CSN1 is a component of the COP9 signalosome(CSN),a conserved protein complex with pleiotropic functions in many organs and cell types.CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylati...CSN1 is a component of the COP9 signalosome(CSN),a conserved protein complex with pleiotropic functions in many organs and cell types.CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylation and the associated deubiquitination activities.In addition,CSN associates with protein kinases and modulates cell signaling,particularly the activator protein 1(AP-1)pathway.We have shown previously that CSN1 suppresses AP-1 transcription activity and inhibits ultraviolet(UV)and serum activation of c-fos expression.Here we show that CSN1 can inhibit phosphorylation of proto-oncogene c-Jun product and repress c-Jun dependent transcription.Further,CSN1 dramatically downregulates ectopic expression of c-Jun N-terminal kinase 1(JNK1)in cultured cells.The decline in JNK1 is not caused by excessive proteolysis or by 3′UTR-dependent mRNA instability,but by CSN1-dependent repression of one or multiple steps in transcriptional and posttranscriptional mechanisms.Thus,in contrast to CSN5/Jab1,which promotes AP-1 activity,CSN1 displays a negative effect on the AP-1 pathway.Finally,we discuss about the dynamic equilibrium of the CSN complexes in regulation of the AP-1 pathway.展开更多
Background:Globally,despite prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key mol...Background:Globally,despite prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies,ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University.The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa.The expression of aspartoacylase(ASPA)in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques.To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis,a comprehensive set of in vitro and in vivo assays were conducted,including orthotopic and tumor-bearing mouse models(n=8 for each group).A combination of experimental approaches,such as Western blotting,luciferase assays,immunoprecipitation assays,mass spectrometry,glutathione S-transferase pulldown experiments,and rescue studies,were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa.The Student‘s t-test was employed to assess the statistical significance between two distinct groups,while one-way analysis of variance was utilized for comparisons involving more than two groups.A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression.The expression of ASPA was found to be significantly down-regulated in PCa tissue samples,and its decreased expression was independently associated with patients’prognosis(HR=0.60,95%CI 0.40–0.92,P=0.018).Our experiments demonstrated that modulation of ASPA activity,either through gain-or loss-of-function,led to the suppression or enhancement of PCa cell proliferation,migration,and invasion,respectively.The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models.Mechanistically,ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets,JNK1/2 and C-Jun,in both PCa cells and mouse models,in an enzyme-independent manner.Importantly,the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models.Moreover,we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples,suggesting a potential regulatory role of ASPA in modulating LYN signaling.Conclusions:Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.展开更多
法尼酯X受体(farnesoid X receptor,FXR)是一种由胆汁酸激活的核受体,参与调控胆汁酸、脂肪、葡萄糖和氨基酸代谢相关的基因表达,FXR活性受到多种翻译后修饰方式的调控。常见FXR翻译后修饰方式包括O-糖基化、磷酸化、乙酰化、SUMO化和...法尼酯X受体(farnesoid X receptor,FXR)是一种由胆汁酸激活的核受体,参与调控胆汁酸、脂肪、葡萄糖和氨基酸代谢相关的基因表达,FXR活性受到多种翻译后修饰方式的调控。常见FXR翻译后修饰方式包括O-糖基化、磷酸化、乙酰化、SUMO化和甲基化等,这些翻译后修饰方式可能影响FXR结合DNA和配体、异源二聚化和亚细胞定位等功能,可能特异性调控下游基因转录表达。不同翻译后修饰可导致FXR稳定性及生物学功能改变,与疾病的发生密切相关。本文拟对近5年FXR的翻译后修饰方式及参与疾病调控的机制作一综述,探讨翻译后修饰方式对FXR生理学功能的影响,为以FXR为靶点的机制研究提供理论依据。展开更多
Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard t...Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard therapy for advanced PCa.In addition to its ligand androgen,accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa,especially in castration resistant prostate cancer(CRPC).To date,a number of posttranscriptional modifications of AR have been identified,including phosphorylation(e.g.by CDK1),acetylation(e.g.by p300 and recognized by BRD4),methylation(e.g.by EZH2),ubiquitination(e.g.by SPOP),and SUMOylation(e.g.by PIAS1).These modifications are essential for the maintenance of protein stability,nuclear localization and transcriptional activity of AR.This review summarizes posttranslational modifications that influence androgen-dependent and-independent activities of AR,PCa progression and therapy resistance.We further emphasize that in addition to androgen,posttranslational modification is another important way to regulate AR activity,suggesting that targeting AR posttranslational modifications,such as proteolysis targeting chimeras(PROTACs)of AR,represents a potential and promising alternate for effective treatment of CRPC.Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.展开更多
