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Du X, Zhao Y, Li J, Xie W, Lyu L, Chen S, Jia C, Yan J, Li P. Expression Patterns of TGF-β1, TβR-I, TβR-II, and Smad2 Reveal Insights into Heterosis for Growth of Hybrid Offspring between Acanthopagrus schlegelii and Pagrus major. Genes (Basel) 2024; 15:945. [PMID: 39062724 PMCID: PMC11276220 DOI: 10.3390/genes15070945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/11/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
TGF-β1/Smads is a classic signaling pathway, which plays important roles in the development process of organisms. Black porgy Acanthopagrus schlegelii and red porgy Pagrus major are valuable economic fishes, and their hybrid offspring show excellent heterosis traits. Yet the molecular regulation mechanism of the heterosis traits is less clear. Here, we explored the TGF-β1/Smads pathway's molecular genetic information for heterosis in A. schlegelii ♂ × P. major ♀ (AP) and A. schlegelii ♀ × P. major ♂ (PA) in terms of growth and development. The mRNA expression levels of TGF-β1, TβR-I, TβR-II, and Smad2 genes in different developmental stages of A. schlegelii were detected. Furthermore, the expression levels of TGF-β1, TβR-I, TβR-II, and Smad2 genes in different tissues of adult (mRNA level) and larva (mRNA and protein level) of A. schlegelii, P. major, and their hybrids were determined by both real-time quantitative PCR and Western blot techniques. The results indicated the ubiquitous expression of these genes in all developmental stages of A. schlegelii and in all tested tissues of A. schlegelii, P. major, and its hybrids. Among them, the mRNA of TGF-β1, TβR-I, and TβR-II genes is highly expressed in the liver, gill, kidney, and muscle of black porgy, red porgy, and their hybrid offspring. There are significant changes in gene and protein expression levels in hybrid offspring, which indirectly reflect hybrid advantage. In addition, there was no correlation between protein and mRNA expression levels of Smad2 protein. The results provide novel data for the differential expression of growth and development genes between the reciprocal hybridization generation of black porgy and red porgy and its parents, which is conducive to further explaining the molecular regulation mechanism of heterosis in the growth and development of hybrid porgy.
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Affiliation(s)
- Xinran Du
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Yue Zhao
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Jingbo Li
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Wenli Xie
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Linna Lyu
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Shuyin Chen
- Jiangsu Institute of Oceanology & Marine Fisheries, Nantong 226007, China; (S.C.); (C.J.)
| | - Chaofeng Jia
- Jiangsu Institute of Oceanology & Marine Fisheries, Nantong 226007, China; (S.C.); (C.J.)
| | - Jie Yan
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
| | - Peng Li
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China; (X.D.); (Y.Z.); (J.L.); (W.X.); (L.L.); (J.Y.)
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Tecalco-Cruz AC, Ríos-López DG, Vázquez-Victorio G, Rosales-Alvarez RE, Macías-Silva M. Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease. Signal Transduct Target Ther 2018; 3:15. [PMID: 29892481 PMCID: PMC5992185 DOI: 10.1038/s41392-018-0015-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 02/16/2018] [Accepted: 03/15/2018] [Indexed: 12/19/2022] Open
Abstract
The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling pathway outcome relies on the control of the spatial and temporal expression of >500 genes, which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway, such as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, as well as by inhibiting Smad association with the p300/CBP coactivators. The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. Thus, these cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. As a result, any alteration in these regulatory mechanisms may lead to disease development. Therefore, the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-β pathway, such as Ski and SnoN, is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated, such as fibrosis and cancer. Proteins that repress molecular signaling through the transforming growth factor-beta (TGF-β) pathway offer promising targets for treating cancer and fibrosis. Marina Macías-Silva and colleagues from the National Autonomous University of Mexico in Mexico City review the ways in which a pair of proteins, called Ski and SnoN, interact with downstream mediators of TGF-β to inhibit the effects of this master growth factor. Aberrant levels of Ski and SnoN have been linked to diverse range of diseases involving cell proliferation run amok, and therapies that regulate the expression of these proteins could help normalize TGF-β signaling to healthier physiological levels. For decades, drug companies have tried to target the TGF-β pathway, with limited success. Altering the activity of these repressors instead could provide a roundabout way of remedying pathogenic TGF-β activity in fibrosis and oncology.