ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive ind...ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive index of time-and dose-dependent specimens. The expression of c-kit was elevated both in positive rate and positive index by TGF-01 in both time- and dose-dependent manners. Ing/ml rhTGF-β1 simultaneously enhanced the expression of c-fms and PDGF-R which is not detected in 50 ng / ml GM-CSF treatment. Endoglin was down-regulated after TGF-β treatment and up-regulated in J6-2 cells after GM-CSF treatment, c-kit Expression was elevated by TGF-β in J6-1 cells while decreased by both in J6-2 cells.展开更多
By radioreceptor binding studies with iodinated TGF-β1, it has been shown that an undifferentiated ES-5 cell expresses approximately 3270 receptors with a dissociation constant Kd=130pM, but after the induction of di...By radioreceptor binding studies with iodinated TGF-β1, it has been shown that an undifferentiated ES-5 cell expresses approximately 3270 receptors with a dissociation constant Kd=130pM, but after the induction of differenti-ation by retinoic acid and dBcAMP, the receptor number of a differentiated RA-ES-5 cell was increased about 80% and the Kd was also increased to 370 pM. Furthermore,more direct evidence supporting the expression of TGF-βtype Ⅰand type Ⅱ receptors in both ES-5 and RA-ES-5 cells has come from dot blot hybridization of cellular mRNA with cDNA probes for type Ⅰ and type Ⅱ recep-tors. Meanwhile, mRNA expression level of types Ⅰ and Ⅱreceptors in RA-ES-5 cells were higher than that in ES-5 cells. Down regulation of TGF-β receptors with a signifi-cant decrease in the rate of cell proliferation in both cells, was found by employing a pretreatment with neutralizing antibody to TGF-β1. The possible role of receptors for TGF-β in cen differentiation is discussed here.展开更多
Transforming growth factor-β （TGF-β） binds with two transmembrane serine/threonine kinase receptors, type Ⅱ （TβRII） and type Ⅰ receptors （TβRⅠ）, and one accessory receptor, type Ⅲ receptor （TβRⅢ）, to...Transforming growth factor-β （TGF-β） binds with two transmembrane serine/threonine kinase receptors, type Ⅱ （TβRII） and type Ⅰ receptors （TβRⅠ）, and one accessory receptor, type Ⅲ receptor （TβRⅢ）, to transduce signals across cell membranes. Previous biochemical studies suggested that TβRI and TβRIII are preexisted homo-dimers. Using single-molecule microscopy to image green fluorescent protein-labeled membrane proteins, for the first time we have demonstrated that TβRI and TβRⅢ could exist as monomers at a low expression level. Upon TGF-β1 stimu- lation, TβRI follows the general ligand-induced receptor dimerization model for activation, but this process is TβRⅡ- dependent. The monomeric status of the non-kinase receptor TβRⅢ is unchanged in the presence of TGF-β1. With the increase of receptor expression, both TβRI and TβRIII can be assembled into dimers on cell surfaces.展开更多
Transforming growth factor-β?(TGF-β) superfamily is a key player in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β,...Transforming growth factor-β?(TGF-β) superfamily is a key player in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β, almost three decades ago, there have been tremendous advances in our understanding of its complex biology. TGF-β?misregulation has been implicated in the pathogenesis of a variety of diseases, including cancer with a direct role in facilitating metastasis, fibrosis and inflammation. Consequently, TGF-β?is currently explored as a prognostic candidate biomarker of tumor invasiveness and metastasis;and it offers an attractive target for cancer therapy. Several anti-TGF-β?approaches, such as TGF-β?antibodies, antisense oligonucleotides and small molecules inhibitors of TGF-β?type 1 receptor kinase, have shown great promise in the preclinical studies. Here, we consider why the TGF-βsignaling pathway is a drug target, the potential clinical applications of TGF-β?inhibition, the issues arising with anti-TGF-β?therapy and how these might be adopted using personalized approaches with a special care for patient selection and timing of therapy so that we may bring forward all the potentials of targeting this pathway for therapeutic uses in both cancer, preferentially in combination therapy, and non-neoplastic diseases.展开更多
