AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions...AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS: Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The li展开更多
Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are charac...Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.展开更多
Light and the plant hormone ethylene regulate many aspects of plant growth and development in an overlapping and interdependent fashion. Little is known regarding how their signal transduction pathways cross-talk to r...Light and the plant hormone ethylene regulate many aspects of plant growth and development in an overlapping and interdependent fashion. Little is known regarding how their signal transduction pathways cross-talk to regulate plant development in a coordinated manner. Here, we report functional characterization of an AP2/DREB-type transcription factor, Arabidopsis RAP2.4, in mediating light and ethylene signaling. Expression of the RAP2.4 gene is down-regulated by light but up-regulated by salt and drought stresses. RAP2.4 protein is constitutively targeted to the nucleus and it can bind to both the ethylene-responsive GCC-box and the dehydration-responsive element （DRE）. We show that RAP2.4 protein possesses an intrinsic transcriptional activation activity in yeast cells and that it can activate a reporter gene driven by the DRE cis-element in Arabidopsis protoplasts. Overexpression of RAP2.4 or mutation in RAP2.4 cause altered expression of representative light-, ethylene-, and drought-responsive genes. Although no salient phenotype was observed with a rap2.4 loss-of-function mutant, constitutive overexpression of RAP2.4 results in defects in multiple developmental processes regulated by light and ethylene, including hypocotyl elongation and gravitropism, apical hook formation and cotyledon expansion, flowering time, root elongation, root hair formation, and drought tolerance. Based on these observations, we propose that RAP2.4 acts at or downstream of a converging point of light and ethylene signaling pathways to coordinately regulate multiple developmental processes and stress responses.展开更多
The molecular mechanisms for NF-κB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiologica...The molecular mechanisms for NF-κB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiological and pathogenesis,particularly the close association of dysregulated NF-κB with tumorgenesis and inflammation.Several novel intracellular molecular events that regulate NF-κB activity have been described recently,including the discovery of an alternative signaling pathway that appears inducing a specific subset genes involved in adoptive immune response.Multi-level and multi-dimensional regulation of NF-κB activity by phosphorylation and acetylation modifications have unveiled and became the hottest targets for potentially tissue specific molecular interventions.Another emerging mechanism for NF-κB-responsive gene's regulation where NF-κB participates the transcriptional regulation independent of its cognate regulatory binding site within the target gene's promoter but facilitating the transaction activity of other involved transcription factors, that implicated an novel transcriptional activities for NF-κB.Thus,the current review will focus on these recent progresses that have been made on NF-κB signaling transduction and transcription.Cellular & Molecular Immunology.2004;1(6):425-435.展开更多
Protein post-translational modification （PTM） by ubiquitination has been observed during many aspects of plant growth, development, and stress responses. The ubiquitin-proteasome system precisely regulates phytohorm...Protein post-translational modification （PTM） by ubiquitination has been observed during many aspects of plant growth, development, and stress responses. The ubiquitin-proteasome system precisely regulates phytohormone signaling by affecting protein activity, localization, assembly, and interaction ability. Absci- sic acid （ABA） is a major phytohormone, and plays important roles in plants under normal or stressed growth conditions. The ABA signaling pathway is composed of phosphatases, kinases, transcription fac- tors, and membrane ion channels. It has been reported that multiple ABA signaling transducers are sub- jected to the regulations by ubiquitination. In particular, recent studies have identified different types of E3 ligases that mediate ubiquitination of ABA receptors in different cell compartments. This review focuses on modulation of these components by monoubiquitination or polyubiquitination that occurs in the plasma membrane, endomembranes, and from the cytosol to the nucleus; this implies the existence of retrograde and trafficking processes that are regulated by ubiquitination in ABA signaling. A number of single-unit E3 ligases, components of multi-subunit E3 ligases, E2s, and specific subunits of the 26S proteasome involved in ABA signal regulation are discussed. Dissecting the precise functions of ubiquitination in the ABA pathway may help us understand key factors in the signaling of other phytohormones regulated by ubiqui- tination and other types of PTMs.展开更多
