Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,...Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,such as spinal cord injury with the embryonic stem cells(ESCs)-derived oligodendrocyte progenitor cells,and dry age-related macular degeneration(AMD)with the ESCs-derived retinal pigment epithelium,and have great application value in clinical regenerative medicine.展开更多
Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understo...Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.展开更多
Protein post-translational modifications(PTMs)are chemical modifications on proteins.PTMs play a key role in many cellular processes by influencing the structure of proteins and dynamically regulating their functions....Protein post-translational modifications(PTMs)are chemical modifications on proteins.PTMs play a key role in many cellular processes by influencing the structure of proteins and dynamically regulating their functions.Therefore,characterizing PTMs at proteome level is critical to provide invaluable insight into the functions of proteins underlying different biological processes.Advances in modern proteomics technologies including sample preparation,chromatography separation as well as mass spectrometry have propelled the PTMs proteome to further depths.During the past decade,to better examine the PTMs with high sensitivity and selectivity,our group have developed a series of MS-based novel analytical approaches to study the protein PTMs.Herein,we mainly introduce these approaches developed by our group and discuss how to overcome the technical obstacles of studying various protein PTMs with mass spectrometry.展开更多
Lysine Lipoylation is a protective and conserved Post Translational Modification(PTM)in proteomics research like prokaryotes and eukaryotes.It is connected with many biological processes and closely linked with many m...Lysine Lipoylation is a protective and conserved Post Translational Modification(PTM)in proteomics research like prokaryotes and eukaryotes.It is connected with many biological processes and closely linked with many metabolic diseases.To develop a perfect and accurate classification model for identifying lipoylation sites at the protein level,the computational methods and several other factors play a key role in this purpose.Usually,most of the techniques and different traditional experimental models have a very high cost.They are time-consuming;so,it is required to construct a predictor model to extract lysine lipoylation sites.This study proposes a model that could predict lysine lipoylation sites with the help of a classification method known as Artificial Neural Network(ANN).The ANN algorithm deals with the noise problem and imbalance classification in lipoylation sites dataset samples.As the result shows in ten-fold cross-validation,a brilliant performance is achieved through the predictor model with an accuracy of 99.88%,and also achieved 0.9976 as the highest value of MCC.So,the predictor model is a very useful and helpful tool for lipoylation sites prediction.Some of the residues around lysine lipoylation sites play a vital part in prediction,as demonstrated during feature analysis.The wonderful results reported through the evaluation and prediction of this model can provide an informative and relative explanation for lipoylation and its molecular mechanisms.展开更多
Apoptotic cell death plays an important role in the maintenance of the normal physiological state and in the pathogenesis of diseases.Granule exocytosis is the main pathway for the immune elimination of virus-infected...Apoptotic cell death plays an important role in the maintenance of the normal physiological state and in the pathogenesis of diseases.Granule exocytosis is the main pathway for the immune elimination of virus-infected cells and tumor cells by cytotoxic T lymphocytes and natural killer cells.In recent study,we have investigated the level of granzyme H in patients with breast cancer and in control subjects using enzymatic method.Our study also included the prediction of different sites of granzyme H that play a role in substrate and inhibitor recognition in apoptosis process by using 3D structural model of the enzyme.The research described the possible post-translational modification sites that may help the enzyme in immune elimination of tumor cells.Our study shows that the level of granzyme H was reduced in patients when compared to normal control subjects.There are a number of amino acids that function as substrate recognition sites in granzyme H.However,inhibitors may inhibit their activity and affect the process of autolysis.展开更多
