Insulin is a central regulator of glycolysis and de novo lipogenesis in the liver. However, hepatic glucose metabolism has been shown to activate the transcription of glycolytic and lipogenenic enzymes independently of insulin. The nuclear liver X receptors LXRa and LXRb play a major role in glucose and lipid metabolism, regulating transcription of glycolytic and lipogenic enzymes in liver, which is believed to be mediated by oxysterol ligand activation and insulin signaling. The majority of hepatic glucose-responsive genes are regulated by carbohydrate response element-binding protein (ChREBP), a transcriptional regulator that requires glucose metabolism via the hexosamine biosynthetic pathway and O-GlcNAc transferase (OGT)-mediated O-GlcNAc modification for full activation. We have previously shown that also LXRs are targets for O-GlcNAc modification in response to glucose and refeeding, promoting lipogenic gene expression. We recently addressed the relative roles of insulin, glucose and LXR in regulating hepatic glycolytic and lipogenic gene expression in vivo by subjecting untreated control and streptozotocin (STZ)-treated LXRa/b +/+ and LXRa/b -/- mice to a fasting-refeeding regime. STZ was used to destroy pancreatic β-cells and insulin production. We found that under hyperglycemic and hypoinsulinemic conditions, LXRs maintained their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), sterol regulatory element-binding protein (SREBP-1c), ChREBPa and the newly identified shorter isoform ChREBPb. ChREBPa expression became dependent on LXR under hyperglycemic and hypoinsulinemic conditions, which was mediated, at least in part, by OGT signaling. Moreover, we found that LXR and OGT interacted and co-localized in the nucleus in Huh7 cells and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling, ChREBP O-GlcNAcylation and activity in vivo . We propose that LXR regulation of nuclear O-GlcNAc signaling and ChREBP O-GlcNAcylation is part of a mechanism linking hepatic glucose utilization with lipid synthesis.
{"title":"Liver X receptors connect nuclear O-GlcNAc signaling to hepatic glucose utilization and lipogenesis","authors":"C. Bindesbøll, L. M. Grønning-Wang","doi":"10.14800/RCI.897","DOIUrl":"https://doi.org/10.14800/RCI.897","url":null,"abstract":"Insulin is a central regulator of glycolysis and de novo lipogenesis in the liver. However, hepatic glucose metabolism has been shown to activate the transcription of glycolytic and lipogenenic enzymes independently of insulin. The nuclear liver X receptors LXRa and LXRb play a major role in glucose and lipid metabolism, regulating transcription of glycolytic and lipogenic enzymes in liver, which is believed to be mediated by oxysterol ligand activation and insulin signaling. The majority of hepatic glucose-responsive genes are regulated by carbohydrate response element-binding protein (ChREBP), a transcriptional regulator that requires glucose metabolism via the hexosamine biosynthetic pathway and O-GlcNAc transferase (OGT)-mediated O-GlcNAc modification for full activation. We have previously shown that also LXRs are targets for O-GlcNAc modification in response to glucose and refeeding, promoting lipogenic gene expression. We recently addressed the relative roles of insulin, glucose and LXR in regulating hepatic glycolytic and lipogenic gene expression in vivo by subjecting untreated control and streptozotocin (STZ)-treated LXRa/b +/+ and LXRa/b -/- mice to a fasting-refeeding regime. STZ was used to destroy pancreatic β-cells and insulin production. We found that under hyperglycemic and hypoinsulinemic conditions, LXRs maintained their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), sterol regulatory element-binding protein (SREBP-1c), ChREBPa and the newly identified shorter isoform ChREBPb. ChREBPa expression became dependent on LXR under hyperglycemic and hypoinsulinemic conditions, which was mediated, at least in part, by OGT signaling. Moreover, we found that LXR and OGT interacted and co-localized in the nucleus in Huh7 cells and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling, ChREBP O-GlcNAcylation and activity in vivo . We propose that LXR regulation of nuclear O-GlcNAc signaling and ChREBP O-GlcNAcylation is part of a mechanism linking hepatic glucose utilization with lipid synthesis.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88451687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Goffin, Chi Zhang, P. England, I. Broutin, B. Kragelund