We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly ...We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.展开更多
Fibroblast growth factors(FGF)and their receptors serve many functions in both the developing and adult organism.Humans contain 18 FGF ligands and four FGF receptors(FGFR).FGF ligands are polypeptide growth factors th...Fibroblast growth factors(FGF)and their receptors serve many functions in both the developing and adult organism.Humans contain 18 FGF ligands and four FGF receptors(FGFR).FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation,differentiation,and migration,morphogenesis,and patterning.FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton.In particular,the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis.In the adult,FGFs and FGFRs are crucial for tissue repair.FGF signaling generally follows one of three transduction pathways:RAS/MAP kinase,PI3/AKT,or PLCg.Each pathway likely regulates specific cellular behaviors.Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions,unregulated cell growth,and tumorigenesis.Additionally,aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis.The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years.Recently,work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors.The majority of FGF-related therapy is aimed at age-related disorders.Increased understanding of FGF signaling and biology may reveal additional therapeutic roles,both in utero and postnatally.This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.展开更多
The fruit of Actinidia arguta is typically climacteric.During ripening,the fruits produce a large amount of ethylene.Although the molecular basis of climacteric fruit ripening has been extensively studied,some aspects...The fruit of Actinidia arguta is typically climacteric.During ripening,the fruits produce a large amount of ethylene.Although the molecular basis of climacteric fruit ripening has been extensively studied,some aspects such as its transcriptional regulation remain unclear.Here,we compared the transcriptomes of A.arguta fruits collected at commercial harvest(sample d0)and at 6 days after harvest(sample d6)using RNA-seq.A total of 3 659 differentially expressed genes(DEGs)between samples d0 and d6 were detected,of which 2 983 and 1 104 could be functionally annotated with Gene Ontology(GO)and Clusters of Orthologous Groups(COG)pathways.DEGs involved in ethylene biosynthesis and signal transduction were identified,including ACO(c79627),ERF061(c105131),and ERF6(c99193).Transcription factors such as ERF,b HLH,NAC,MADS,and MYB were also differentially expressed between samples d0 and d6.Selected DEGs were subjected to further analysis using quantitative reverse transcription-polymerase chain reaction(q RT-PCR),and the results coincided with those of RNA-seq.Our data revealed additional transcription factors that are involved in the regulation of fruit ripening.These results provide useful information for future research on the transcriptional regulation of fruit ripening.展开更多
BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,includi...BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determi展开更多
Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protrud...Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protruding eyes(analogous to those of Chinese dragons).Although the strain has been selected for about 400 years,the mechanism of its eye development remains unclear.In this study,a stable dragon-eye goldfish strain with a clear genetic background was rapidly established and studied.We found that upregulation of the PPAR signaling pathway accompanied by an increase in lipid accumulation might trigger the morphological and structural transformation of the eye in dragon-eye goldfish.At the developmental stage of proptosis(eye protrusion),downregulation of the phototransduction pathway was consistent with the structural defects and myopia of the dragon-eye strain.With the impairment of retinal development,cytokine-induced inflammation was activated,especially after proptosis,similar to the pathologic symptoms of many human ocular diseases.In addition,differentially expressed transcription factors were significantly enriched in the PAX and homeobox families,two well-known transcription factor families involved in eye development.Therefore,our findings reveal the dynamic changes in key pathways during eye development in dragon-eye goldfish,and provide insights into the molecular mechanisms underlying drastically altered eyes in goldfish and human ocular disease.展开更多