It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular ...It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.展开更多
c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studie...c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper(bZIP)transcription factor that acts as homo-or heterodimer,binding to DNA and regulating gene transcription.Later on,it was shown that extracellular signals can induce post-translational modifications of c-Jun,resulting in altered transcriptional activity and target gene expression.More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk,amplify and integrate different signals for tissue development and disease.One example of such scheme is the autocrine amplification loop,in which signal-induced AP-1 activates the c-Jun gene promoter,while increased c-Jun expression feedbacks to potentiate AP-1 activity.Another example of such scheme,based on recent characterization of gene knockout mice,is that c-Jun integrates signals of several developmental pathways,including EGFR-ERK,EGFR-RhoA-ROCK,and activin B-MAP3K1-JNK for embryonic eyelid closure.After more than two decades of extensive research,c-Jun remains at the center stage of a molecular network with mysterious functional properties,some of which are yet to be discovered.In this article,we will provide a brief historical overview of studies on c-Jun regulation and function,and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.展开更多
Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually oc...Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually occur as chemical modifications at amino acid residues, including SUMOylation, phosphorylation, palmitoylation, acetylation, etc. These complex biochemical modifications tightly regulate and control a variety of cellular processes. Several forms of post-translational modifications of huntingtin （Htt） have been described. These modifications affect Htt metabolism, protein-protein interactions and cellular toxicity. Cleavage and clearance of mutant Htt, and the interactions between mutant Htt and other cellular proteins are important biochemical events leading to Huntington＇s disease （HD）. Therefore, identifying signaling pathways of Htt modification and evaluating the significance of Htt modifications would lead to a better understanding of the normal function of wild-type Htt and the pathogenic mechanisms of mutant Htt.展开更多
Post-translational modifications(PTMs)are central to the modulation of protein activity,stability,subcellular localization,and interaction with partners.They greatly expand the diversity and functionality of the prote...Post-translational modifications(PTMs)are central to the modulation of protein activity,stability,subcellular localization,and interaction with partners.They greatly expand the diversity and functionality of the proteome and have taken the center stage as key players in regulating numerous cellular and physiological processes.Increasing evidence indicates that in addition to a single regulatory PTM,many proteins are modified by multiple different types of PTMs in an orchestrated manner to collectively modulate the biological outcome.Such PTM crosstalk creates a combinatorial explosion in the number of proteoforms in a cell and greatly improves the ability of plants to rapidly mount and fine-tune responses to different external and internal cues.While PTM crosstalk has been investigated in depth in humans,animals,and yeast,the study of interplay between different PTMs in plants is still at its infant stage.In the past decade,investigations showed that PTMs are widely involved and play critical roles in the regulation of interactions between plants and pathogens.In particular,ubiquitination has emerged as a key regulator of plant immunity.This review discusses recent studies of the crosstalk between ubiquitination and six other PTMs,i.e.,phosphorylation,SUMOylation,poly(ADP-ribosyl)ation,acetylation,redox modification,and glycosylation,in the regulation of plant immunity.The two basic ways by which PTMs communicate as well as the underlying mechanisms and diverse outcomes of the PTM crosstalk in plant immunity are highlighted.展开更多
Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the P...Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.展开更多
基金supported by research grants from the National Institutes of Health(GM61812)to NWthe Human Frontier Long Term Fellowship(LT0084/1998-M)to TTa collaborative grant from The Kyoto University Foundation(2007-2008)to NW,SM,and TT.
