There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific wit...There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.展开更多
The arachidonic acid(AA)metabolic pathway participates in various physiological processes as well as in the development of malignancies.We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atla...The arachidonic acid(AA)metabolic pathway participates in various physiological processes as well as in the development of malignancies.We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas(TCGA)prostate cancer(PCa)dataset and found that the gene encoding soluble epoxide hydrolase(EPHX2)is frequently deleted in PCa.EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry.The expression data were analyzed in conjunction with clinicopathological variables.Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time.Furthermore,EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa,respectively.In addition,EPHX2 protein expression correlated negatively with Ki67 expression.In conclusion,EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.展开更多
The tumor suppressor p53 is a multifunctional, highly regulated, and promoter-specific transcriptional factor that is uniquely sensitive to DNA damage and cellular stress signaling. The mechanisms by which p53 directs...The tumor suppressor p53 is a multifunctional, highly regulated, and promoter-specific transcriptional factor that is uniquely sensitive to DNA damage and cellular stress signaling. The mechanisms by which p53 directs a damaged cell down either a cell growth arrest or an apoptotic pathway remain poorly understood. Evidence suggests that the in vivo functions of p53 seem to balance the cell-fate choice with the type and severity of damage that occurs. The concept of antirepression, or inhibition of factors that normally keep p53 at bay, may help explain the physiological mechanisms for p53 activation. These factors also provide novel chemotherapeutic targets for the reactivation of p53 in tumors harboring a wild-type copy of the gene.展开更多
AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepa...AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.展开更多
Organoids are in vitro microstructures similar to the source tissue formed by the self-organizing construction of stem cells from various sources.It is now widely recognized as a powerful in vitro model to facilitate ...Organoids are in vitro microstructures similar to the source tissue formed by the self-organizing construction of stem cells from various sources.It is now widely recognized as a powerful in vitro model to facilitate cancer research and personalized precision therapy.Since the successful establishment of the first organoid model in 2009,there has been a global upsurge in organoid research.At present,organoids have been widely used in research on the mechanism of cancer occurrence and development,the study of cell interactions in the tumor microenvironment,the development and screening of new drugs,and the individualized precision treatment of cancer.In addition,the development of organoid chip technology and the establishment of organoid biobanks are expected to further promote the irreplaceable role of organoids in precision medical treatment.In this review,we offer a comprehensive outline of the historical development of organoids and their advantages,focusing on the latest progress and application of organoids in cancer research.We also discuss the problems that need to be solved and the potential applications of organoids.This review summarizes the impact and potential of organoids in cancer research and treatment,and we also provide a comprehensive view of organoid applications in cancer.展开更多
Dear Editor,p53 acts as a transcription factor to modulate various types of cellular processes to suppress tumor development(Tackmann and Zhang,2017).The exquisite regulation of p53 functions is of vital importance fo...Dear Editor,p53 acts as a transcription factor to modulate various types of cellular processes to suppress tumor development(Tackmann and Zhang,2017).The exquisite regulation of p53 functions is of vital importance for cell fate decisions.Although it is well accepted that p53-mediated cell-cycle arrest,senescence,and apoptosis serve as major tumor suppression mechanisms,recent studies suggest that other unconventional activities such as ferroptosis are also critically involved in its tumor suppressor function(Li et al.,2012).We and others found that p53 plays an important role in modulating ferroptotic responses through its metabolic targets(Jiang et al.,2015;Jennis et al.,2016;Wang et al.,2016).Ferroptosis is a regulated form of iron-dependent,non-apoptotic cell death characterized by excessive reactive oxygen species(ROS)generation and accumulation of lipid peroxidates(Stockwell et al.,2020).Lipid peroxides are normally eliminated by glutathione peroxidase 4(GPX4)and its co-factor glutathione(GSH),which convert lipid hydroperoxides to non-toxic lipid alcohols.Thus,ferroptosis can be artificially induced by pharmacological agents that disrupt this lipid repair system,allowing lethal accumulation of lipid peroxides.Such agents include direct GPX4 enzymatic inhibitors,as