Active endogenous metabolites regulate the viability of cells. This process is controlled by a series ofinteractions between small metabolites and large proteins. Previously, several studies had reported thatmetabolit...Active endogenous metabolites regulate the viability of cells. This process is controlled by a series ofinteractions between small metabolites and large proteins. Previously, several studies had reported thatmetabolite regulates the protein functions, such as diacylglycerol to protein kinase C, lactose regulationof the lac repressor, and HIF-1α stabilization by 2-hydroxyglutarate. However, decades old traditionalbiochemical methods are insufficient to systematically investigate the bio-molecular reactions for a high-throughput discovery. Here, we have reviewed an update on the recently developed chemical proteomicscalled activity-based protein profiling （ABPP）. ABPP is able to identify proteins interacted eithercovalently or non-covalently with metabolites significantly. Thus, ABPP will facilitate the characteriza-tion of specific metabolite regulating; proteins in human disease progression.展开更多
Hepatocellular carcinoma(HCC)typically develops in the context of chronic liver disease,where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations.Epi...Hepatocellular carcinoma(HCC)typically develops in the context of chronic liver disease,where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations.Epigenetic regulation encompasses multiple mechanisms that govern the transcription machinery accessibility to DNA.This process is regulated by the addition and removal of covalent marks on chromatin,which can either affect DNA-histone interactions or serve as scaffolds for other proteins,among other mechanisms.Recent research has revealed that epigenetic alterations can disrupt chromatin homeostasis,redirecting transcriptional regulation to favour cancer-promoting states.Consequently,these alterations play a pivotal role in the acquisition of cancer hallmarks and provide insights into several biological processes involved in hepatocarcinogenesis.This review highlights the key epigenetic mechanisms underlying the development,progression and dissemination of HCC,with a particular focus on DNA methylation and histone post-translational modifications.This knowledge is relevant for guiding the development of innovative therapeutic approaches based on epigenetic modulators.展开更多
Dear Editor,During mitosis,the precise separation of chromosomes relies on the accurate connection between kinetochores and microtubules(Liu et al.,2020).Centromere protein C(CENP-C)is a central hub for kinetochore as...Dear Editor,During mitosis,the precise separation of chromosomes relies on the accurate connection between kinetochores and microtubules(Liu et al.,2020).Centromere protein C(CENP-C)is a central hub for kinetochore assembly and its cell-cycle function depends on post-translational modifications.Previous yeast and Caenorhabditis elegans studies suggest that the mitotic kinase polo-like kinase 1(PLK1)binds to the PEST-rich domain of CENP-C(Hinshaw et al.,2023;Taylor et al.,2023).Yeast CENP-C can be co-phosphorylated at 11 sites by DDK and CDC5(yeast PLK1),facilitating the assembly of the inner kinetochore,the constitutive centromere-associated network(CCAN).However,these phosphorylation sites are not conserved in humans(Hinshaw et al.,2023),raising the question of whether PLK1 regulates human inner kinetochore assembly via CENP-C.展开更多
Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,t...Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,to key molecular signals modulating signaling pathways,thereby influencing cell fates.Recently,Zhang’s work introduced a novel post-translational modification(PTM),lactylation,revealing a previously unidentified identity of lactate.Further findings in Plantae and Bacteria have projected lactylation as a common PTM among biological kingdoms.展开更多
Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)ar...Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.展开更多
To the Editor:O-linkedβ-N-acetylglucosaminylation(OGlcNAcylation)is a crucial post-translational modification regulated by two enzymes,O-GlcNAc transferase(OGT)and O-GlcNAcase(OGA).Dysregulation of O-GlcNAcylation ha...To the Editor:O-linkedβ-N-acetylglucosaminylation(OGlcNAcylation)is a crucial post-translational modification regulated by two enzymes,O-GlcNAc transferase(OGT)and O-GlcNAcase(OGA).Dysregulation of O-GlcNAcylation has been implicated in numerous disease processes,particularly in tumorigenesis.Lung cancer is the leading cause of cancer-related mortality worldwide.Most patients with lung cancer are diagnosed at an advanced stage,which poses grave risks to their lives.O-GlcNAcylation facilitates cancer cell adaption to adverse environments,playing a critical role in the onset and progression of lung cancer.This article provides a brief overview of O-GlcNAcylation properties and recent advancements in its study across various diseases,with a particular focus on lung cancer.展开更多
