LEF1/TCFs are high mobility group box-containing transcriptional factors mediating canonical Wnt/β-catenin signaling during early embryogenesis and tumorigenesis. β-Catenin forms a complex with LEF 1/TCFs and transa...LEF1/TCFs are high mobility group box-containing transcriptional factors mediating canonical Wnt/β-catenin signaling during early embryogenesis and tumorigenesis. β-Catenin forms a complex with LEF 1/TCFs and transactivates LEF1/TCF-mediated transcriptions during dorsalization. Although LEF-mediated transcription is also implicated in ventralization, the underlying molecular mechanism is not well understood. Using the vertebrate Xenopus laevis model system, we found that Xom, which is a ventralizing homeobox protein with dual roles of transcriptional activation and repression, forms a complex with LEF 1/TCF through its homeodomain and transactivates LEF 1/TCF-mediated transcription through its N-terminal transactivation domain （TAD）. Our data show that Xom lacking the N-terminal TAD fails to transactivate ventral genes, such as BMP4 and Xom itself, but retains the ability to suppress transcriptional activation of dorsal gene promoters, such as the Goosecoid promoter, indicating that transactivation and repression are separable functions of Xom. It has been postulated that Xom forms a positive re-enforcement loop with BMP4 to promote ventral- ization and to suppress dorsal gene expression. Consistent with an essential role of Xom transactivation of LEF1/TCFs during early embryogenesis, we found that expression of the dominant-negative Xom mutant that lacks the TAD fails to re-enforce the ventral signaling of BMP4 and causes a catastrophic effect during gastrulation. Our data suggest that the functional interaction of Xom and LEF 1/TCF-factors is essential for ventral cell fate determination and that LEF 1/TCF factors may function as a point of convergence to mediate the combined signaling of Wnt/β-catenin and BMP4/Xom pathways during early embryogenesis.展开更多
Both the Wnt/β-catenin and Bone morphogenetic protein （Bmp） signaling pathways play critical roles in dorsal-ventral patterning of the Xenopus embryos. The lymphoid enhancer binding factor （Lef） / T cell factor ...Both the Wnt/β-catenin and Bone morphogenetic protein （Bmp） signaling pathways play critical roles in dorsal-ventral patterning of the Xenopus embryos. The lymphoid enhancer binding factor （Lef） / T cell factor （Tcf） have been viewed as dedicated transcription factors of the Wnt/β-catenin signaling pathway that are activated by β-catenin binding. Now a Xenopus ventral specific transcription factor Xom has also been identified to bear transactivation activity by binding to Lef/Tcf factors [1].展开更多
Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,y...Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,yet its mechanism in preventing hepatic"inflammation-carcinoma transformation"remains incompletely understood.In the current research,clinical HCC specimens underwent analysis using hematoxylin-eosin(H&E)staining and immunohistochemistry(IHC)to evaluate the expression of fibrosis markers,M2 macrophage markers,and CXCL12.In vitro,transforming growth factor-β1(TGF-β1)-induced LX-2 cells and a co-culture system of LX-2,THP-1,and HCC cells were established.Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT),flow cytometry,and Transwell assays.Reverse transcription-quantitative polymerase chain reaction(RT-qPCR),Western blotting and immunofluorescence evaluated the differential expression of molecules.The interaction betweenβ-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation(Co-IP),dual luciferase,and chromatin immunoprecipitation(ChIP)assays.A DEN-induced rat model was developed to investigate BDMC’s role in liver fibrosis-associated HCC(LFAHCC)development in vivo.Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages.BDMC delayed liver fibrosis progression to HCC in vivo.BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells(HSCs).Furthermore,BDMC suppressed M2 macrophage-induced fibrosis and HCC cell proliferation and metastasis.Mechanistically,BDMC repressed TCF4/β-catenin complex formation,thereby reducing CXCL12 transcription in LX-2 cells.Moreover,CXCL12 overexpression reversed BDMC’s inhibitory effect on macrophage M2 polarization and its mediation of fibrosis,as well as HCC proliferation and metastasis.BDMC significantly suppressed LFAHCC development through CXCL12 in rats.In conclusion,BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressingβ-catenin/TCF4-mediated CXCL12 transcription.展开更多