AIM: To assess the impact of eukaryotic elongation factor 1 alpha 2 (eEF1A2) on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, migration and invasion, and determine the underlying mechanisms.METHODS: eE...AIM: To assess the impact of eukaryotic elongation factor 1 alpha 2 (eEF1A2) on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, migration and invasion, and determine the underlying mechanisms.METHODS: eEF1A2 levels were detected in 62 HCC tissue samples and paired pericarcinomatous specimens, and the human HCC cell lines SK-HEP-1, HepG2 and BEF-7402, by real-time PCR and immunohistochemistry. Experimental groups included eEF1A2 silencing in BEL-7402 cells with lentivirus eEF1A2-shRNA (KD group) and eEF1A2 overexpression in SK-HEP-1 cells with eEF1A2 plasmid (OE group). Non-transfected cells (control group) and lentivirus-based empty vector transfected cells (NC group) were considered control groups. Cell proliferation (MTT and colony formation assays), apoptosis (Annexin V-APC assay), cell cycle (DNA ploidy assay), and migration and invasion (Transwell assays) were assessed. Protein levels of PI3K/Akt/NF-κB signaling effectors were evaluated by Western blot.RESULTS: eEF1A2 mRNA and protein levels were significantly higher in HCC cancer tissue samples than in paired pericarcinomatous and normal specimens. SK-HEP-1 cells showed lower eEF1A2 mRNA levels; HepG2 and BEL-7402 cells showed higher eEF1A2 mRNA levels, with BEL-7402 cells displaying the highest amount. Efficient eEF1A2 silencing resulted in reduced cell proliferation, migration and invasion, increased apoptosis, and induced cell cycle arrest. The PI3K/Akt/NF-κB signaling pathway was notably inhibited. Inversely, eEF1A2 overexpression resulted in promoted cell proliferation, migration and invasion.CONCLUSION: eEF1A2, highly expressed in HCC, is a potential oncogene. Its silencing significantly decreases HCC tumorigenesis, likely by inhibiting PI3K/Akt/NF-κB signaling.展开更多
Anther development in flowering plants involves the formation of several cell types, including the tapetal and pollen mother cells. The use of genetic and molecular tools has led to the identification and characteriza...Anther development in flowering plants involves the formation of several cell types, including the tapetal and pollen mother cells. The use of genetic and molecular tools has led to the identification and characterization of genes that are critical for normal cell division and differentiation in Arabidopsis early anther development. We review here several recent studies on these genes, including the demonstration that the putative receptor protein kinases BAM1 and BAM2 together play essential roles in the control of early cell division and differentiation. In addition, we discuss the hypothesis that BAM1/2 may form a positive-negative feedback regulatory loop with a previously identified key regulator, SPOROCYTELESS （also called NOZZLE）, to control the balance between sporogenous and somatic cell types in the anther. Furthermore, we summarize the isolation and functional analysis of the DYSFUNCTIONAL TAPETUM1 （DYT1） gene in promoting proper tapetal cell differentiation. Our finding that DYT1 encodes a putative transcription factor of the bHLH family, as well as relevant expression analyses, strongly supports a model that DYT1 serves as a critical link between upstream factors and downstream target genes that are critical for normal tapetum development and function. These studies, together with other recently published works, indicate that cell-cell communication and transcriptional control are key processes essential for cell fate specification in anther development.展开更多
基金the key,project of the tenth-five foundation of PLA,No.01Z011
文摘AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS: Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The li
基金Supported by Grants from the Foundation of Aase and Ejnar Danielsenthe Foundation of Axel Muusfeldtthe A P Mφller Foundation("Fonden til Lgevidenskabens Fremme")
文摘Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.
基金We thank Dr Jungmook Kim （Chonnam National University, Korea） for sharing the 4x DRE：：GUS reporter construct （Kim et al., 2002）. We also thank Erica Fishel and Ling Xu for technical assistance during this work. We thank Zhi-Liang Zheng （Lehman College, City University of New York）, Pradeep Kachroo （University of Kentucky）, and Elizabeth Estabrook （Boyce Thompson Institute） for their read- ing and comments on the manuscript. Thanks are also due to ABRC for distributing seeds and cDNA clones. This research was partially supported by set-up funds from Boyce Thompson Institute, Triad Foundation, and National Science Foundation （MCB-0420932 and IOS-0641639） to H.W.