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- 1Instituto de Investigaciones Biomédicas at Universidad Nacional Autónoma de México, Mexico city, 04510 Mexico
| | - Diana G Ríos-López
- 2Instituto de Fisiología Celular at Universidad Nacional Autónoma de México, Mexico city, 04510 Mexico
| | | | - Reyna E Rosales-Alvarez
- 2Instituto de Fisiología Celular at Universidad Nacional Autónoma de México, Mexico city, 04510 Mexico
| | - Marina Macías-Silva
- 2Instituto de Fisiología Celular at Universidad Nacional Autónoma de México, Mexico city, 04510 Mexico
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Lucarelli P, Schilling M, Kreutz C, Vlasov A, Boehm ME, Iwamoto N, Steiert B, Lattermann S, Wäsch M, Stepath M, Matter MS, Heikenwälder M, Hoffmann K, Deharde D, Damm G, Seehofer D, Muciek M, Gretz N, Lehmann WD, Timmer J, Klingmüller U. Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression. Cell Syst 2018; 6:75-89.e11. [DOI: 10.1016/j.cels.2017.11.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 06/23/2017] [Accepted: 11/14/2017] [Indexed: 12/11/2022]
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Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis. J Mol Neurosci 2015; 57:605-13. [PMID: 26319266 DOI: 10.1007/s12031-015-0643-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 08/17/2015] [Indexed: 01/30/2023]
Abstract
Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). The immunopathogenesis of this disease involves an impaired balance of T helper (Th) 17 cells and regulatory T (Tregs) cells. MS is an autoinflammatory disease characterized by the degeneration of the CNS. For many years, MS has been considered to be an autoreactive Th1 and Th17 cell-dominated disease. The activity and number of Th17 cells are increased in MS; however, the function and number of Treg cells are reduced. Therefore, in MS, the balance between Th17 cells and Treg cells is impaired. Th17 cells produce pro-inflammatory cytokines, which play a role in experimental autoimmune encephalomyelitis (EAE) and MS. However, Treg cell-mediated production of cytokines maintains immune homeostasis and can ameliorate the progression of MS. These observations, therefore, confirm the pathogenic and protective role of Th17 and Treg cells, respectively, and highlight the importance of maintaining the balance of both of these cell types. Evidence suggests that vitamin A and its active metabolites (all-trans-retinoic acid and 9-cis-retinoic acid) modulate the imbalance of Th17 and Treg cells through multiple molecular pathways and can be considered as a promising target in the prevention and treatment of MS.
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Meng M, Li YQ, Yan MX, Kou Y, Ren HB. Effects of epigallocatechin gallate on diethyldithiocarbamate-induced pancreatic fibrosis in rats. Biol Pharm Bull 2007; 30:1091-6. [PMID: 17541159 DOI: 10.1248/bpb.30.1091] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epigallocatechin gallate (EGCG), a major component of green tea extracts, is known to have anti-fibrotic properties in many organs. The aim of present study was to investigate effects of EGCG on rat pancreatic fibrosis induced by diethyldithiocarbamate (DDC). Oral gavages of different dose of EGCG (50, 100 and 200 mg/kg daily for 8 weeks) ameliorated histological changes and significantly suppressed collagen deposition in a dose-dependent manner. Meanwhile, administration of EGCG inhibited overexpression of TGF-beta1 and alpha-smooth muscle actin (a symbol of activation of pancreatic stellate cells). Moreover, EGCG has a potent influence on expression of Smads (downstream transcription factor of TGF-beta1). EGCG suppressed the expression of Smad3 and enhanced the expression of Smad7. In conclusion, our results demonstrated that EGCG attenuated rat pancreatic fibrosis induced by DDC and therefore may be an anti-fibrogenic candidate in the pancreatic fibrosis.