Thymine DNA glycosylase CrDG）, an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in em- bryonic development to maintain epigenetic stability and facilitate the active DNA de...Thymine DNA glycosylase CrDG）, an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in em- bryonic development to maintain epigenetic stability and facilitate the active DNA demethylation. Here we report a novel role of TDG in Wnt signaling as a transcriptional coactivator of β-catenin/TCFs complex. Our data show that TDG binds to the transcriptional factor family LEF1/TCFs and potentiates β-catenin/TCFs transactivation, while TDG depletion suppresses Wnt3a-stimulated reporter activity or target gene transcription. Next, we show that CBP, a known coactivator, is also required for TDG function through forming a coopera- tive complex on target promoters. Moreover, there is an elevation of TDG levels in human colon cancer tissue, and knockdown of TDG inhibits proliferation of the colon cells. Overall, our results reveal that TDG, as a new coactivator, promotes β-catenin/TCFs transacti- vation and functionally cooperates with CBP in canonical Wnt signaUng.展开更多
An important factor in the emergence and progre sion of osteosarcoma(OS)is the dysregulated expression of microRNAs(miRNAs).Transcription factor 7-like 1(TCF7LI),a member of the T cell factor/lymphoid enhancer factor(...An important factor in the emergence and progre sion of osteosarcoma(OS)is the dysregulated expression of microRNAs(miRNAs).Transcription factor 7-like 1(TCF7LI),a member of the T cell factor/lymphoid enhancer factor(TCF/LEF)transcription factor family,interacts with the Wnt signaling pathway regulator β-catenin and acts as a DNA-specific binding protein.This study sought to elucidate the impact of the interaction between miR 3293p and TCF7L1 on.the growth and apoptosis of OS and analyze the regulatory expression relationship between miRNA and mRNA in osteosarcoma cells using a variety of approaches.MiR329-3p was significantly downregulated,while TCF7L1 was considerably up-regulated in all examined OS cell lines.Additionally,a clinical comparison study was performed using the TCGA database.Subsequently,the regulatory relationship between miR-329-3p and TCF7L1 on the proliferation and apoptosis of OS cells was verified through in vitro and in vivo experiments.When miR 329-3p was transfected into the OS cell line,the expression of TCF7L1 decreased,the proliferation of OS cells was inhibited,the cytoskeleton disintegrated,and the nucleus condensed to fom apoptotic bodies.The expression of proteins that indicate apoptosis increased simultaneously.The cell cycle was arrested in the G0/G1 phase,and the G1/S transition was blocked.The introduction of miR 3293p also inhibited downstream Cyclin D1 of the Wnt pathway.Xenograf experiments indicated that the overexpression of miR-329-3p signi ficanly inhibited the growth of OS xenografts in nude mice,and the expression of TCF7L1 and C-Myc in tumor tssues decreased.MiR 329-3p was significantly reduced in OS cells and played a suppressive role in tumorigenesis and proliferation by targeting TCF7L1 both in vitro and in vivo.Osteosarcoma cell cycle arrest and pathway inhibition were observed upon the regulation of TCF7LI by miR 3293p.Summarizing these results,it can be inferred that miR.3293p exerts anticancer efects in osteosarcoma by inhibiting TCF7L1.展开更多
文摘LEF1/TCFs are high mobility group box-containing transcriptional factors mediating canonical Wnt/β-catenin signaling during early embryogenesis and tumorigenesis. β-Catenin forms a complex with LEF 1/TCFs and transactivates LEF1/TCF-mediated transcriptions during dorsalization. Although LEF-mediated transcription is also implicated in ventralization, the underlying molecular mechanism is not well understood. Using the vertebrate Xenopus laevis model system, we found that Xom, which is a ventralizing homeobox protein with dual roles of transcriptional activation and repression, forms a complex with LEF 1/TCF through its homeodomain and transactivates LEF 1/TCF-mediated transcription through its N-terminal transactivation domain （TAD）. Our data show that Xom lacking the N-terminal TAD fails to transactivate ventral genes, such as BMP4 and Xom itself, but retains the ability to suppress transcriptional activation of dorsal gene promoters, such as the Goosecoid promoter, indicating that transactivation and repression are separable functions of Xom. It has been postulated that Xom forms a positive re-enforcement loop with BMP4 to promote ventral- ization and to suppress dorsal gene expression. Consistent with an essential role of Xom transactivation of LEF1/TCFs during early embryogenesis, we found that expression of the dominant-negative Xom mutant that lacks the TAD fails to re-enforce the ventral signaling of BMP4 and causes a catastrophic effect during gastrulation. Our data suggest that the functional interaction of Xom and LEF 1/TCF-factors is essential for ventral cell fate determination and that LEF 1/TCF factors may function as a point of convergence to mediate the combined signaling of Wnt/β-catenin and BMP4/Xom pathways during early embryogenesis.
文摘Both the Wnt/β-catenin and Bone morphogenetic protein （Bmp） signaling pathways play critical roles in dorsal-ventral patterning of the Xenopus embryos. The lymphoid enhancer binding factor （Lef） / T cell factor （Tcf） have been viewed as dedicated transcription factors of the Wnt/β-catenin signaling pathway that are activated by β-catenin binding. Now a Xenopus ventral specific transcription factor Xom has also been identified to bear transactivation activity by binding to Lef/Tcf factors [1].