The prolactin receptor (PRLR) is an archetype cytokine receptor. It is a single-pass transmembrane receptor with limited complexity that is devoid of enzyme activity. Intracellular signaling involves various receptor-associated kinases including Jak2, Erk1/2, Src and Akt. As the PRLR is emerging as a relevant target in Oncology the understanding of the molecular basis of its activation is crucial. In the frame of an inter-disciplinary consortium involving biophysicists, structural biologists and cell biologists, we have successfully combined complementary approaches such as optical and nuclear magnetic resonance spectroscopic analyses, X-ray crystallography, surface plasmon resonance and cell-based assays to start elucidate the structural features of ligand-receptor interaction. However, the features of the PRLR extracellular domain (ECD) that participate in the transmission of the hormonal message across the cell membrane and/or in selective activation of intracellular signaling cascades remained uncharacterized. In two recently published studies, we identified residues 146 and 170 as two key residues of the PRLR-ECD that control critical receptor properties including basal signaling activity, ligand sensitivity, species specificity, folding, stability and receptor turnover. These two residues are in close proximity of each other in the membrane proximal domain of the PRLR-ECD and participate in a network of interactions with other residues, in particular within a specific residue quartet. Strikingly, these residues are involved in, or close to, the receptor dimerization interface, suggesting that their mechanism of action may involve structural reorientation of the receptor chains that are necessary to (selectively) disseminate the signal from the ECD to the intracellular domain. The identification of such residues in this and other cytokine receptors should affect future structure-directed drug development strategies aimed at providing pathway-selective treatment strategies.
{"title":"Structural motifs in the extracellular domain of the prolactin receptor govern fold and functionality","authors":"V. Goffin, Chi Zhang, P. England, I. Broutin, B. Kragelund","doi":"10.14800/RCI.883","DOIUrl":"https://doi.org/10.14800/RCI.883","url":null,"abstract":"The prolactin receptor (PRLR) is an archetype cytokine receptor. It is a single-pass transmembrane receptor with limited complexity that is devoid of enzyme activity. Intracellular signaling involves various receptor-associated kinases including Jak2, Erk1/2, Src and Akt. As the PRLR is emerging as a relevant target in Oncology the understanding of the molecular basis of its activation is crucial. In the frame of an inter-disciplinary consortium involving biophysicists, structural biologists and cell biologists, we have successfully combined complementary approaches such as optical and nuclear magnetic resonance spectroscopic analyses, X-ray crystallography, surface plasmon resonance and cell-based assays to start elucidate the structural features of ligand-receptor interaction. However, the features of the PRLR extracellular domain (ECD) that participate in the transmission of the hormonal message across the cell membrane and/or in selective activation of intracellular signaling cascades remained uncharacterized. In two recently published studies, we identified residues 146 and 170 as two key residues of the PRLR-ECD that control critical receptor properties including basal signaling activity, ligand sensitivity, species specificity, folding, stability and receptor turnover. These two residues are in close proximity of each other in the membrane proximal domain of the PRLR-ECD and participate in a network of interactions with other residues, in particular within a specific residue quartet. Strikingly, these residues are involved in, or close to, the receptor dimerization interface, suggesting that their mechanism of action may involve structural reorientation of the receptor chains that are necessary to (selectively) disseminate the signal from the ECD to the intracellular domain. The identification of such residues in this and other cytokine receptors should affect future structure-directed drug development strategies aimed at providing pathway-selective treatment strategies.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"388 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88645053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiovascular disease (CVD) is the deadliest disease in the US and finding cures for CVD has been a pressing and challenging problem in biomedical science. Atherosclerosis is a pathological condition caused by an elevated plasma LDL cholesterol level and its deposition in the arterial wall. Although cholesterol-lowering therapies are currently effective in reducing circulating LDL cholesterol level, clinical trials have shown limited impact on reducing CVD risk. Thus, a supplemental treatment is urgently needed. Subendothelial LDL retention in the arterial wall is an early step in the atherogenic process, and finding the regulators that can be targeted to block this retention offers an alternative approach for early prevention. This review first presents the current understanding about the mechanism of the atherosclerosis development, and then focus on perlecan and its role in atherosclerosis. Perlecan is a major arterial proteoglycan consisting of a core protein and three heparan sulfate (HS) side chains. Many studies have linked perlecan to atherosclerosis because its HS side chains interact with LDL. Recently, we reported that the perlecan core protein also interacts with LDL via its LDL receptor (LDLR)-like domain II. Critical to the interaction is the sialic acid modification on the domain. In this review, the recent findings and the potential role of the arterial sialic acid in the early subendothelial LDL retention are discussed.