well as the small molecule erastin,which suppress glutathione synthesis and indirectly suppress GPX4 activation(Stockwell et al.,2020).Although activation of p53 expression is able to modulate ferroptosis induced by GPX4 inhibition in certain cell types(Jiang et al.,2015),p53-mediated ferroptotic responses are also observed upon ROS-induced stress,apparently through a GPX4-independent manner(Chu et al.,2019).Nevertheless,the molecular factors that modulate p53-dependent ferroptosis upon ROS stress need further elucidation.Sirt3 is a NAD-dependent deacetylase predominantly localized in mitochondria,which functions in multiple metabolic pathways,including electron transport chain,fatty acid oxidation,amino acid metabolism,redox balance,and the tricarboxylic acid(TCA)cycle(Van de Ven et al.,2017).Here,we identified Sirt3 as a novel repressor in p53-mediated ferroptosis induced by ROS stress.展开更多
Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better st...Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better strategy for cancer therapy.The canonical activities of p53,such as cell cycle arrest,senescence,and apoptosis,are well accepted as the major checkpoints in stress responses and tumor suppression.展开更多
Tumors are the result of accumulated genomic alterations that cooperate synergistically to produce uncontrollable cell growth.Although identifying recurrent alterations among large collections of tumors provides a way...Tumors are the result of accumulated genomic alterations that cooperate synergistically to produce uncontrollable cell growth.Although identifying recurrent alterations among large collections of tumors provides a way to pinpoint genes that endow a selective advantage in oncogenesis and progression,it fails to address the genetic interactions behind this selection process.A non-random pattern of co-mutated genes is evidence for selective forces acting on tumor cells that harbor combinations of these genetic alterations.Although existing methods have successfully identified mutually exclusive gene sets,no current method can systematically discover more general genetic relationships.We develop Genomic Alteration Modules using Total Correlation(GAMToC),an information theoretic frameworkthat integrates copynumberandmutation datato identify genemodules with any non-randompattern of joint alteration.Additionally,wepresent theSeed-GAMToCprocedure,which uncoversthe mutational context of any putative cancer gene.The software is publicly available.Applied to glioblastoma multiforme samples,GAMToC results show distinct subsets of co-occurring mutations,suggesting distinct mutational routes to cancer and providing new insight into mutations associated with proneural,proneural/G-CIMP,and classical types of the disease.The results recapitulate known relationships such as mutual exclusive mutations,place these alterations in the context of other mutations,and find more complex relationships such as conditional mutual exclusivity.展开更多
Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer dev...Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development.It is well accepted that ferroptosis,an iron-dependent programmed cell death,acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways.SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo.The levels of SLC7A11 are dynamically regulated by various types of stresses,such as oxidative stress,nutrient deprivation,endoplasmic reticulum stress,radiation,oncogenic stress,DNA damage,and immune stress.SLC7A11 can be transcriptionally regulated by both activators such as ATF4,NRF2,and ETS1,and repressors including BACH1,p53,ATF3,and STAT1 during stress responses.Moreover,SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress.Patients’data show that SLC7A11 is overexpressed in various types of human cancers,and higher levels of SLC7A11 predict poorer overall survival.Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation,invasion,and metastasis,as well as counteracting cancer stem cells and overcoming chemoresistance.This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.展开更多
Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature prot...Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones,folding enzymes,and degradation machineries.Disruptions in this network lead to dysproteostasis,a pathological state implicated in a growing list of human diseases,including neurodegenerative disorders,metabolic syndromes,and cancer.In this review,we provide a comprehensive and multidimensional analysis of protein folding biology,tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics.We explore the historical progression of protein folding research,including landmark discoveries of secondary structure,chaperone biology,and energy landscape theory.We detail the roles of key molecular chaperones across cytosolic,mitochondrial,and endoplasmic reticulum compartments,emphasizing their collaborative actions in protein folding and quality control.We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences,paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity.We then examine therapeutic innovations targeting proteostasis,including chaperone modulators,proteostasis pathway inhibitors,and emerging strategies to increase proteome resilience.By consolidating insights at the molecular,cellular,and systems levels,this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.展开更多
