In eukaryotic cells,both alternative splicing and alternative polyadenylation(APA)play essential roles in the gene regulation network.U1 small ribonucleoprotein particle(U1 snRNP)is a major component of spliceosome,an...In eukaryotic cells,both alternative splicing and alternative polyadenylation(APA)play essential roles in the gene regulation network.U1 small ribonucleoprotein particle(U1 snRNP)is a major component of spliceosome,and U1 snRNP complex can suppress proximal APA sites through crosstalking with 3end processing factors.However,here we show that both knockdown and overexpression of SNRPA,SNRPC,SNRNP70,and SNRPD2,the U1 snRNP proteins,promote the usage of proximal APA sites at the transcriptome level.SNRNP70 can drive the phase transition of PABPN1 from droplet to aggregate,which may reduce the repressive effects of PABPN1 on the proximal APA sites.Additionally,SNRNP70 can also promote the proximal APA sites by recruiting CPSF6,suggesting that the function of CPSF6 on APA is related with other RNA-binding proteins and cell context-dependent.Consequently,these results reveal that,on the contrary to U1 snRNP complex,the free proteins of U1 snRNP complex can promote proximal APA sites through the interaction with 3end processing machinery.展开更多
In the originally published version of this article(p.822),there was an error in the second affiliation of author Chengming Zhang.The erroneous affiliation was given as‘University of the Chinese Academy of Sciences’...In the originally published version of this article(p.822),there was an error in the second affiliation of author Chengming Zhang.The erroneous affiliation was given as‘University of the Chinese Academy of Sciences’.This has now been corrected to‘University of Chinese Academy of Sciences’.展开更多
Dear Editor,Abl1,when fused with BCR,expresses fusion protein BCR‒ABL that underlies the etiology of chronic myeloid leukemia and is therapeutically targeted by Imatinib Mesylate(Khatri et al.,2016).However,the functi...Dear Editor,Abl1,when fused with BCR,expresses fusion protein BCR‒ABL that underlies the etiology of chronic myeloid leukemia and is therapeutically targeted by Imatinib Mesylate(Khatri et al.,2016).However,the function of proto-oncogene product Abl1 remains not fully understood.This non-receptor tyrosine kinase can be activated by growth factors,DNA damage,oxidative stress,and microbial pathogens(Wang,2014).Cell-based studies suggest that Abl1 phosphorylates proteins in DNA damage response(DDR)and other signaling pathways,promoting p53 expression as well as cell cycle arrest and apoptosis(Gonfloni et al.,2009).Abl1 deletion leads to runtedness,osteoporosis,and other developmental defects in mice.Interestingly,it has been reported that Abl1 kinase is activated in many solid tumors and Abl1 is implicated in EphB2-mediated intestinal adenoma growth and colorectal cancer(CRC)invasion and metastasis(Kundu et al.,2015;Sonoshita et al.,2015).However,a recent study showed that Abl1 expression is reduced in most CRC patient samples(Uhlen et al.,2015).Thus,the function of Abl1 in CRC initiation warrants further investigation.展开更多
Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and bio...Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR–IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.展开更多
Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis rely strictly on the identification of cell-in-cell structures (CICs), a unique morpholog...Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis rely strictly on the identification of cell-in-cell structures (CICs), a unique morphological readout that can only be quantified manually at present. Moreover, the manual CIC quantification is generally over-simplified as CIC counts, which represents a major hurdle against profound mechanistic investigations. In this study, we take advantage of artificial intelligence technology to develop an automatic identification method for CICs (AIM-CICs), which performs comprehensive CIC analysis in an automated and efficient way. The AIM-CICs, developed on the algorithm of convolutional neural network, can not only differentiate between CICs and non-CICs (the area under the receiver operating characteristic curve (AUC) > 0.99), but also accurately categorize CICs into five subclasses based on CIC stages and cell number involved (AUC > 0.97 for all subclasses). The application of AIM-CICs would systemically fuel research on CIC-mediated cell death, such as high-throughput screening.展开更多
Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis,with high mortality and no proven therapy.Here,we reported a severe uremic calciphylaxis patient with progr...Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis,with high mortality and no proven therapy.Here,we reported a severe uremic calciphylaxis patient with progressive skin ischemia,large areas of painful malodorous ulcers,and mummified legs.Because of the worsening symptoms and signs refractory to conventional therapies,treatment with human amnion-derived mesenchymal stem cells(hAMSCs)was approved.Preclinical release inspections of hAMSCs,efficacy,and safety assessment,including cytokine secretory ability,immunocompetence,tumorigenicity,and genetics analysis in vitro,were introduced.We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats,abnormal immune response tests in C57BL/6 mice,and tumorigenicity tests in neonatal Balbc-nu nude mice.After the preclinical research,the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers.When followed up to 15 months,the blood-based markers of bone and mineral metabolism improved,with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells.Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis,and 20 months later,the re-epithelialization restored the integrity of the damaged site.No infusion or local treatment-related adverse events occurred.Thus,this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification,stimulating angiogenesis and myogenesis,anti-inflammatory and immune modulation,multidifferentiation,re-epithelialization,and restoration of integrity.展开更多
The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)outbreak be-gan in December 2019,causing the illness known as the novel coronavirus disease 2019(COVID-19).The virus spread rapidly worldwide to become a ...The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)outbreak be-gan in December 2019,causing the illness known as the novel coronavirus disease 2019(COVID-19).The virus spread rapidly worldwide to become a global public health emergency.As of November 15,2020,more than 53 million confirmed cases and over 1 million deaths worldwide have been reported(World Health Organization,2020).展开更多
Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by pro...Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration.However,it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion.Here we show that ezrin is acetylated by p300/CBP-associated factor(PCAF)in breast cancer cells in response to CCL18 stimulation.Ezrin physically interacts with PCAF and is a cognate substrate of PCAF.The acetylation site of ezrin was mapped by mass spectrometric analyses,and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion.Mechanistically,the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation.Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567.Using atomic force microscopic measurements,our study revealed that acetylation of ezrin induced its unfolding into a dominant structure,which prevents ezrin phosphorylation at Thr567.Thus,these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion.This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.展开更多
It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 su...It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain,we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs.Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone,the major regions for postnatal NSC activities.Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages.Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis.These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.展开更多
Hsp90 is an abundant and special molecular chaperone considered to be the regulator of many transcription factors and signaling kinases. Its high abundance is indicative of its involvement in some more fundamental pro...Hsp90 is an abundant and special molecular chaperone considered to be the regulator of many transcription factors and signaling kinases. Its high abundance is indicative of its involvement in some more fundamental processes. In this study, we provide evidence that Hsp90 is required for microtubule stabilization, Golgi organization, and vesicular trafficking. We showed that Hsp90 is bound to microtubule-associated protein 4 (MAP4), which is essential for maintaining microtubule acetylation and stabilization. Hsp90 depletion led to the decrease in MAP4, causing microtubule deacetylation and destabilization. Furthermore, in Hsp90-depleted cells, the Golgi apparatus was fragmented and anterograde vesicle trafficking was impaired, with phenotypes similar to those induced by silencing MAP4. These disruptive effects of Hsp90 depletion could be rescued by the expression of exogenous MAP4 or the treatment of trichostatin A that increases microtubule acetylation as well as stability. Thus, microtubule stability is an essential cellular event regulated by Hsp90.展开更多
It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative spl...It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.展开更多
The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which ...The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.展开更多
Infertility is a problem faced by millions worldwide.In a recent paper published in Cell,Hayashi et al.(2011)provided a potential solution for male infertility through the generation of functional spermatozoa that can...Infertility is a problem faced by millions worldwide.In a recent paper published in Cell,Hayashi et al.(2011)provided a potential solution for male infertility through the generation of functional spermatozoa that can give rise to healthy offspring from embryonic stem cells and induced pluripotent stem cells.展开更多
Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical applica...Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.展开更多
Dear Editor,The hallmarks of cancer comprise several distinct biological characteristics acquired during the multistep development of human tumors with the unique feature of genomic instability(Shen,2011).These cancer...Dear Editor,The hallmarks of cancer comprise several distinct biological characteristics acquired during the multistep development of human tumors with the unique feature of genomic instability(Shen,2011).These cancer characteristics include sustaining proliferative signaling,evading growth suppressors,resisting cell death,enabling replicative immortality,inducing angiogenesis,and activating invasion and metastasis(Chen et al.,2011;Song et al.,2018).Triple-negative breast cancer(TNBC),an aggressive disease with increased risks for visceral metastases,has a poor prognosis due to unavailable and viable therapeutic targets(Bianchini et al.,2016).A TNBC diagnosis indicates that cancer cells test negative for three key receptors:estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2(Bianchini et al.,2016).The absence of these three receptors renders existing hormone and targeted therapies ineffective.展开更多
Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;...Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;Zhao and Li, 2017;Cheng and Leung, 2018). Rapid accumulation of such high-dimensional biological data is driving the system-level study from describing complex phenomena to understanding molecular mechanisms (Park et al., 2018;Sun et al., 2018) and from analyzi ng in dividual components to understanding their networks and systems (Chen et al., 2009;Chen, 2017).展开更多
Mesoangioblasts(MABs)are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration.Molecular circuits that regulate the myogenic commitment of MABs are still poorl...Mesoangioblasts(MABs)are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration.Molecular circuits that regulate the myogenic commitment of MABs are still poorly characterized.The critical role of bone morphogenetic protein(BMP)signalling during proliferation and differentiation of adult myogenic precursors,such as satellite cells,has recently been established.Weevaluated whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in vivo.Addition of BMP inhibited MAB myogenic differentiation,whereas interference with the interactions between BMPs and receptor complexes induced differentiation.Similarly,siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin(DM)also improved myogenic differentiation,demonstrating a novel role of SMAD8.Moreover,using a transgenic mouse model of Smad8 deletion,we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation.Furthermore,once injected into a-Sarcoglycan(Sgca)-null muscles,DM-treated MABs were more efficacious to restore a-sarcoglycan(aSG)protein levels and re-establish functional muscle properties.Similarly,in acute muscle damage,DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated cells.Finally,SMADs also control the myogenic commitment of human MABs(hMABs).BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.展开更多
Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction...Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.展开更多
基金supported by the National Natural Science Foundation of China(31971332 to Y.F.,91942301 and 81430099 to A.X,and 32000450 to L.C.).