{"title":"The perlecan LDL-binding receptor needs sugar: Implication of perlecan core protein interaction with LDL for atherosclerosis","authors":"Yu-Xin Xu","doi":"10.14800/RCI.867","DOIUrl":"https://doi.org/10.14800/RCI.867","url":null,"abstract":"Cardiovascular disease (CVD) is the deadliest disease in the US and finding cures for CVD has been a pressing and challenging problem in biomedical science. Atherosclerosis is a pathological condition caused by an elevated plasma LDL cholesterol level and its deposition in the arterial wall. Although cholesterol-lowering therapies are currently effective in reducing circulating LDL cholesterol level, clinical trials have shown limited impact on reducing CVD risk. Thus, a supplemental treatment is urgently needed. Subendothelial LDL retention in the arterial wall is an early step in the atherogenic process, and finding the regulators that can be targeted to block this retention offers an alternative approach for early prevention. This review first presents the current understanding about the mechanism of the atherosclerosis development, and then focus on perlecan and its role in atherosclerosis. Perlecan is a major arterial proteoglycan consisting of a core protein and three heparan sulfate (HS) side chains. Many studies have linked perlecan to atherosclerosis because its HS side chains interact with LDL. Recently, we reported that the perlecan core protein also interacts with LDL via its LDL receptor (LDLR)-like domain II. Critical to the interaction is the sialic acid modification on the domain. In this review, the recent findings and the potential role of the arterial sialic acid in the early subendothelial LDL retention are discussed.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84291685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Y. Miki, Misaki Fue, K. Takagi, Chiaki Hashimoto, S. Tanaka, Takashi Suzuki, K. Ito
The androgen receptor (AR) is known to play critical roles in the malignancy of prostate cancer as well as the management of male reproductive organs. Endometrial carcinoma, one of the major female cancers, is considered an androgen-related cancer. However, the importance of androgen signaling through its receptor in endometrial carcinomas has not yet been clarified. We recently demonstrated the significance of androgen signaling and intracrine dihydrotestosterone (DHT) in endometrial carcinomas as follows: 1) A positive status of androgen receptor (AR) was significantly associated with high rates of progression-free survival (PFS), but not with endometrial cancer-specific survival (ECSS) in endometrial carcinoma patients; 2) The potent androgen DHT was synthesized from testosterone by 5α-reductase in endometrial carcinoma tissues; and 3) endometrial carcinoma patients that were AR/5α-reductase type 1 double-negative had significantly worse PFS and ECSS. These findings suggest that androgen signaling exerts anti-cancer effects through the intratumoral DHT-AR pathway in endometrial carcinomas. In this highlight article, we describe androgen signaling in endometrial carcinomas, focusing mainly on our recent study entitled “The role of 5α-reductase type 1 associated with intratumoral dihydrotestosterone concentrations in human endometrial carcinoma” and discuss the findings of some previous related studies.