Glycosylation is one of the most complex and important post-translational modifications in proteins,playing essential roles in cellular signaling,protein folding,and immune responses[1].Despite its biological sig-nifi...Glycosylation is one of the most complex and important post-translational modifications in proteins,playing essential roles in cellular signaling,protein folding,and immune responses[1].Despite its biological sig-nificance,low abundance and high heterogeneity of glycoproteins pose significant analytical challenges.In a recent study published in National Science Review,a team of scientists led by Prof.Haojie Lu from Fudan University developed a groundbreaking strategy to address these challenges,offering a robust and scalable method for the comprehensive profiling of protein glycosylation[2].展开更多
Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of ...Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.展开更多
The post translational modifications of histone variants are playing an important role in the structure of chromatin, the regulation of gene activities and the diagnosis of diseases, and conducting in-depth researches...The post translational modifications of histone variants are playing an important role in the structure of chromatin, the regulation of gene activities and the diagnosis of diseases, and conducting in-depth researches and discovering new sites depend on new and rational analytical methods to some extent. In this work, the combinatorial method of high resolution LTQ-Orbitrap mass spectrometry and multiple enzymes was employed to identify the post translational modifications （PTMs） of histone H4 of human liver cells. The novel methylation site, argnine 67 （R 67）, was observed besides some sites reported previously such as lysine 31 （K 31）, lysine 44 （K 44）, argnine 55 （R 55） and lysine 59 （K 59） in the global domain. Meanwhile, various combinations of acetylation of lysine 5 （K 5）, lysine 8 （K 8）, lysine 12 （K 12）, lysine 16 （K 16） and methylation of lysine 20 （K 20） in the NH2-terminal tails were also identified after the LC-MS/MS analysis of trypsin, Arg-C, Glu-C and chymotrypsin digests.展开更多
基金supported by the National Key Research and Development Program of China(2024YFA0916400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0480000)+5 种基金the National Natural Science Foundation of China(32025010,32488301,92254301,92357302,92157202,32241002,32261160376,32322022,and 32471358)Major Project of Guangzhou National Laboratory(GZNL2024A03006 and GZNL2024B01003)the Key Research Program,CAS(ZDBS-ZRKJZ-TLC003,YSBR-075 and 188GJHZ2024048GC)Guangdong Province Science and Technology Program(2023B0303000023,2023B1111050005,2023B1212060050,2023B1212120009,2024B1515040020,and 2024A1515010782)Guangzhou Science and Technology Program(202206060002 and 2025A04J7110)Health@InnoHK funding support from the Innovation Technology Commission of the Hong Kong SAR,and Major Research Project(GIBHMRP25-01)Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences.
文摘Pluripotent stem cells(PSCs)possess the ability to proliferate indefinitely,self-renew,and differentiate into three germ layers.These pluripotent characteristics allow PSCs to be used to treat many incurable diseases,such as spinal cord injury with the embryonic stem cells(ESCs)-derived oligodendrocyte progenitor cells,and dry age-related macular degeneration(AMD)with the ESCs-derived retinal pigment epithelium,and have great application value in clinical regenerative medicine.
文摘Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.
基金the National Key Research and Development Pro-gram of China(2016YFA0501303)NSF of China(Grants 21974025 and 31670835)Shanghai Key Laboratory of Clinical Geriatric Medicine(13dz2260700)for financial support.
文摘Protein post-translational modifications(PTMs)are chemical modifications on proteins.PTMs play a key role in many cellular processes by influencing the structure of proteins and dynamically regulating their functions.Therefore,characterizing PTMs at proteome level is critical to provide invaluable insight into the functions of proteins underlying different biological processes.Advances in modern proteomics technologies including sample preparation,chromatography separation as well as mass spectrometry have propelled the PTMs proteome to further depths.During the past decade,to better examine the PTMs with high sensitivity and selectivity,our group have developed a series of MS-based novel analytical approaches to study the protein PTMs.Herein,we mainly introduce these approaches developed by our group and discuss how to overcome the technical obstacles of studying various protein PTMs with mass spectrometry.