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Affiliation(s)
- Min Meng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
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Song SL, Gong ZJ, Huang YQ, Zhang QR, Huang TX. JinSanE decoction, a chinese herbal medicine, inhibits expression of TGF-beta1/Smads in experimental hepatic fibrosis in rats. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2007; 34:1047-61. [PMID: 17163593 DOI: 10.1142/s0192415x0600451x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The study is to investigate the effects of a Chinese herbal medicine, JinSanE decoction, on the TGF-beta1/Smads signal transduction pathway in a carbon tetrachloride (CCl(4))-induced hepatic fibrosis model in rats. Rats were randomly divided into 4 study groups: namely, a normal control group, a hepatic fibrosis model group, and 2 treatment groups with different doses of JinSanE (6 and 12 g/kg). Ten rats in each group were sacrificed at 4 and 8 weeks after exposure to CCl(4) respectively. The levels of TGF-beta1 and TRII mRNA in liver tissue were analyzed by RT-PCR. The expressions of TGF-beta1, Smad3 and Smad7 in liver tissues were evaluated by immunohistochemistry. The liver histopathology was examined by hematoxylin and eosin (HE) staining and electron microscopy respectively. The liver hydroxyproline (HYP), liver function and hyaluronic acid (HA) were examined by biochemistry and radioimmunoassay (RIA) respectively. Compared with the hepatic fibrosis model group, the levels of TGF-beta1, TRII mRNA and Smad3 expression significantly decreased in the 2 treatment groups. The expression of Smad7 was significantly increased in the liver of the rats treated with JinSanE (p < 0.05 or p < 0.01). The histological changes of fibrotic liver were obviously improved in the treatment rats. The levels of liver HYP, serum liver function and HA were also remarkably improved in the treatment rats. Moreover, the effects of JinSanE occurred in a dose- and time-dependent manner in the process of the protection of liver injury and fibrosis. JinSanE decoction had a protective effect on liver injury and could ameliorate hepatic fibrosis in rats. The mechanisms might be associated with their effects of down-regulating TGF-beta1, TRII mRNA and Smad3, and up-regulating Smad7.
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Affiliation(s)
- Shi-Ling Song
- State Key Laboratory of Virology, Department of Infectious Diseases, Renmin Hospital, Wuhan University, Wuhan 430060, China
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Song SL, Gong ZJ, Zhang QR, Huang TX. Effects of Chinese traditional compound, JinSanE, on expression of TGF-β1 and TGF-β1 type II receptor mRNA, Smad3 and Smad7 on experimental hepatic fibrosis in vivo. World J Gastroenterol 2005; 11:2269-76. [PMID: 15818738 PMCID: PMC4305811 DOI: 10.3748/wjg.v11.i15.2269] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The transforming growth factor-beta (TGF-β)/Smad signaling pathway system plays a prominent role in the control of cell growth and extracellular matrix formation in the progression of liver fibrogenesis. Smad proteins can either positively or negatively regulate TGF-β responses. In this study, the therapeutic effects of Chinese traditional compound decoction, JinSanE, and the changes of TGF-β/Smad signaling pathway system in carbon tetrachloride (CCl4)-induced rat experimental liver fibrosis were examined.
METHODS: Seventy-two healthy Wistar rats were assigned to groups including normal control group, CCl4 model group, JinSanE treatment group I and JinSanE treatment group II. Each group contained 18 rats. All groups, except the normal control group, received CCl4 subcutaneous injection for 8 wk. Rats in JinSanE groups I and II were orally treated with JinSanE daily at the 1st and 5th wk, respectively, after exposure to CCl4. The expression of TGF-β1 and TGF-β1 type II receptor (TRII) mRNA in the liver was determined by reverse transcription polymerase chain reaction, and the expression of TGF-β1, Smad3 and Smad7 by immunohistochemistry. The liver histopathology was also examined by HE staining and observed under electron microscope. The activities of several serum fibrosis-associated enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), the levels of serum hyaluronic acid (HA) were assayed.