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
基金supported by the National Natural Science Foundation of China(No.81904182)the Training Program for Excellent Young Innovators of Changsha(No.kq2209020)+1 种基金the Excellent Youth Project of Hunan University of Chinese Medicine(No.2022XJB006)the Excellent Youth Project of Natural Science Foundation of Heilongjiang Province(No.YQ2022H015).
文摘Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,yet its mechanism in preventing hepatic"inflammation-carcinoma transformation"remains incompletely understood.In the current research,clinical HCC specimens underwent analysis using hematoxylin-eosin(H&E)staining and immunohistochemistry(IHC)to evaluate the expression of fibrosis markers,M2 macrophage markers,and CXCL12.In vitro,transforming growth factor-β1(TGF-β1)-induced LX-2 cells and a co-culture system of LX-2,THP-1,and HCC cells were established.Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT),flow cytometry,and Transwell assays.Reverse transcription-quantitative polymerase chain reaction(RT-qPCR),Western blotting and immunofluorescence evaluated the differential expression of molecules.The interaction betweenβ-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation(Co-IP),dual luciferase,and chromatin immunoprecipitation(ChIP)assays.A DEN-induced rat model was developed to investigate BDMC’s role in liver fibrosis-associated HCC(LFAHCC)development in vivo.Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages.BDMC delayed liver fibrosis progression to HCC in vivo.BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells(HSCs).Furthermore,BDMC suppressed M2 macrophage-induced fibrosis and HCC cell proliferation and metastasis.Mechanistically,BDMC repressed TCF4/β-catenin complex formation,thereby reducing CXCL12 transcription in LX-2 cells.Moreover,CXCL12 overexpression reversed BDMC’s inhibitory effect on macrophage M2 polarization and its mediation of fibrosis,as well as HCC proliferation and metastasis.BDMC significantly suppressed LFAHCC development through CXCL12 in rats.In conclusion,BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressingβ-catenin/TCF4-mediated CXCL12 transcription.
文摘Thymine DNA glycosylase CrDG）, an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in em- bryonic development to maintain epigenetic stability and facilitate the active DNA demethylation. Here we report a novel role of TDG in Wnt signaling as a transcriptional coactivator of β-catenin/TCFs complex. Our data show that TDG binds to the transcriptional factor family LEF1/TCFs and potentiates β-catenin/TCFs transactivation, while TDG depletion suppresses Wnt3a-stimulated reporter activity or target gene transcription. Next, we show that CBP, a known coactivator, is also required for TDG function through forming a coopera- tive complex on target promoters. Moreover, there is an elevation of TDG levels in human colon cancer tissue, and knockdown of TDG inhibits proliferation of the colon cells. Overall, our results reveal that TDG, as a new coactivator, promotes β-catenin/TCFs transacti- vation and functionally cooperates with CBP in canonical Wnt signaUng.
基金The Fund of National Cancer Center Research and Development(26-A-4),The Grants-in-Aid for Scientific Research(Grant Nos.15K10451,16K10866 and 16K20063)from Japan Society for the Promotion of Science.
文摘An important factor in the emergence and progre sion of osteosarcoma(OS)is the dysregulated expression of microRNAs(miRNAs).Transcription factor 7-like 1(TCF7LI),a member of the T cell factor/lymphoid enhancer factor(TCF/LEF)transcription factor family,interacts with the Wnt signaling pathway regulator β-catenin and acts as a DNA-specific binding protein.This study sought to elucidate the impact of the interaction between miR 3293p and TCF7L1 on.the growth and apoptosis of OS and analyze the regulatory expression relationship between miRNA and mRNA in osteosarcoma cells using a variety of approaches.MiR329-3p was significantly downregulated,while TCF7L1 was considerably up-regulated in all examined OS cell lines.Additionally,a clinical comparison study was performed using the TCGA database.Subsequently,the regulatory relationship between miR-329-3p and TCF7L1 on the proliferation and apoptosis of OS cells was verified through in vitro and in vivo experiments.When miR 329-3p was transfected into the OS cell line,the expression of TCF7L1 decreased,the proliferation of OS cells was inhibited,the cytoskeleton disintegrated,and the nucleus condensed to fom apoptotic bodies.The expression of proteins that indicate apoptosis increased simultaneously.The cell cycle was arrested in the G0/G1 phase,and the G1/S transition was blocked.The introduction of miR 3293p also inhibited downstream Cyclin D1 of the Wnt pathway.Xenograf experiments indicated that the overexpression of miR-329-3p signi ficanly inhibited the growth of OS xenografts in nude mice,and the expression of TCF7L1 and C-Myc in tumor tssues decreased.MiR 329-3p was significantly reduced in OS cells and played a suppressive role in tumorigenesis and proliferation by targeting TCF7L1 both in vitro and in vivo.Osteosarcoma cell cycle arrest and pathway inhibition were observed upon the regulation of TCF7LI by miR 3293p.Summarizing these results,it can be inferred that miR.3293p exerts anticancer efects in osteosarcoma by inhibiting TCF7L1.