文摘In eukaryotic cells,both alternative splicing and alternative polyadenylation(APA)play essential roles in the gene regulation network.U1 small ribonucleoprotein particle(U1 snRNP)is a major component of spliceosome,and U1 snRNP complex can suppress proximal APA sites through crosstalking with 3end processing factors.However,here we show that both knockdown and overexpression of SNRPA,SNRPC,SNRNP70,and SNRPD2,the U1 snRNP proteins,promote the usage of proximal APA sites at the transcriptome level.SNRNP70 can drive the phase transition of PABPN1 from droplet to aggregate,which may reduce the repressive effects of PABPN1 on the proximal APA sites.Additionally,SNRNP70 can also promote the proximal APA sites by recruiting CPSF6,suggesting that the function of CPSF6 on APA is related with other RNA-binding proteins and cell context-dependent.Consequently,these results reveal that,on the contrary to U1 snRNP complex,the free proteins of U1 snRNP complex can promote proximal APA sites through the interaction with 3end processing machinery.
文摘In the originally published version of this article(p.822),there was an error in the second affiliation of author Chengming Zhang.The erroneous affiliation was given as‘University of the Chinese Academy of Sciences’.This has now been corrected to‘University of Chinese Academy of Sciences’.
基金The work was supported by the National Key Research and Development Program of China(2017YFA0103602 and 2018YFA0800803)the National Natural Science Foundation of Chino(81520108012 and 91749201).
文摘Dear Editor,Abl1,when fused with BCR,expresses fusion protein BCR‒ABL that underlies the etiology of chronic myeloid leukemia and is therapeutically targeted by Imatinib Mesylate(Khatri et al.,2016).However,the function of proto-oncogene product Abl1 remains not fully understood.This non-receptor tyrosine kinase can be activated by growth factors,DNA damage,oxidative stress,and microbial pathogens(Wang,2014).Cell-based studies suggest that Abl1 phosphorylates proteins in DNA damage response(DDR)and other signaling pathways,promoting p53 expression as well as cell cycle arrest and apoptosis(Gonfloni et al.,2009).Abl1 deletion leads to runtedness,osteoporosis,and other developmental defects in mice.Interestingly,it has been reported that Abl1 kinase is activated in many solid tumors and Abl1 is implicated in EphB2-mediated intestinal adenoma growth and colorectal cancer(CRC)invasion and metastasis(Kundu et al.,2015;Sonoshita et al.,2015).However,a recent study showed that Abl1 expression is reduced in most CRC patient samples(Uhlen et al.,2015).Thus,the function of Abl1 in CRC initiation warrants further investigation.
基金the Natural Science Foundation of China(81472603 and 81672879).
文摘Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR–IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.
基金This workwas supported by Beijing Municipal Natural Science Foundation(KZ202110025029 to H.H.)the National Key R&D Program of China(2022YFC3600100 to Q.S.and H.H.)+2 种基金the National Natural Science Foundation of China(32100608 to C.W.,82002918 and 31970685 to Q.S.)Beijing Municipal Administration of Hospitals Incubating Program(PX2021033 to H.H.)Beijing Postdoctoral Research Foundation(2021-ZZ-027 to M.T.).