{"title":"Androgen receptor and intracrine androgen signaling in endometrial carcinomas","authors":"Y. Miki, Misaki Fue, K. Takagi, Chiaki Hashimoto, S. Tanaka, Takashi Suzuki, K. Ito","doi":"10.14800/RCI.853","DOIUrl":"https://doi.org/10.14800/RCI.853","url":null,"abstract":"The androgen receptor (AR) is known to play critical roles in the malignancy of prostate cancer as well as the management of male reproductive organs. Endometrial carcinoma, one of the major female cancers, is considered an androgen-related cancer. However, the importance of androgen signaling through its receptor in endometrial carcinomas has not yet been clarified. We recently demonstrated the significance of androgen signaling and intracrine dihydrotestosterone (DHT) in endometrial carcinomas as follows: 1) A positive status of androgen receptor (AR) was significantly associated with high rates of progression-free survival (PFS), but not with endometrial cancer-specific survival (ECSS) in endometrial carcinoma patients; 2) The potent androgen DHT was synthesized from testosterone by 5α-reductase in endometrial carcinoma tissues; and 3) endometrial carcinoma patients that were AR/5α-reductase type 1 double-negative had significantly worse PFS and ECSS. These findings suggest that androgen signaling exerts anti-cancer effects through the intratumoral DHT-AR pathway in endometrial carcinomas. In this highlight article, we describe androgen signaling in endometrial carcinomas, focusing mainly on our recent study entitled “The role of 5α-reductase type 1 associated with intratumoral dihydrotestosterone concentrations in human endometrial carcinoma” and discuss the findings of some previous related studies.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75602140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marion Weber-Boyavt, Henriikka Kentala, V. Olkkonen
The functions of lipids as signaling compounds and their interorganelle transport are topics that have recently moved to the center stage of cell biological and biomedical research. In this context the concept of membrane contact sites (MCS), sites of close apposition of organelle membranes, is an emerging major theme. An increasing number of studies have revealed crucial roles of such contacts as sites with prominent functions in interorganelle lipid transport and metabolism as well as signaling nodes, and molecular machineries operating at MCSs are being identified (reviewed by ). One of the protein families reported to localize at membrane contacts are the Oxysterol-binding protein/OSBP-related proteins (ORPs), sterol/phospholipid binding proteins implicated in a variety of cellular functions: lipid metabolism and transport, vesicle transport and signaling cascades .
{"title":"A family of sterol sensors/transporters at membrane contact sites: Regulation of ORP-VAP complexes by sterol ligands","authors":"Marion Weber-Boyavt, Henriikka Kentala, V. Olkkonen","doi":"10.14800/RCI.830","DOIUrl":"https://doi.org/10.14800/RCI.830","url":null,"abstract":"The functions of lipids as signaling compounds and their interorganelle transport are topics that have recently moved to the center stage of cell biological and biomedical research. In this context the concept of membrane contact sites (MCS), sites of close apposition of organelle membranes, is an emerging major theme. An increasing number of studies have revealed crucial roles of such contacts as sites with prominent functions in interorganelle lipid transport and metabolism as well as signaling nodes, and molecular machineries operating at MCSs are being identified (reviewed by ). One of the protein families reported to localize at membrane contacts are the Oxysterol-binding protein/OSBP-related proteins (ORPs), sterol/phospholipid binding proteins implicated in a variety of cellular functions: lipid metabolism and transport, vesicle transport and signaling cascades .","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87889004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Adenosine is a potent anti-inflammatory molecule that plays an important role in many diseases. Extracellular levels of adenosine are determined by a combination of membrane transporters and ecto-nucleotidases such as CD73. Therapeutic targeting of the adenosinergic pathway, such as administration of adenosine receptor agonists, could be a valuable approach in the treatment of rheumatoid arthritis(RA). Until recently, the role of CD73 in RA pathogenesis had not been established. Using CD73-deficient gene-targeted mice, we demonstrated that CD73 plays a critical protective role in collagen-induced arthritis (CIA) in mice. Our findings, together with the results of recently published human studies, thus suggests that enhancement of CD73 activity may be a novel therapeutic approach in RA.
