7, physiological saline); intraventricular injection of alloxan, the O-GLcNAc transferase inhibitor, was performed in the high-dose and low-dose alloxan intraventricular injection groups to interfere the brain glucose metabolism. Morris water maze was used to detect the learning and memory abilities of mice. Western blotting and immunohistochemistry were used to analyze the alterations of phosphorylation and O-Glycosylation of neurofilament in mice brain induced by alloxan intraventricular injection. Results In the located navigation tests, the swimming time and distance to find the platform in the mice of alloxan administration were significantly increased as compared with those in the control group (P＜ 0.05); in space exploration experiments, compared with those in the control mice, the number of crossing the hidden platform was decreased and the initial angle of entry to water was increased in the mice of alloxan administration (P＜0.05). Western blotting and immunohistochemistry displayed that phosphorylation was obviously increased and the O-Glycosylation was significantly reduced in the cytoskletal neurofilament of the mice with alloxan administration as compared with those in the control group (P＜0.05), which was similar to the alteration of neurofilament's modification in AD brain. Conclusion The inventricular injection of alloxan could impair the learning and memory of mice, which might have a relation with the dysregulation of phosphorylation and O-Glycosylation in neurofilament caused by the impaired glucose metabolism, which is similar to the alteration of phosphorylation and O-Glycosylation in neurofilament in AD brain.