The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression.The exquisite regulation of p53 functions is of vital importance for cell f...The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression.The exquisite regulation of p53 functions is of vital importance for cell fate decisions.Among the multiple layers of mechanisms controlling p53 function,posttranslational modifications (PTMs) represent an efficient and precise way.Major p53 PTMs include phosphorylation,ubiquitination,acetylation,and methylation.Meanwhile,other PTMs like sumoylation,neddylation,O-GlcNAcylation,adenosine diphosphate (ADP)-ribosylation,hydroxylation,and p-hydroxybutyrylation are also shown to play various roles in p53 regulation.By independent action or interaction,PTMs affect p53 stability,conformation,localization,and binding partners.Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases,especially in cancers.This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.展开更多
The p53 tumor suppressor is a sequence-specific transcription factor that undergoes an abundance of post-translational modifications for its regulation and activation.Acetylation of p53 is an important reversible enzy...The p53 tumor suppressor is a sequence-specific transcription factor that undergoes an abundance of post-translational modifications for its regulation and activation.Acetylation of p53 is an important reversible enzymatic process that occurs in response to DNA damage and genotoxic stress and is indispensible for p53 transcriptional activity.p53 was the first non-histone protein shown to be acetylated by histone acetyl transferases,and a number of more recent in vivo models have underscored the importance of this type of modification for p53 activity.Here,we review the current knowledge and recent findings of p53 acetylation and deacetylation and discuss the implications of these processes for the p53 pathway.展开更多
It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase a...It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deu- biquitinase herpesvirus-associated ubiquitin-specific protease （HAUSP, also known as USP7） plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.展开更多
Dear Editor,The passage of DNA replication forks during eukaryotic cell division disrupts the nucleosomes they encounter,and de novo assembly of nucleosomes onto replicated DNA must take place to restore chromatin str...Dear Editor,The passage of DNA replication forks during eukaryotic cell division disrupts the nucleosomes they encounter,and de novo assembly of nucleosomes onto replicated DNA must take place to restore chromatin structure.There are two sources of histones for the replicationcoupled nucleosome assembly.展开更多
文摘There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.
基金Financial support for this study was supported by Yunnan Fundamental Research Projects(No.2019FE001[-277]and 2019FE001[-005])the Project for Innovation Team of Yunnan Provincial Science and Technology Department,China(No.2018HC005)Qujing Affiliated Hospital of Kunming Medical University(2019YJKT11 and 2020YJKT03).
文摘The arachidonic acid(AA)metabolic pathway participates in various physiological processes as well as in the development of malignancies.We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas(TCGA)prostate cancer(PCa)dataset and found that the gene encoding soluble epoxide hydrolase(EPHX2)is frequently deleted in PCa.EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry.The expression data were analyzed in conjunction with clinicopathological variables.Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time.Furthermore,EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa,respectively.In addition,EPHX2 protein expression correlated negatively with Ki67 expression.In conclusion,EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.
文摘The tumor suppressor p53 is a multifunctional, highly regulated, and promoter-specific transcriptional factor that is uniquely sensitive to DNA damage and cellular stress signaling. The mechanisms by which p53 directs a damaged cell down either a cell growth arrest or an apoptotic pathway remain poorly understood. Evidence suggests that the in vivo functions of p53 seem to balance the cell-fate choice with the type and severity of damage that occurs. The concept of antirepression, or inhibition of factors that normally keep p53 at bay, may help explain the physiological mechanisms for p53 activation. These factors also provide novel chemotherapeutic targets for the reactivation of p53 in tumors harboring a wild-type copy of the gene.
文摘AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.
基金supported by the National Natural Science Foundation of China(82241049,81922042,and 82172285 to X.Z.82072999 and 82273320 to J.L.)+1 种基金the 1$3$5 Project of Excellent Development of Discipline of West China Hospital of Sichuan University(ZYYC21001 to X.Z.)the“Zero to One”Innovation Research Project of Sichuan University(2022SCUH0029 to J.L.).