文摘Lysine Lipoylation is a protective and conserved Post Translational Modification(PTM)in proteomics research like prokaryotes and eukaryotes.It is connected with many biological processes and closely linked with many metabolic diseases.To develop a perfect and accurate classification model for identifying lipoylation sites at the protein level,the computational methods and several other factors play a key role in this purpose.Usually,most of the techniques and different traditional experimental models have a very high cost.They are time-consuming;so,it is required to construct a predictor model to extract lysine lipoylation sites.This study proposes a model that could predict lysine lipoylation sites with the help of a classification method known as Artificial Neural Network(ANN).The ANN algorithm deals with the noise problem and imbalance classification in lipoylation sites dataset samples.As the result shows in ten-fold cross-validation,a brilliant performance is achieved through the predictor model with an accuracy of 99.88%,and also achieved 0.9976 as the highest value of MCC.So,the predictor model is a very useful and helpful tool for lipoylation sites prediction.Some of the residues around lysine lipoylation sites play a vital part in prediction,as demonstrated during feature analysis.The wonderful results reported through the evaluation and prediction of this model can provide an informative and relative explanation for lipoylation and its molecular mechanisms.
文摘Apoptotic cell death plays an important role in the maintenance of the normal physiological state and in the pathogenesis of diseases.Granule exocytosis is the main pathway for the immune elimination of virus-infected cells and tumor cells by cytotoxic T lymphocytes and natural killer cells.In recent study,we have investigated the level of granzyme H in patients with breast cancer and in control subjects using enzymatic method.Our study also included the prediction of different sites of granzyme H that play a role in substrate and inhibitor recognition in apoptosis process by using 3D structural model of the enzyme.The research described the possible post-translational modification sites that may help the enzyme in immune elimination of tumor cells.Our study shows that the level of granzyme H was reduced in patients when compared to normal control subjects.There are a number of amino acids that function as substrate recognition sites in granzyme H.However,inhibitors may inhibit their activity and affect the process of autolysis.
基金supported by the National Natural Science Foundation of China(No.81672440)Innovation Program of Science and Research from the DICP,CAS(No.DICP TMSR201601)the 100 Talents Program of Chinese Academy of Sciences
文摘Active endogenous metabolites regulate the viability of cells. This process is controlled by a series ofinteractions between small metabolites and large proteins. Previously, several studies had reported thatmetabolite regulates the protein functions, such as diacylglycerol to protein kinase C, lactose regulationof the lac repressor, and HIF-1α stabilization by 2-hydroxyglutarate. However, decades old traditionalbiochemical methods are insufficient to systematically investigate the bio-molecular reactions for a high-throughput discovery. Here, we have reviewed an update on the recently developed chemical proteomicscalled activity-based protein profiling （ABPP）. ABPP is able to identify proteins interacted eithercovalently or non-covalently with metabolites significantly. Thus, ABPP will facilitate the characteriza-tion of specific metabolite regulating; proteins in human disease progression.
基金funded by grants from PICT-2021-I-A-00975(GM,JB),PICT-2018-1036(JB)and PICT-2021-CAT-II-0012(GM,JB).
文摘Hepatocellular carcinoma(HCC)typically develops in the context of chronic liver disease,where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations.Epigenetic regulation encompasses multiple mechanisms that govern the transcription machinery accessibility to DNA.This process is regulated by the addition and removal of covalent marks on chromatin,which can either affect DNA-histone interactions or serve as scaffolds for other proteins,among other mechanisms.Recent research has revealed that epigenetic alterations can disrupt chromatin homeostasis,redirecting transcriptional regulation to favour cancer-promoting states.Consequently,these alterations play a pivotal role in the acquisition of cancer hallmarks and provide insights into several biological processes involved in hepatocarcinogenesis.This review highlights the key epigenetic mechanisms underlying the development,progression and dissemination of HCC,with a particular focus on DNA methylation and histone post-translational modifications.This knowledge is relevant for guiding the development of innovative therapeutic approaches based on epigenetic modulators.
基金supported by grants from the Ministry of Science and Technology of China and the National Natural Science Foundation of China(2022YFA1303100,32090040,92254302,W2411017,2022YFA0806800,and 92153302)the Plans for Major Provincial Science&Technology Projects of Anhui Province(202303a0702003)+2 种基金the Ministry of Education(IRT_17R102)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19040000)the Fundamental Research Funds for the Central Universities(KB9100000007,KB9100000006,and KB9100000013).