文摘CSN1 is a component of the COP9 signalosome(CSN),a conserved protein complex with pleiotropic functions in many organs and cell types.CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylation and the associated deubiquitination activities.In addition,CSN associates with protein kinases and modulates cell signaling,particularly the activator protein 1(AP-1)pathway.We have shown previously that CSN1 suppresses AP-1 transcription activity and inhibits ultraviolet(UV)and serum activation of c-fos expression.Here we show that CSN1 can inhibit phosphorylation of proto-oncogene c-Jun product and repress c-Jun dependent transcription.Further,CSN1 dramatically downregulates ectopic expression of c-Jun N-terminal kinase 1(JNK1)in cultured cells.The decline in JNK1 is not caused by excessive proteolysis or by 3′UTR-dependent mRNA instability,but by CSN1-dependent repression of one or multiple steps in transcriptional and posttranscriptional mechanisms.Thus,in contrast to CSN5/Jab1,which promotes AP-1 activity,CSN1 displays a negative effect on the AP-1 pathway.Finally,we discuss about the dynamic equilibrium of the CSN complexes in regulation of the AP-1 pathway.
基金supported by the Science and Technology Department of Hubei Province Key Project(YYXKNL2022001)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT320-004)+2 种基金the Hubei Provincial Natural Science Foundation(2021CFB453)the Science,Technology and Innovation Seed Fund of Zhongnan Hospital of Wuhan University(CXPY2020031)the Climbing Program for Medical Talents of Zhongnan Hospital of Wuhan University(PDJH202206,PDJH202208)。
文摘Background:Globally,despite prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies,ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University.The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa.The expression of aspartoacylase(ASPA)in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques.To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis,a comprehensive set of in vitro and in vivo assays were conducted,including orthotopic and tumor-bearing mouse models(n=8 for each group).A combination of experimental approaches,such as Western blotting,luciferase assays,immunoprecipitation assays,mass spectrometry,glutathione S-transferase pulldown experiments,and rescue studies,were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa.The Student‘s t-test was employed to assess the statistical significance between two distinct groups,while one-way analysis of variance was utilized for comparisons involving more than two groups.A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression.The expression of ASPA was found to be significantly down-regulated in PCa tissue samples,and its decreased expression was independently associated with patients’prognosis(HR=0.60,95%CI 0.40–0.92,P=0.018).Our experiments demonstrated that modulation of ASPA activity,either through gain-or loss-of-function,led to the suppression or enhancement of PCa cell proliferation,migration,and invasion,respectively.The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models.Mechanistically,ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets,JNK1/2 and C-Jun,in both PCa cells and mouse models,in an enzyme-independent manner.Importantly,the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models.Moreover,we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples,suggesting a potential regulatory role of ASPA in modulating LYN signaling.Conclusions:Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.
文摘法尼酯X受体(farnesoid X receptor,FXR)是一种由胆汁酸激活的核受体,参与调控胆汁酸、脂肪、葡萄糖和氨基酸代谢相关的基因表达,FXR活性受到多种翻译后修饰方式的调控。常见FXR翻译后修饰方式包括O-糖基化、磷酸化、乙酰化、SUMO化和甲基化等,这些翻译后修饰方式可能影响FXR结合DNA和配体、异源二聚化和亚细胞定位等功能,可能特异性调控下游基因转录表达。不同翻译后修饰可导致FXR稳定性及生物学功能改变,与疾病的发生密切相关。本文拟对近5年FXR的翻译后修饰方式及参与疾病调控的机制作一综述,探讨翻译后修饰方式对FXR生理学功能的影响,为以FXR为靶点的机制研究提供理论依据。
基金supported by Mayo Clinic Foundation(MC-HH999 to Haojie Huang).