Human gastric cancer MKN-45 cells which are resistant to TGF-β growth inhibition and possess TGF-β type Ⅰ and type Ⅲ receptors, but not type Ⅱ receptors, have been used as a model system to reconstitute these caf...Human gastric cancer MKN-45 cells which are resistant to TGF-β growth inhibition and possess TGF-β type Ⅰ and type Ⅲ receptors, but not type Ⅱ receptors, have been used as a model system to reconstitute these caflcer cells with TGF-β RII cDNA. The results of these experiments indicated that the reexpression of TGF-g RII gene in MKN-45 cells can restore their sensitivity to TGFβ growth inhibition, decrease their growth rate, reduce their cloning efficiency in soft agar and tumorigenicity in nude mice in stable transfectants, in comparison with their control MKN-45 cells. Among different RII transfectants,their difference in the changes of these parameters, as a result of the regain of autocrine negative growth control by TGF-β, is roughly proportional to their level of expression of transfected RII mRNA. From these data, it is concluded that the inactivation of TGF-β RII gene is related to the escape of growth control by TGF-β in MKN-45 cells. The importance of the study of the interplay of TGF-β and its receptor system in the negative growth control of gastric cancer, and possibly also of other cancers, is discussed.展开更多
Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β...Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,metabolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an IC_(50) of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.展开更多
Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aime...Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aimed to investigate whether NDQ ameliorate CRF by inhibiting transforming growth factor-β1(TGF-β1)-induced EMT in human renal tubular epithelial HK-2 cells.Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide assay and colony formation assay were used to investigate the cytotoxicity of NDQ in HK-2 cells.Morphological changes of HK-2 cells after TGF-β1 or/and NDQ treatment were observed under a microscope.Wound-healing,migration and invasion assays were performed to determine the cell movement,migratory and invasive abilities,respectively.Western blot analysis was carried out to examine the protein levels of TGF-βreceptor I(TβRI)and epithelial-mesenchymal transition(EMT)-associated factors.Fluorescence confocal microscopy was applied to observe the organization of filamentous actin.Results NDQ suppressed TβRI expression dose-dependently.NDQ inhibited TGF-β1-stimulated EMT in HK-2 cells,supported by the evidences that NDQ prevented morphology change,attenuated cell migration and invasion,downregulated EMT factors and reorganized filamentous actin distribution in TGF-β1-stimulated HK-2 cells.Conclusions NDQ attenuates chronic renal failure which may be associated with inhibition of TβRI expression and EMT process.展开更多
Transforming growth factor-β(TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in variou...Transforming growth factor-β(TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation.Receptor tyrosine kinases(RTKs), such as epidermal growth factor receptor(EGFR), fibroblast growth factor receptor(FGFR),vascular endothelial growth factor receptor(VEGFR) and platelet-derived growth factor receptor(PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity,while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.展开更多
The transforming growth factor-β(TGF-β)family controls embryogenesis,stem cell differentiation,and tissue homeostasis.However,how post-translation modifications contribute to fine-tuning of TGF-βfamily signaling re...The transforming growth factor-β(TGF-β)family controls embryogenesis,stem cell differentiation,and tissue homeostasis.However,how post-translation modifications contribute to fine-tuning of TGF-βfamily signaling responses is not well understood.Inhibitory(I)-Smads can antagonize TGF-β/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-βreceptor for proteasomal degradation.A proteomic interaction screen identified Vpr binding protein(VprBP)as novel binding partner of Smad7.Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation,Smad2–Smad4 interaction,as well as TGF-βtarget gene expression.VprBP was found to promote Smad7–Smurf1–TβRI complex formation and induce proteasomal degradation of TGF-βtype I receptor(TβRI).Moreover,VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination.In multiple adult and mouse embryonic stem cells,depletion of VprBP promotes TGF-βor Activin-induced responses.In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression,and VprBP attenuated mesoderm induction during zebrafish embryogenesis.Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-βand Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.展开更多
Single-particle tracking photoactivated local- ization microscopy （sptPALM） has recently emerged as a powerful tool for high-density imaging and tracking of individual molecules in living cells. In this work, we hav...Single-particle tracking photoactivated local- ization microscopy （sptPALM） has recently emerged as a powerful tool for high-density imaging and tracking of individual molecules in living cells. In this work, we have monitored and compared the diffusion dynamics of TGF-β type II receptor （TβRII） at high expression level using both traditional single-particle tracking （SPT） and sptPALM. The ligand-induced aggregation of TβRII oligomers was further indicated by sptPALM. Due to the capacity of distinguishing and tracking single molecules within diffraction limit, sptPALM outperforms traditional SPT by providing more accurate biophysical information,展开更多
Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various ...Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various cell activities and a large number of cytokine biological activities,the activation of signal pathways and so on are involved in the development of DN.At present,the clinical treatment of DN is mainly Western medicine,but it has limitations such as strong toxicity,high side effects and poor compliance.Therefore,the discovery of natural anti-DN substances has also become an important means to treat DN.Mulberry leaves are the dry leaves of Morus alba L.It is not only a traditional Chinese medicine,but also a dual-purpose medicinal material for medicine and food.It has the effects of dispelling wind and clearing heat,cooling blood and brightening eyes,tonifying and so on.Mulberry leaf polysaccharide(MLP)is a kind of high molecular compound in mulberry leaves.It has many pharmacological effects,such as hypoglycemic,antioxidant,anti-stress,anti-virus and so on.Therefore,the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy are reviewed in this paper,so as to provide references for further research and application.The pathogenesis of DN is complex,and the mechanism of renal injury has not been completely clarified.The current studies believe that DN is closely related to heredity,abnormal glucose metabolism,abnormal lipid metabolism,microcirculation disorder,cytokine action,oxidative stress and so on.Relevant studies show that the pharmacological effects of mulberry leaf polysaccharide in the prevention and treatment of DN mainly include:①Effect on transforming factor-β1(TGF-β1):TGF-β1 has become an important cytokine involved in the formation of renal fibrosis by regulating cell proliferation and differentiation and the production of extracellular matrix(ECM).MLP can significantly inhibit TGF-β1 protein,and then inhibit the synthesis of extracellular matrix by renal interstitial fibroblasts and inhibit the realization of fibrosis.②Effect on insulin receptor substrate(IRS-1):IRS-1 is an important signal molecule at the beginning of IR signal transduction.The decrease of IRS-1 gene expression or the decrease of expression can affect the effective transmission of IR signal and lead to the development and deterioration of diabetes. MPL can significantly increase the expression of IRS-1 mRNA in liver tissue of DN rats, so as to prevent and treat DN. ③ Effect on the expression of resistin protein in adipose tis sue. Resistin is a secretory polypeptide derived from adipose tissue and is specifically expressed in white adipose tissue and is closely related to type 2 diabetes mellitus (T2DM). Experimental studies show that MLP can effectively reduce the expression of resistin protein in white adipose tissue of T2DM rats, indicating that MLP may reduce the level of IR by inhibiting the expression of resistin in adipose tissue, thereby reducing the insulin resistance state of T2DM rats, so as to achieve the goal of treating diabetes. ④ Effect on adiponectin receptor 1 (AdipoR1): adiponectin can improve insulin resistance, reduce blood glucose and lipid. AdipoR1 is mainly expressed in skeletal muscle and kidney. Studies have shown that AdipoR1 is closely related to the occurrence and development of DN. The results showed that MLP could reduce the blood glucose and blood lipid level and up regulate the expression of AdipoR1 mRNA in DN rats, suggesting that MLP may delay the occurrence and development of DN. This article reviewed the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy, and provided a useful basis for further development and utilization of mul berry leaf polysaccharides in the treatment of DN.展开更多
基金Supported by National Natural Sciences Foundation. The abstract of this work was published in Exp Hematol (1994:22:743)
文摘ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive index of time-and dose-dependent specimens. The expression of c-kit was elevated both in positive rate and positive index by TGF-01 in both time- and dose-dependent manners. Ing/ml rhTGF-β1 simultaneously enhanced the expression of c-fms and PDGF-R which is not detected in 50 ng / ml GM-CSF treatment. Endoglin was down-regulated after TGF-β treatment and up-regulated in J6-2 cells after GM-CSF treatment, c-kit Expression was elevated by TGF-β in J6-1 cells while decreased by both in J6-2 cells.