{"title":"CD73 in Autoimmune Arthritis","authors":"P. Chrobak, J. Stagg","doi":"10.14800/RCI.834","DOIUrl":"https://doi.org/10.14800/RCI.834","url":null,"abstract":"Abstract Adenosine is a potent anti-inflammatory molecule that plays an important role in many diseases. Extracellular levels of adenosine are determined by a combination of membrane transporters and ecto-nucleotidases such as CD73. Therapeutic targeting of the adenosinergic pathway, such as administration of adenosine receptor agonists, could be a valuable approach in the treatment of rheumatoid arthritis(RA). Until recently, the role of CD73 in RA pathogenesis had not been established. Using CD73-deficient gene-targeted mice, we demonstrated that CD73 plays a critical protective role in collagen-induced arthritis (CIA) in mice. Our findings, together with the results of recently published human studies, thus suggests that enhancement of CD73 activity may be a novel therapeutic approach in RA.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85781854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Growth is a highly coordinated process which is sustained by several growth factors and apoptotic factors. Any disturbance in this delicate balance leads to pathologies and genes that have such potential to produce tumors when mutated are known as oncogenes. EGFR an important growth factor that is involved in several physiological processes is presently one of the most common genes in targeted cancer therapies. Though, its potential as an oncogene target in head and neck epithelial tumors like squamous cell carcinoma is gaining importance and opening doors to revolutionizing cancer treatment modalities, its role in other head and neck epithelia like odontogenic epithelia remains vague and needs attention. The present article highlights some of the key findings in our research evaluating the role of EGFR in physiologic odontogenic epithelium that is comprised within pericoronal follicles. The research involved study of immunohistochemical examination of 35 pericoronal follicles removed from patients with asymptomatic impacted tooth extractions. The follicles were assessed for intensity, percentage of staining and location of the EGFR stain. The follicles predominantly showed intense staining pattern and location of EGFR positivity in most epithelium and rests were combined both cytoplasmic and membrane positivity. These findings reemphasize the inherent proliferative potential present in follicles and their role in formation of odontogenic tumors like ameloblastomas in long term impacted teeth. The potential of EGFR as a treatment target in odontogenic tumors also remains plausible.
{"title":"Role of Epidermal growth factor receptor in odontogenic epithelium and development of odontogenic lesions.","authors":"Bhavna C. Mohan, P. Angadi","doi":"10.14800/RCI.824","DOIUrl":"https://doi.org/10.14800/RCI.824","url":null,"abstract":"Growth is a highly coordinated process which is sustained by several growth factors and apoptotic factors. Any disturbance in this delicate balance leads to pathologies and genes that have such potential to produce tumors when mutated are known as oncogenes. EGFR an important growth factor that is involved in several physiological processes is presently one of the most common genes in targeted cancer therapies. Though, its potential as an oncogene target in head and neck epithelial tumors like squamous cell carcinoma is gaining importance and opening doors to revolutionizing cancer treatment modalities, its role in other head and neck epithelia like odontogenic epithelia remains vague and needs attention. The present article highlights some of the key findings in our research evaluating the role of EGFR in physiologic odontogenic epithelium that is comprised within pericoronal follicles. The research involved study of immunohistochemical examination of 35 pericoronal follicles removed from patients with asymptomatic impacted tooth extractions. The follicles were assessed for intensity, percentage of staining and location of the EGFR stain. The follicles predominantly showed intense staining pattern and location of EGFR positivity in most epithelium and rests were combined both cytoplasmic and membrane positivity. These findings reemphasize the inherent proliferative potential present in follicles and their role in formation of odontogenic tumors like ameloblastomas in long term impacted teeth. The potential of EGFR as a treatment target in odontogenic tumors also remains plausible.