文摘Light and the plant hormone ethylene regulate many aspects of plant growth and development in an overlapping and interdependent fashion. Little is known regarding how their signal transduction pathways cross-talk to regulate plant development in a coordinated manner. Here, we report functional characterization of an AP2/DREB-type transcription factor, Arabidopsis RAP2.4, in mediating light and ethylene signaling. Expression of the RAP2.4 gene is down-regulated by light but up-regulated by salt and drought stresses. RAP2.4 protein is constitutively targeted to the nucleus and it can bind to both the ethylene-responsive GCC-box and the dehydration-responsive element （DRE）. We show that RAP2.4 protein possesses an intrinsic transcriptional activation activity in yeast cells and that it can activate a reporter gene driven by the DRE cis-element in Arabidopsis protoplasts. Overexpression of RAP2.4 or mutation in RAP2.4 cause altered expression of representative light-, ethylene-, and drought-responsive genes. Although no salient phenotype was observed with a rap2.4 loss-of-function mutant, constitutive overexpression of RAP2.4 results in defects in multiple developmental processes regulated by light and ethylene, including hypocotyl elongation and gravitropism, apical hook formation and cotyledon expansion, flowering time, root elongation, root hair formation, and drought tolerance. Based on these observations, we propose that RAP2.4 acts at or downstream of a converging point of light and ethylene signaling pathways to coordinately regulate multiple developmental processes and stress responses.
文摘The molecular mechanisms for NF-κB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiological and pathogenesis,particularly the close association of dysregulated NF-κB with tumorgenesis and inflammation.Several novel intracellular molecular events that regulate NF-κB activity have been described recently,including the discovery of an alternative signaling pathway that appears inducing a specific subset genes involved in adoptive immune response.Multi-level and multi-dimensional regulation of NF-κB activity by phosphorylation and acetylation modifications have unveiled and became the hottest targets for potentially tissue specific molecular interventions.Another emerging mechanism for NF-κB-responsive gene's regulation where NF-κB participates the transcriptional regulation independent of its cognate regulatory binding site within the target gene's promoter but facilitating the transaction activity of other involved transcription factors, that implicated an novel transcriptional activities for NF-κB.Thus,the current review will focus on these recent progresses that have been made on NF-κB signaling transduction and transcription.Cellular & Molecular Immunology.2004;1(6):425-435.
文摘Protein post-translational modification （PTM） by ubiquitination has been observed during many aspects of plant growth, development, and stress responses. The ubiquitin-proteasome system precisely regulates phytohormone signaling by affecting protein activity, localization, assembly, and interaction ability. Absci- sic acid （ABA） is a major phytohormone, and plays important roles in plants under normal or stressed growth conditions. The ABA signaling pathway is composed of phosphatases, kinases, transcription fac- tors, and membrane ion channels. It has been reported that multiple ABA signaling transducers are sub- jected to the regulations by ubiquitination. In particular, recent studies have identified different types of E3 ligases that mediate ubiquitination of ABA receptors in different cell compartments. This review focuses on modulation of these components by monoubiquitination or polyubiquitination that occurs in the plasma membrane, endomembranes, and from the cytosol to the nucleus; this implies the existence of retrograde and trafficking processes that are regulated by ubiquitination in ABA signaling. A number of single-unit E3 ligases, components of multi-subunit E3 ligases, E2s, and specific subunits of the 26S proteasome involved in ABA signal regulation are discussed. Dissecting the precise functions of ubiquitination in the ABA pathway may help us understand key factors in the signaling of other phytohormones regulated by ubiqui- tination and other types of PTMs.
基金grants fromthe Chinese Academy of Sciences (No. KJ951-BI608), the National Natural Sciences FOundation ofChina (No. 39625007 and
文摘We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.