文摘By radioreceptor binding studies with iodinated TGF-β1, it has been shown that an undifferentiated ES-5 cell expresses approximately 3270 receptors with a dissociation constant Kd=130pM, but after the induction of differenti-ation by retinoic acid and dBcAMP, the receptor number of a differentiated RA-ES-5 cell was increased about 80% and the Kd was also increased to 370 pM. Furthermore,more direct evidence supporting the expression of TGF-βtype Ⅰand type Ⅱ receptors in both ES-5 and RA-ES-5 cells has come from dot blot hybridization of cellular mRNA with cDNA probes for type Ⅰ and type Ⅱ recep-tors. Meanwhile, mRNA expression level of types Ⅰ and Ⅱreceptors in RA-ES-5 cells were higher than that in ES-5 cells. Down regulation of TGF-β receptors with a signifi-cant decrease in the rate of cell proliferation in both cells, was found by employing a pretreatment with neutralizing antibody to TGF-β1. The possible role of receptors for TGF-β in cen differentiation is discussed here.
基金This work was supported by the National Natural Science Foundation of China （90713024, 20821003, 30921004）, the National Basic Research Program of China （2007CB935601, 2010CB833706） and the Chinese Academy of Sciences.
文摘Transforming growth factor-β （TGF-β） binds with two transmembrane serine/threonine kinase receptors, type Ⅱ （TβRII） and type Ⅰ receptors （TβRⅠ）, and one accessory receptor, type Ⅲ receptor （TβRⅢ）, to transduce signals across cell membranes. Previous biochemical studies suggested that TβRI and TβRIII are preexisted homo-dimers. Using single-molecule microscopy to image green fluorescent protein-labeled membrane proteins, for the first time we have demonstrated that TβRI and TβRⅢ could exist as monomers at a low expression level. Upon TGF-β1 stimu- lation, TβRI follows the general ligand-induced receptor dimerization model for activation, but this process is TβRⅡ- dependent. The monomeric status of the non-kinase receptor TβRⅢ is unchanged in the presence of TGF-β1. With the increase of receptor expression, both TβRI and TβRIII can be assembled into dimers on cell surfaces.
文摘Transforming growth factor-β?(TGF-β) superfamily is a key player in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β, almost three decades ago, there have been tremendous advances in our understanding of its complex biology. TGF-β?misregulation has been implicated in the pathogenesis of a variety of diseases, including cancer with a direct role in facilitating metastasis, fibrosis and inflammation. Consequently, TGF-β?is currently explored as a prognostic candidate biomarker of tumor invasiveness and metastasis;and it offers an attractive target for cancer therapy. Several anti-TGF-β?approaches, such as TGF-β?antibodies, antisense oligonucleotides and small molecules inhibitors of TGF-β?type 1 receptor kinase, have shown great promise in the preclinical studies. Here, we consider why the TGF-βsignaling pathway is a drug target, the potential clinical applications of TGF-β?inhibition, the issues arising with anti-TGF-β?therapy and how these might be adopted using personalized approaches with a special care for patient selection and timing of therapy so that we may bring forward all the potentials of targeting this pathway for therapeutic uses in both cancer, preferentially in combination therapy, and non-neoplastic diseases.