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78771163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immune checkpoints play a vital role in regulating the immune system. They preserve the immunological balance between preventing continuous activated immune responses and defending against chronic infections and cancer. Blocking the immune inhibitory checkpoints pathways recently emerged as a ‘game changer’ approach in cancer and antiviral immunotherapy. Modeling these pathways at the atomic level provides a key step toward rationally designing selective blockers for these pathways. Current crystal structures for the immune checkpoints are mainly not for human and are very limited in their scope of interactions. Our team has been focused on building atomistic models for these proteins, characterizing their protein-protein interactions and designing new inhibitory drugs for their activity. This article highlights our recent study on modelling the human Programmed Death-1 (hPD-1) pathway by characterizing the interactions between hPD-1 and its two human ligands. In this study, we showed that hPD1 binds differently to its two ligands. We also showed that the modes of binding for each ligand are different between mouse and human, emphasizing the limited information in current mouse crystal structures. Our findings enhanced the understanding of the receptor-ligand(s) interactions and formed a significant step toward building a full model for the whole PD1 pathway. This undoubtedly will foster the ongoing efforts to develop antibodies and small molecule drugs against this important T cell immune-regulatory mechanism.
{"title":"Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway","authors":"Marawan Ahmed, K. Barakat","doi":"10.14800/RCI.825","DOIUrl":"https://doi.org/10.14800/RCI.825","url":null,"abstract":"Immune checkpoints play a vital role in regulating the immune system. They preserve the immunological balance between preventing continuous activated immune responses and defending against chronic infections and cancer. Blocking the immune inhibitory checkpoints pathways recently emerged as a ‘game changer’ approach in cancer and antiviral immunotherapy. Modeling these pathways at the atomic level provides a key step toward rationally designing selective blockers for these pathways. Current crystal structures for the immune checkpoints are mainly not for human and are very limited in their scope of interactions. Our team has been focused on building atomistic models for these proteins, characterizing their protein-protein interactions and designing new inhibitory drugs for their activity. This article highlights our recent study on modelling the human Programmed Death-1 (hPD-1) pathway by characterizing the interactions between hPD-1 and its two human ligands. In this study, we showed that hPD1 binds differently to its two ligands. We also showed that the modes of binding for each ligand are different between mouse and human, emphasizing the limited information in current mouse crystal structures. Our findings enhanced the understanding of the receptor-ligand(s) interactions and formed a significant step toward building a full model for the whole PD1 pathway. This undoubtedly will foster the ongoing efforts to develop antibodies and small molecule drugs against this important T cell immune-regulatory mechanism.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88820033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Androgens and glucocorticoids have competitive and compensatory effects in several physiological and pathophysiological processes. Although blood androgen levels affect blood glucocorticoid levels and vice versa, it does not fully explain the relationship between the effects of androgens and glucocorticoids. Androgens and glucocorticoids exert their functions through binding to androgen receptor (AR) and glucocorticoid receptor (GR), respectively. AR homodimer and GR homodimer bind to the androgen response element (ARE) and glucocorticoid response element (GRE), respectively, where they positively or negatively regulate transcription. AR/GR heterodimer can also form but whether it has a physiological role is unclear. Notably, some ARE/GRE sites are recognized by both AR and GR. This review focuses on the functional interventions between androgen signaling and glucocorticoid signaling in target cells that are involved in muscle atrophy, lipid metabolism in adipocytes and hepatocytes, and pancreatic β-cell death. Androgens and glucocorticoids exert opposite effects by differentially regulating key genes ( e.g. , insulin-like growth factor-1, atrogin-1, and thioredoxin-interacting protein) involved in these physiological processes. We also review functional compensation between these steroids in the development of castration-resistant prostate cancer in which glucocorticoids compensate for the castration-induced loss of AR function by activating key genes ( e.g. , serum/glucocorticoid-regulated kinase 1). The gene expressions regulated by androgens and glucocorticoids are regulated through at least three different mechanisms in target cells: (i) regulation of applicable ligand levels by modulation of steroid metabolite enzyme levels, (ii) regulation of each other's receptor levels, and (iii) competitive binding between AR and GR on ARE/GRE sites. Recent findings shed light on the complicated relationship between androgen signaling and glucocorticoid signaling in various cellular processes.