基金supported in part by research grants from the NIH K08 Career Development Award(RRR,NIH 5K08DE20140-5)the American Society of Plastic Surgeons/Plastic Surgery Foundation’s(PSF)Pilot Research Grant Program(RRR).EMF and JR were recipients of the Pritzker Research Fellowship funded through a NIH T-35 training grant(NIDDK).
文摘Fibroblast growth factors(FGF)and their receptors serve many functions in both the developing and adult organism.Humans contain 18 FGF ligands and four FGF receptors(FGFR).FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation,differentiation,and migration,morphogenesis,and patterning.FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton.In particular,the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis.In the adult,FGFs and FGFRs are crucial for tissue repair.FGF signaling generally follows one of three transduction pathways:RAS/MAP kinase,PI3/AKT,or PLCg.Each pathway likely regulates specific cellular behaviors.Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions,unregulated cell growth,and tumorigenesis.Additionally,aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis.The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years.Recently,work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors.The majority of FGF-related therapy is aimed at age-related disorders.Increased understanding of FGF signaling and biology may reveal additional therapeutic roles,both in utero and postnatally.This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.
基金The Innovative Program for Fruit Tree Research of Liaoning Province, China (LNGSCYTX-13/14-4) supported this study
文摘The fruit of Actinidia arguta is typically climacteric.During ripening,the fruits produce a large amount of ethylene.Although the molecular basis of climacteric fruit ripening has been extensively studied,some aspects such as its transcriptional regulation remain unclear.Here,we compared the transcriptomes of A.arguta fruits collected at commercial harvest(sample d0)and at 6 days after harvest(sample d6)using RNA-seq.A total of 3 659 differentially expressed genes(DEGs)between samples d0 and d6 were detected,of which 2 983 and 1 104 could be functionally annotated with Gene Ontology(GO)and Clusters of Orthologous Groups(COG)pathways.DEGs involved in ethylene biosynthesis and signal transduction were identified,including ACO(c79627),ERF061(c105131),and ERF6(c99193).Transcription factors such as ERF,b HLH,NAC,MADS,and MYB were also differentially expressed between samples d0 and d6.Selected DEGs were subjected to further analysis using quantitative reverse transcription-polymerase chain reaction(q RT-PCR),and the results coincided with those of RNA-seq.Our data revealed additional transcription factors that are involved in the regulation of fruit ripening.These results provide useful information for future research on the transcriptional regulation of fruit ripening.
基金Supported by Medicine and Health Science and Technology Plan Projects of Zhejiang Province,No.2018KY569Zhejiang Provincial Natural Science Foundation of China,No.LY17H030002
文摘BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determi
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences(XDB31000000)the National Natural Science Foundation of China(31930111)+2 种基金the China Agriculture Research System(CARS-45-07)the Autonomous Project of the State Key Laboratory of Freshwater Ecology and Biotechnology(2019FBZ04)supported by the Wuhan Branch,Supercomputing Centre,Chinese Academy of Sciences,China。
文摘Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protruding eyes(analogous to those of Chinese dragons).Although the strain has been selected for about 400 years,the mechanism of its eye development remains unclear.In this study,a stable dragon-eye goldfish strain with a clear genetic background was rapidly established and studied.We found that upregulation of the PPAR signaling pathway accompanied by an increase in lipid accumulation might trigger the morphological and structural transformation of the eye in dragon-eye goldfish.At the developmental stage of proptosis(eye protrusion),downregulation of the phototransduction pathway was consistent with the structural defects and myopia of the dragon-eye strain.With the impairment of retinal development,cytokine-induced inflammation was activated,especially after proptosis,similar to the pathologic symptoms of many human ocular diseases.In addition,differentially expressed transcription factors were significantly enriched in the PAX and homeobox families,two well-known transcription factor families involved in eye development.Therefore,our findings reveal the dynamic changes in key pathways during eye development in dragon-eye goldfish,and provide insights into the molecular mechanisms underlying drastically altered eyes in goldfish and human ocular disease.