文摘Dear Editor,During mitosis,the precise separation of chromosomes relies on the accurate connection between kinetochores and microtubules(Liu et al.,2020).Centromere protein C(CENP-C)is a central hub for kinetochore assembly and its cell-cycle function depends on post-translational modifications.Previous yeast and Caenorhabditis elegans studies suggest that the mitotic kinase polo-like kinase 1(PLK1)binds to the PEST-rich domain of CENP-C(Hinshaw et al.,2023;Taylor et al.,2023).Yeast CENP-C can be co-phosphorylated at 11 sites by DDK and CDC5(yeast PLK1),facilitating the assembly of the inner kinetochore,the constitutive centromere-associated network(CCAN).However,these phosphorylation sites are not conserved in humans(Hinshaw et al.,2023),raising the question of whether PLK1 regulates human inner kinetochore assembly via CENP-C.
基金supported by the National Natural Science Foundation of China(NSFC)(T2225006,T2488301,and 82272948 to M.L.)the Beijing Municipal Natural Science Foundation(Key Program Z220011 to M.L.).
文摘Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,to key molecular signals modulating signaling pathways,thereby influencing cell fates.Recently,Zhang’s work introduced a novel post-translational modification(PTM),lactylation,revealing a previously unidentified identity of lactate.Further findings in Plantae and Bacteria have projected lactylation as a common PTM among biological kingdoms.
基金supported by the National Key R&D Program of China(2023YFC2507300)the National Natural Science Foundation of China(82273761,81970483,82170537 and 82222010)the Medical Innovation and Development Project of Lanzhou University(lzuyxcx-2022-156,China).
文摘Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.
基金National Natural Science Foundation of China(No.82000052)Sichuan Science and Technology Program(2022YFS0632)joint foundation of Luzhou Government and Southwest Medical University(Nos.2020LZXNYDJ11,2021LZXNYD-J25)
文摘To the Editor:O-linkedβ-N-acetylglucosaminylation(OGlcNAcylation)is a crucial post-translational modification regulated by two enzymes,O-GlcNAc transferase(OGT)and O-GlcNAcase(OGA).Dysregulation of O-GlcNAcylation has been implicated in numerous disease processes,particularly in tumorigenesis.Lung cancer is the leading cause of cancer-related mortality worldwide.Most patients with lung cancer are diagnosed at an advanced stage,which poses grave risks to their lives.O-GlcNAcylation facilitates cancer cell adaption to adverse environments,playing a critical role in the onset and progression of lung cancer.This article provides a brief overview of O-GlcNAcylation properties and recent advancements in its study across various diseases,with a particular focus on lung cancer.
文摘Glycosylation is one of the most complex and important post-translational modifications in proteins,playing essential roles in cellular signaling,protein folding,and immune responses[1].Despite its biological sig-nificance,low abundance and high heterogeneity of glycoproteins pose significant analytical challenges.In a recent study published in National Science Review,a team of scientists led by Prof.Haojie Lu from Fudan University developed a groundbreaking strategy to address these challenges,offering a robust and scalable method for the comprehensive profiling of protein glycosylation[2].
基金This study was supported by the National Institutes of Health(NIH)CA157481 awarded to RB.
文摘Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.
基金Project supported by the National Science and Technology Key Project （No. 2009CB825607）, National Natural Science Foundation of China （Nos. 20875016, 31070732）, Ministry of Education of China （20080246011）, Shanghai Projects （Shuguang Eastern Scholar and B 109）.
文摘The post translational modifications of histone variants are playing an important role in the structure of chromatin, the regulation of gene activities and the diagnosis of diseases, and conducting in-depth researches and discovering new sites depend on new and rational analytical methods to some extent. In this work, the combinatorial method of high resolution LTQ-Orbitrap mass spectrometry and multiple enzymes was employed to identify the post translational modifications （PTMs） of histone H4 of human liver cells. The novel methylation site, argnine 67 （R 67）, was observed besides some sites reported previously such as lysine 31 （K 31）, lysine 44 （K 44）, argnine 55 （R 55） and lysine 59 （K 59） in the global domain. Meanwhile, various combinations of acetylation of lysine 5 （K 5）, lysine 8 （K 8）, lysine 12 （K 12）, lysine 16 （K 16） and methylation of lysine 20 （K 20） in the NH2-terminal tails were also identified after the LC-MS/MS analysis of trypsin, Arg-C, Glu-C and chymotrypsin digests.