文摘Human gastric cancer MKN-45 cells which are resistant to TGF-β growth inhibition and possess TGF-β type Ⅰ and type Ⅲ receptors, but not type Ⅱ receptors, have been used as a model system to reconstitute these caflcer cells with TGF-β RII cDNA. The results of these experiments indicated that the reexpression of TGF-g RII gene in MKN-45 cells can restore their sensitivity to TGFβ growth inhibition, decrease their growth rate, reduce their cloning efficiency in soft agar and tumorigenicity in nude mice in stable transfectants, in comparison with their control MKN-45 cells. Among different RII transfectants,their difference in the changes of these parameters, as a result of the regain of autocrine negative growth control by TGF-β, is roughly proportional to their level of expression of transfected RII mRNA. From these data, it is concluded that the inactivation of TGF-β RII gene is related to the escape of growth control by TGF-β in MKN-45 cells. The importance of the study of the interplay of TGF-β and its receptor system in the negative growth control of gastric cancer, and possibly also of other cancers, is discussed.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81703463 and 81603277)the National Key R&D Program of China(Grant No.:U1508220)the Liaoning Distinguished Professor Project for Qing Li,and the Doctoral Scientific Research Foundation of Liaoning Province(Grant No.:20170520199).
文摘Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-I(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,metabolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an IC_(50) of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.
基金This work was supported by the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(GDHVPS2018)the National Hong Kong Scholars program(XJ2016059)+2 种基金the Natural Science Foundation of Guangdong Province(2020A1515011239)the Guangzhou Science and Technology Project(202102021241)the Administration of Traditional Chinese Medicine of Guangdong Province(20211253)and the Guangzhou Consun Pharmaceuticals Co.,Ltd..These funding bodies played no role in the design of the study,collection,analysis and interpretation of data,and in writing the manuscript.
文摘Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aimed to investigate whether NDQ ameliorate CRF by inhibiting transforming growth factor-β1(TGF-β1)-induced EMT in human renal tubular epithelial HK-2 cells.Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide assay and colony formation assay were used to investigate the cytotoxicity of NDQ in HK-2 cells.Morphological changes of HK-2 cells after TGF-β1 or/and NDQ treatment were observed under a microscope.Wound-healing,migration and invasion assays were performed to determine the cell movement,migratory and invasive abilities,respectively.Western blot analysis was carried out to examine the protein levels of TGF-βreceptor I(TβRI)and epithelial-mesenchymal transition(EMT)-associated factors.Fluorescence confocal microscopy was applied to observe the organization of filamentous actin.Results NDQ suppressed TβRI expression dose-dependently.NDQ inhibited TGF-β1-stimulated EMT in HK-2 cells,supported by the evidences that NDQ prevented morphology change,attenuated cell migration and invasion,downregulated EMT factors and reorganized filamentous actin distribution in TGF-β1-stimulated HK-2 cells.Conclusions NDQ attenuates chronic renal failure which may be associated with inhibition of TβRI expression and EMT process.
文摘Transforming growth factor-β(TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation.Receptor tyrosine kinases(RTKs), such as epidermal growth factor receptor(EGFR), fibroblast growth factor receptor(FGFR),vascular endothelial growth factor receptor(VEGFR) and platelet-derived growth factor receptor(PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity,while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.
基金This research was supported by Cancer Genomics Centre Netherlands and a grant from the National Natural Science Foundation of China(31471315).
文摘The transforming growth factor-β(TGF-β)family controls embryogenesis,stem cell differentiation,and tissue homeostasis.However,how post-translation modifications contribute to fine-tuning of TGF-βfamily signaling responses is not well understood.Inhibitory(I)-Smads can antagonize TGF-β/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-βreceptor for proteasomal degradation.A proteomic interaction screen identified Vpr binding protein(VprBP)as novel binding partner of Smad7.Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation,Smad2–Smad4 interaction,as well as TGF-βtarget gene expression.VprBP was found to promote Smad7–Smurf1–TβRI complex formation and induce proteasomal degradation of TGF-βtype I receptor(TβRI).Moreover,VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination.In multiple adult and mouse embryonic stem cells,depletion of VprBP promotes TGF-βor Activin-induced responses.In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression,and VprBP attenuated mesoderm induction during zebrafish embryogenesis.Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-βand Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.