基金Supported by the Middle-Young Age Backbone Talent Cultivation Program of Fujian Health System,No.2013-ZQNJC-2Key Projects of Science and Technology Plan of Fujian Province,No.2014Y0009
文摘AIM: To assess the impact of eukaryotic elongation factor 1 alpha 2 (eEF1A2) on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, migration and invasion, and determine the underlying mechanisms.METHODS: eEF1A2 levels were detected in 62 HCC tissue samples and paired pericarcinomatous specimens, and the human HCC cell lines SK-HEP-1, HepG2 and BEF-7402, by real-time PCR and immunohistochemistry. Experimental groups included eEF1A2 silencing in BEL-7402 cells with lentivirus eEF1A2-shRNA (KD group) and eEF1A2 overexpression in SK-HEP-1 cells with eEF1A2 plasmid (OE group). Non-transfected cells (control group) and lentivirus-based empty vector transfected cells (NC group) were considered control groups. Cell proliferation (MTT and colony formation assays), apoptosis (Annexin V-APC assay), cell cycle (DNA ploidy assay), and migration and invasion (Transwell assays) were assessed. Protein levels of PI3K/Akt/NF-κB signaling effectors were evaluated by Western blot.RESULTS: eEF1A2 mRNA and protein levels were significantly higher in HCC cancer tissue samples than in paired pericarcinomatous and normal specimens. SK-HEP-1 cells showed lower eEF1A2 mRNA levels; HepG2 and BEL-7402 cells showed higher eEF1A2 mRNA levels, with BEL-7402 cells displaying the highest amount. Efficient eEF1A2 silencing resulted in reduced cell proliferation, migration and invasion, increased apoptosis, and induced cell cycle arrest. The PI3K/Akt/NF-κB signaling pathway was notably inhibited. Inversely, eEF1A2 overexpression resulted in promoted cell proliferation, migration and invasion.CONCLUSION: eEF1A2, highly expressed in HCC, is a potential oncogene. Its silencing significantly decreases HCC tumorigenesis, likely by inhibiting PI3K/Akt/NF-κB signaling.
基金Supported by a grant from the US Department of Energy and by funds from the Eberly College of Science, the Department of Biology, and the Huck Institutes of the Life Sciences at the Pennsylvania State University. Publication of this paper is supported by the National Natural Science Foundation of China （30624808） and Science Publication Foundation of the Chinese Academy of Sciences.This manuscript was largely based on a lecture given at Changsha in May 2006 and is not meant to be a comprehensive review of the field of anther and pollen development. We apologize for not including some of the recent works because of time constraints. We thank B. Bliss, B. Feng, Y. Hu, A. Surce and A. Wijeratne for helpful comments on the manuscript.
文摘Anther development in flowering plants involves the formation of several cell types, including the tapetal and pollen mother cells. The use of genetic and molecular tools has led to the identification and characterization of genes that are critical for normal cell division and differentiation in Arabidopsis early anther development. We review here several recent studies on these genes, including the demonstration that the putative receptor protein kinases BAM1 and BAM2 together play essential roles in the control of early cell division and differentiation. In addition, we discuss the hypothesis that BAM1/2 may form a positive-negative feedback regulatory loop with a previously identified key regulator, SPOROCYTELESS （also called NOZZLE）, to control the balance between sporogenous and somatic cell types in the anther. Furthermore, we summarize the isolation and functional analysis of the DYSFUNCTIONAL TAPETUM1 （DYT1） gene in promoting proper tapetal cell differentiation. Our finding that DYT1 encodes a putative transcription factor of the bHLH family, as well as relevant expression analyses, strongly supports a model that DYT1 serves as a critical link between upstream factors and downstream target genes that are critical for normal tapetum development and function. These studies, together with other recently published works, indicate that cell-cell communication and transcriptional control are key processes essential for cell fate specification in anther development.