RESULTS: Hepatic fibrosis caused by CCl4 was significantly inhibited in the JinSanE-treated groups. The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the JinSanE-treated groups than in the model control group. The expression of TGF-β1, TRII and Smad3 was significantly higher in the model group than that in the JinSanE-treated groups, and the active/total TGF-β1 ratio in the JinSanE groups was suppressed. Expression of TRII mRNA and Smad3 proteins showed a distribution pattern similar to that of TGF-β1 with a direct correlation in terms of the degree of hepatic fibrosis. The amount of positive staining Smad7 cells was significantly less in the model group than in the JinSanE-treated groups and the normal group. The contents of ALT, AST and HA were significantly lower in the JinSanE-treated groups than those in the model group.
CONCLUSION: Traditional Chinese medicine, JinSanE, prevents the progression of hepatic damage and fibrosis through the inhibition of TGF-β1, TRII and Smad3 signal proteins, and increases expression of Smad7 signal protein in vivo.
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Affiliation(s)
- Shi-Ling Song
- Department of Infectious Diseases, Renmin Hospital, Key Laboratory of Virology for Ministry of Education, Wuhan University, Wuhan 430060, Hubei Province, China
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Abstract
Transforming growth factor-betas (TGF-betas) regulate pivotal cellular processes such as proliferation, differentiation and apoptosis. After ligand binding, the signals are transmitted by two types of transmembrane serine/threonine kinase receptors. The type I receptor phosphorylates Smad proteins, intracellular effectors which upon oligomerization enter the nucleus to regulate transcription following assembly with transcriptional co-factors and co-modulators. The cellular distribution of TGF-beta receptors along with their oligomerization mode and their complex formation with different cell surface receptors represent crucial steps in determining the initiation of distinct signalling cascades. In addition, the broad array of intracellular proteins that influence the TGF-beta pathway demonstrates that signal transduction does not proceed in a linear fashion but rather comprises a complex network of cascades that mutually influence each other. The present review describes the intricate control of TGF-beta signal transduction on various levels of the cascade with particular focus (i) on the assembly of different receptor subtypes and (ii) on the multitude of crosstalk with signal transducers from other pathways. Integration of the TGF-beta/Smad pathway into the signalling network has taken on added importance as it substantially contributes to elicit the plethora of cell- and tissue-specific effects of TGF-beta.
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Affiliation(s)
- Marion Lutz
- Department of Physiological Chemistry II, Biocenter, University of Würzburg, 97074 Würzburg, Germany
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Altmann CR, Chang C, Muñoz-Sanjuán I, Bell E, Heke M, Rifkin DB, Brivanlou AH. The latent-TGFbeta-binding-protein-1 (LTBP-1) is expressed in the organizer and regulates nodal and activin signaling. Dev Biol 2002; 248:118-27. [PMID: 12142025 DOI: 10.1006/dbio.2002.0716] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The latent TGF-beta binding proteins (LTBP) are believed to control the availability of TGF-beta in the extracellular milieu. To gain insight into the potential roles of LTBP in early development, we isolated the Xenopus LTBP-1 (xLTBP-1) cDNA. The cDNA encodes a protein similar to the mammalian LTBP-1 in both size and domain structure. In addition, we found a novel longer splice isoform of xLTBP. The RNAs for both forms of xLTBP displayed temporal regulation and the shorter transcript is expressed maternally. Both transcripts also display spatial regulation and are found in the dorsal mesoderm of the organizer. In animal cap experiments, LTBP-1 potentiates the activity of activin and nodal. The activity of LTBP-1 did not appear to require covalent association with activin as the addition of medium containing activin and LTBP-1 to animal caps enhanced the activin effect. These results indicate that LTBP-1 may be part of the regulatory system that establishes the threshold of morphogen activity for activins and nodals in the dorsal side of the embryo during gastrulation.
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Affiliation(s)
- Curtis R Altmann
- Laboratory of Molecular Embryology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
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Moustakas A, Heldin CH. From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction. Genes Dev 2002; 16:1867-71. [PMID: 12154118 DOI: 10.1101/gad.1016802] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Qin BY, Lam SS, Correia JJ, Lin K. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. Genes Dev 2002; 16:1950-63. [PMID: 12154125 PMCID: PMC186427 DOI: 10.1101/gad.1002002] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.
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Affiliation(s)
- Bin Y Qin
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
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