基金supported by the National Basic Research Program of China(2013CB933701)the National Natural Science Foundation of China(21127901+2 种基金9141311991213305)the Chinese Academy of Science
文摘Single-particle tracking photoactivated local- ization microscopy （sptPALM） has recently emerged as a powerful tool for high-density imaging and tracking of individual molecules in living cells. In this work, we have monitored and compared the diffusion dynamics of TGF-β type II receptor （TβRII） at high expression level using both traditional single-particle tracking （SPT） and sptPALM. The ligand-induced aggregation of TβRII oligomers was further indicated by sptPALM. Due to the capacity of distinguishing and tracking single molecules within diffraction limit, sptPALM outperforms traditional SPT by providing more accurate biophysical information,
文摘Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various cell activities and a large number of cytokine biological activities,the activation of signal pathways and so on are involved in the development of DN.At present,the clinical treatment of DN is mainly Western medicine,but it has limitations such as strong toxicity,high side effects and poor compliance.Therefore,the discovery of natural anti-DN substances has also become an important means to treat DN.Mulberry leaves are the dry leaves of Morus alba L.It is not only a traditional Chinese medicine,but also a dual-purpose medicinal material for medicine and food.It has the effects of dispelling wind and clearing heat,cooling blood and brightening eyes,tonifying and so on.Mulberry leaf polysaccharide(MLP)is a kind of high molecular compound in mulberry leaves.It has many pharmacological effects,such as hypoglycemic,antioxidant,anti-stress,anti-virus and so on.Therefore,the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy are reviewed in this paper,so as to provide references for further research and application.The pathogenesis of DN is complex,and the mechanism of renal injury has not been completely clarified.The current studies believe that DN is closely related to heredity,abnormal glucose metabolism,abnormal lipid metabolism,microcirculation disorder,cytokine action,oxidative stress and so on.Relevant studies show that the pharmacological effects of mulberry leaf polysaccharide in the prevention and treatment of DN mainly include:①Effect on transforming factor-β1(TGF-β1):TGF-β1 has become an important cytokine involved in the formation of renal fibrosis by regulating cell proliferation and differentiation and the production of extracellular matrix(ECM).MLP can significantly inhibit TGF-β1 protein,and then inhibit the synthesis of extracellular matrix by renal interstitial fibroblasts and inhibit the realization of fibrosis.②Effect on insulin receptor substrate(IRS-1):IRS-1 is an important signal molecule at the beginning of IR signal transduction.The decrease of IRS-1 gene expression or the decrease of expression can affect the effective transmission of IR signal and lead to the development and deterioration of diabetes. MPL can significantly increase the expression of IRS-1 mRNA in liver tissue of DN rats, so as to prevent and treat DN. ③ Effect on the expression of resistin protein in adipose tis sue. Resistin is a secretory polypeptide derived from adipose tissue and is specifically expressed in white adipose tissue and is closely related to type 2 diabetes mellitus (T2DM). Experimental studies show that MLP can effectively reduce the expression of resistin protein in white adipose tissue of T2DM rats, indicating that MLP may reduce the level of IR by inhibiting the expression of resistin in adipose tissue, thereby reducing the insulin resistance state of T2DM rats, so as to achieve the goal of treating diabetes. ④ Effect on adiponectin receptor 1 (AdipoR1): adiponectin can improve insulin resistance, reduce blood glucose and lipid. AdipoR1 is mainly expressed in skeletal muscle and kidney. Studies have shown that AdipoR1 is closely related to the occurrence and development of DN. The results showed that MLP could reduce the blood glucose and blood lipid level and up regulate the expression of AdipoR1 mRNA in DN rats, suggesting that MLP may delay the occurrence and development of DN. This article reviewed the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy, and provided a useful basis for further development and utilization of mul berry leaf polysaccharides in the treatment of DN.