文摘Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard therapy for advanced PCa.In addition to its ligand androgen,accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa,especially in castration resistant prostate cancer(CRPC).To date,a number of posttranscriptional modifications of AR have been identified,including phosphorylation(e.g.by CDK1),acetylation(e.g.by p300 and recognized by BRD4),methylation(e.g.by EZH2),ubiquitination(e.g.by SPOP),and SUMOylation(e.g.by PIAS1).These modifications are essential for the maintenance of protein stability,nuclear localization and transcriptional activity of AR.This review summarizes posttranslational modifications that influence androgen-dependent and-independent activities of AR,PCa progression and therapy resistance.We further emphasize that in addition to androgen,posttranslational modification is another important way to regulate AR activity,suggesting that targeting AR posttranslational modifications,such as proteolysis targeting chimeras(PROTACs)of AR,represents a potential and promising alternate for effective treatment of CRPC.Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.
文摘It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.
文摘c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper(bZIP)transcription factor that acts as homo-or heterodimer,binding to DNA and regulating gene transcription.Later on,it was shown that extracellular signals can induce post-translational modifications of c-Jun,resulting in altered transcriptional activity and target gene expression.More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk,amplify and integrate different signals for tissue development and disease.One example of such scheme is the autocrine amplification loop,in which signal-induced AP-1 activates the c-Jun gene promoter,while increased c-Jun expression feedbacks to potentiate AP-1 activity.Another example of such scheme,based on recent characterization of gene knockout mice,is that c-Jun integrates signals of several developmental pathways,including EGFR-ERK,EGFR-RhoA-ROCK,and activin B-MAP3K1-JNK for embryonic eyelid closure.After more than two decades of extensive research,c-Jun remains at the center stage of a molecular network with mysterious functional properties,some of which are yet to be discovered.In this article,we will provide a brief historical overview of studies on c-Jun regulation and function,and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.
基金supported by grants from the National Natural Science Foundation of China (No.30600197)
文摘Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually occur as chemical modifications at amino acid residues, including SUMOylation, phosphorylation, palmitoylation, acetylation, etc. These complex biochemical modifications tightly regulate and control a variety of cellular processes. Several forms of post-translational modifications of huntingtin （Htt） have been described. These modifications affect Htt metabolism, protein-protein interactions and cellular toxicity. Cleavage and clearance of mutant Htt, and the interactions between mutant Htt and other cellular proteins are important biochemical events leading to Huntington＇s disease （HD）. Therefore, identifying signaling pathways of Htt modification and evaluating the significance of Htt modifications would lead to a better understanding of the normal function of wild-type Htt and the pathogenic mechanisms of mutant Htt.
基金supported by a grant from the National Science Foundation(IOS-1645659)to L.Z.No conflict of interest declared.
文摘Post-translational modifications(PTMs)are central to the modulation of protein activity,stability,subcellular localization,and interaction with partners.They greatly expand the diversity and functionality of the proteome and have taken the center stage as key players in regulating numerous cellular and physiological processes.Increasing evidence indicates that in addition to a single regulatory PTM,many proteins are modified by multiple different types of PTMs in an orchestrated manner to collectively modulate the biological outcome.Such PTM crosstalk creates a combinatorial explosion in the number of proteoforms in a cell and greatly improves the ability of plants to rapidly mount and fine-tune responses to different external and internal cues.While PTM crosstalk has been investigated in depth in humans,animals,and yeast,the study of interplay between different PTMs in plants is still at its infant stage.In the past decade,investigations showed that PTMs are widely involved and play critical roles in the regulation of interactions between plants and pathogens.In particular,ubiquitination has emerged as a key regulator of plant immunity.This review discusses recent studies of the crosstalk between ubiquitination and six other PTMs,i.e.,phosphorylation,SUMOylation,poly(ADP-ribosyl)ation,acetylation,redox modification,and glycosylation,in the regulation of plant immunity.The two basic ways by which PTMs communicate as well as the underlying mechanisms and diverse outcomes of the PTM crosstalk in plant immunity are highlighted.
基金This work was supported by the National Natural Science Foundation of China(81622005)Beijing Natural Science Foundation(7172213).
文摘Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.