文摘Organoids are in vitro microstructures similar to the source tissue formed by the self-organizing construction of stem cells from various sources.It is now widely recognized as a powerful in vitro model to facilitate cancer research and personalized precision therapy.Since the successful establishment of the first organoid model in 2009,there has been a global upsurge in organoid research.At present,organoids have been widely used in research on the mechanism of cancer occurrence and development,the study of cell interactions in the tumor microenvironment,the development and screening of new drugs,and the individualized precision treatment of cancer.In addition,the development of organoid chip technology and the establishment of organoid biobanks are expected to further promote the irreplaceable role of organoids in precision medical treatment.In this review,we offer a comprehensive outline of the historical development of organoids and their advantages,focusing on the latest progress and application of organoids in cancer research.We also discuss the problems that need to be solved and the potential applications of organoids.This review summarizes the impact and potential of organoids in cancer research and treatment,and we also provide a comprehensive view of organoid applications in cancer.
文摘Dear Editor,p53 acts as a transcription factor to modulate various types of cellular processes to suppress tumor development(Tackmann and Zhang,2017).The exquisite regulation of p53 functions is of vital importance for cell fate decisions.Although it is well accepted that p53-mediated cell-cycle arrest,senescence,and apoptosis serve as major tumor suppression mechanisms,recent studies suggest that other unconventional activities such as ferroptosis are also critically involved in its tumor suppressor function(Li et al.,2012).We and others found that p53 plays an important role in modulating ferroptotic responses through its metabolic targets(Jiang et al.,2015;Jennis et al.,2016;Wang et al.,2016).Ferroptosis is a regulated form of iron-dependent,non-apoptotic cell death characterized by excessive reactive oxygen species(ROS)generation and accumulation of lipid peroxidates(Stockwell et al.,2020).Lipid peroxides are normally eliminated by glutathione peroxidase 4(GPX4)and its co-factor glutathione(GSH),which convert lipid hydroperoxides to non-toxic lipid alcohols.Thus,ferroptosis can be artificially induced by pharmacological agents that disrupt this lipid repair system,allowing lethal accumulation of lipid peroxides.Such agents include direct GPX4 enzymatic inhibitors,as well as the small molecule erastin,which suppress glutathione synthesis and indirectly suppress GPX4 activation(Stockwell et al.,2020).Although activation of p53 expression is able to modulate ferroptosis induced by GPX4 inhibition in certain cell types(Jiang et al.,2015),p53-mediated ferroptotic responses are also observed upon ROS-induced stress,apparently through a GPX4-independent manner(Chu et al.,2019).Nevertheless,the molecular factors that modulate p53-dependent ferroptosis upon ROS stress need further elucidation.Sirt3 is a NAD-dependent deacetylase predominantly localized in mitochondria,which functions in multiple metabolic pathways,including electron transport chain,fatty acid oxidation,amino acid metabolism,redox balance,and the tricarboxylic acid(TCA)cycle(Van de Ven et al.,2017).Here,we identified Sirt3 as a novel repressor in p53-mediated ferroptosis induced by ROS stress.
文摘Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better strategy for cancer therapy.The canonical activities of p53,such as cell cycle arrest,senescence,and apoptosis,are well accepted as the major checkpoints in stress responses and tumor suppression.
基金This work was funded in part by 1R01CA185486-01,1 R01 CA179044-01A1,NIH P50 MH094267-01NIH 1 U54 CA121852-05.J.W.is also supported by Precision Medicine Fellowship(UL1 TR000040).
文摘Tumors are the result of accumulated genomic alterations that cooperate synergistically to produce uncontrollable cell growth.Although identifying recurrent alterations among large collections of tumors provides a way to pinpoint genes that endow a selective advantage in oncogenesis and progression,it fails to address the genetic interactions behind this selection process.A non-random pattern of co-mutated genes is evidence for selective forces acting on tumor cells that harbor combinations of these genetic alterations.Although existing methods have successfully identified mutually exclusive gene sets,no current method can systematically discover more general genetic relationships.We develop Genomic Alteration Modules using Total Correlation(GAMToC),an information theoretic frameworkthat integrates copynumberandmutation datato identify genemodules with any non-randompattern of joint alteration.Additionally,wepresent theSeed-GAMToCprocedure,which uncoversthe mutational context of any putative cancer gene.The software is publicly available.Applied to glioblastoma multiforme samples,GAMToC results show distinct subsets of co-occurring mutations,suggesting distinct mutational routes to cancer and providing new insight into mutations associated with proneural,proneural/G-CIMP,and classical types of the disease.The results recapitulate known relationships such as mutual exclusive mutations,place these alterations in the context of other mutations,and find more complex relationships such as conditional mutual exclusivity.