{"title":"Competitive and compensatory effects of androgen signaling and glucocorticoid signaling","authors":"Naoki Harada, H. Inui, R. Yamaji","doi":"10.14800/RCI.785","DOIUrl":"https://doi.org/10.14800/RCI.785","url":null,"abstract":"Androgens and glucocorticoids have competitive and compensatory effects in several physiological and pathophysiological processes. Although blood androgen levels affect blood glucocorticoid levels and vice versa, it does not fully explain the relationship between the effects of androgens and glucocorticoids. Androgens and glucocorticoids exert their functions through binding to androgen receptor (AR) and glucocorticoid receptor (GR), respectively. AR homodimer and GR homodimer bind to the androgen response element (ARE) and glucocorticoid response element (GRE), respectively, where they positively or negatively regulate transcription. AR/GR heterodimer can also form but whether it has a physiological role is unclear. Notably, some ARE/GRE sites are recognized by both AR and GR. This review focuses on the functional interventions between androgen signaling and glucocorticoid signaling in target cells that are involved in muscle atrophy, lipid metabolism in adipocytes and hepatocytes, and pancreatic β-cell death. Androgens and glucocorticoids exert opposite effects by differentially regulating key genes ( e.g. , insulin-like growth factor-1, atrogin-1, and thioredoxin-interacting protein) involved in these physiological processes. We also review functional compensation between these steroids in the development of castration-resistant prostate cancer in which glucocorticoids compensate for the castration-induced loss of AR function by activating key genes ( e.g. , serum/glucocorticoid-regulated kinase 1). The gene expressions regulated by androgens and glucocorticoids are regulated through at least three different mechanisms in target cells: (i) regulation of applicable ligand levels by modulation of steroid metabolite enzyme levels, (ii) regulation of each other's receptor levels, and (iii) competitive binding between AR and GR on ARE/GRE sites. Recent findings shed light on the complicated relationship between androgen signaling and glucocorticoid signaling in various cellular processes.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85811532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fibroproliferative disorders are an ongoing clinical issue that is prevalent within society today. These disorders generally manifest themselves by an overproduction of fibrotic tissue with unknown provocation resulting in numerous detrimental defects. Cellular migration of blood-borne cells via the chemotactic pathway, consisting of stromal cell-derived factor 1 and its receptor, CXCR4, has been strongly implicated in post-burn hypertrophic scar formation. Evidence has shown this pathway has potential as a therapeutic target in the formation of hypertrophic scar and likely in other fibroproliferative disorders.
{"title":"A Potential Role of SDF-1/CXCR4 Chemotactic Pathway in Wound Healing and Hypertrophic Scar Formation","authors":"L. Campeau, Jie Ding, E. Tredget","doi":"10.14800/RCI.791","DOIUrl":"https://doi.org/10.14800/RCI.791","url":null,"abstract":"Fibroproliferative disorders are an ongoing clinical issue that is prevalent within society today. These disorders generally manifest themselves by an overproduction of fibrotic tissue with unknown provocation resulting in numerous detrimental defects. Cellular migration of blood-borne cells via the chemotactic pathway, consisting of stromal cell-derived factor 1 and its receptor, CXCR4, has been strongly implicated in post-burn hypertrophic scar formation. Evidence has shown this pathway has potential as a therapeutic target in the formation of hypertrophic scar and likely in other fibroproliferative disorders.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74850090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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