基金supported by the National Cancer Institute of the National Institutes of Health(USA)(No.R35CA253059,RO1CA258390,RO1CA254970 to W.G.).
文摘Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development.It is well accepted that ferroptosis,an iron-dependent programmed cell death,acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways.SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo.The levels of SLC7A11 are dynamically regulated by various types of stresses,such as oxidative stress,nutrient deprivation,endoplasmic reticulum stress,radiation,oncogenic stress,DNA damage,and immune stress.SLC7A11 can be transcriptionally regulated by both activators such as ATF4,NRF2,and ETS1,and repressors including BACH1,p53,ATF3,and STAT1 during stress responses.Moreover,SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress.Patients’data show that SLC7A11 is overexpressed in various types of human cancers,and higher levels of SLC7A11 predict poorer overall survival.Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation,invasion,and metastasis,as well as counteracting cancer stem cells and overcoming chemoresistance.This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.
基金funded by the Norwegian Research Council(303353)the Norwegian Cancer Society(247110)+1 种基金Helse Sør-Øst(2021022,2022041,2023078)Anders Jahre fund(102583101,10,000)。
文摘Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function.This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones,folding enzymes,and degradation machineries.Disruptions in this network lead to dysproteostasis,a pathological state implicated in a growing list of human diseases,including neurodegenerative disorders,metabolic syndromes,and cancer.In this review,we provide a comprehensive and multidimensional analysis of protein folding biology,tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics.We explore the historical progression of protein folding research,including landmark discoveries of secondary structure,chaperone biology,and energy landscape theory.We detail the roles of key molecular chaperones across cytosolic,mitochondrial,and endoplasmic reticulum compartments,emphasizing their collaborative actions in protein folding and quality control.We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences,paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity.We then examine therapeutic innovations targeting proteostasis,including chaperone modulators,proteostasis pathway inhibitors,and emerging strategies to increase proteome resilience.By consolidating insights at the molecular,cellular,and systems levels,this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.
文摘The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression.The exquisite regulation of p53 functions is of vital importance for cell fate decisions.Among the multiple layers of mechanisms controlling p53 function,posttranslational modifications (PTMs) represent an efficient and precise way.Major p53 PTMs include phosphorylation,ubiquitination,acetylation,and methylation.Meanwhile,other PTMs like sumoylation,neddylation,O-GlcNAcylation,adenosine diphosphate (ADP)-ribosylation,hydroxylation,and p-hydroxybutyrylation are also shown to play various roles in p53 regulation.By independent action or interaction,PTMs affect p53 stability,conformation,localization,and binding partners.Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases,especially in cancers.This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.
文摘The p53 tumor suppressor is a sequence-specific transcription factor that undergoes an abundance of post-translational modifications for its regulation and activation.Acetylation of p53 is an important reversible enzymatic process that occurs in response to DNA damage and genotoxic stress and is indispensible for p53 transcriptional activity.p53 was the first non-histone protein shown to be acetylated by histone acetyl transferases,and a number of more recent in vivo models have underscored the importance of this type of modification for p53 activity.Here,we review the current knowledge and recent findings of p53 acetylation and deacetylation and discuss the implications of these processes for the p53 pathway.
文摘It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deu- biquitinase herpesvirus-associated ubiquitin-specific protease （HAUSP, also known as USP7） plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.
基金supported by the National Key Research and Development Program of China(2019YFA0508900)the National Natural Science Foundation of China(32330021,31991162,32200477)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB37010100)。
文摘Dear Editor,The passage of DNA replication forks during eukaryotic cell division disrupts the nucleosomes they encounter,and de novo assembly of nucleosomes onto replicated DNA must take place to restore chromatin structure.There are two sources of histones for the replicationcoupled nucleosome assembly.