文摘Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis rely strictly on the identification of cell-in-cell structures (CICs), a unique morphological readout that can only be quantified manually at present. Moreover, the manual CIC quantification is generally over-simplified as CIC counts, which represents a major hurdle against profound mechanistic investigations. In this study, we take advantage of artificial intelligence technology to develop an automatic identification method for CICs (AIM-CICs), which performs comprehensive CIC analysis in an automated and efficient way. The AIM-CICs, developed on the algorithm of convolutional neural network, can not only differentiate between CICs and non-CICs (the area under the receiver operating characteristic curve (AUC) > 0.99), but also accurately categorize CICs into five subclasses based on CIC stages and cell number involved (AUC > 0.97 for all subclasses). The application of AIM-CICs would systemically fuel research on CIC-mediated cell death, such as high-throughput screening.
基金funded by the National Natural Science Foundation of China(81270408,81570666,81730041,and 81671447)the International Society of Nephrology(ISN)Clinical Research Program(18-01-0247)+7 种基金Construction Program of Jiangsu Provincial Clinical Research Center Support System(BL2014084)Jiangsu Province Key Medical Personnel Project(ZDRCA2016002)CKD Anemia Research Foundation from China International Medical Foundation(Z-2017-24-2037)Outstanding Young and Middle-Aged Talents Support Program of The First Affiliated Hospital of Nanjing Medical University(Jiangsu Province Hospital)the National Key Research and Development Program of China(2017YFC1001303)the Program of Jiangsu Province Clinical Medical Center(YXZXB2016001,BL2012009)the State Key Laboratory of Reproductive Medicine Program(SKLRM-GC201803)the Program of Jiangsu Commission of Health(H201605).
文摘Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis,with high mortality and no proven therapy.Here,we reported a severe uremic calciphylaxis patient with progressive skin ischemia,large areas of painful malodorous ulcers,and mummified legs.Because of the worsening symptoms and signs refractory to conventional therapies,treatment with human amnion-derived mesenchymal stem cells(hAMSCs)was approved.Preclinical release inspections of hAMSCs,efficacy,and safety assessment,including cytokine secretory ability,immunocompetence,tumorigenicity,and genetics analysis in vitro,were introduced.We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats,abnormal immune response tests in C57BL/6 mice,and tumorigenicity tests in neonatal Balbc-nu nude mice.After the preclinical research,the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers.When followed up to 15 months,the blood-based markers of bone and mineral metabolism improved,with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells.Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis,and 20 months later,the re-epithelialization restored the integrity of the damaged site.No infusion or local treatment-related adverse events occurred.Thus,this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification,stimulating angiogenesis and myogenesis,anti-inflammatory and immune modulation,multidifferentiation,re-epithelialization,and restoration of integrity.
基金H.Y.was supported by the Program for Professors of Special Appointment(Eastern Scholar)at the Shanghai Institutions of Higher Learning(SSF151005)This work was supported by the National Natural Science Foundation of China(82073166 to H.Y.)+2 种基金the National Key Research and Development Program of China(2020YFA0804200)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)the Zhangjiang Lab.
文摘The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)outbreak be-gan in December 2019,causing the illness known as the novel coronavirus disease 2019(COVID-19).The virus spread rapidly worldwide to become a global public health emergency.As of November 15,2020,more than 53 million confirmed cases and over 1 million deaths worldwide have been reported(World Health Organization,2020).
基金This work was supported in part by grants from the National Natural Science Foundation of China(81630080,31430054,91854203,31301105,31320103904,31621002,31671405,91853115,21922706,81572283,31271518,31471275,and 31870759)National Key Research and Development Program of China(2017YFA0503600 and 2016YFA0100500)+2 种基金Ministry of Education(IRT_17R102 and 20113402130010)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB19000000)Central University Grants WK2340000066.
文摘Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration.However,it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion.Here we show that ezrin is acetylated by p300/CBP-associated factor(PCAF)in breast cancer cells in response to CCL18 stimulation.Ezrin physically interacts with PCAF and is a cognate substrate of PCAF.The acetylation site of ezrin was mapped by mass spectrometric analyses,and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion.Mechanistically,the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation.Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567.Using atomic force microscopic measurements,our study revealed that acetylation of ezrin induced its unfolding into a dominant structure,which prevents ezrin phosphorylation at Thr567.Thus,these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion.This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.
文摘It remains unknown whether H3K4 methylation,an epigenetic modification associated with gene activation,regulates fate determination of the postnatal neural stem and progenitor cells(NSPCs).By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain,we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs.Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone,the major regions for postnatal NSC activities.Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages.Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis.These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.
基金This work was supported by the National Natural Science Foundation of China(31571387).
文摘Hsp90 is an abundant and special molecular chaperone considered to be the regulator of many transcription factors and signaling kinases. Its high abundance is indicative of its involvement in some more fundamental processes. In this study, we provide evidence that Hsp90 is required for microtubule stabilization, Golgi organization, and vesicular trafficking. We showed that Hsp90 is bound to microtubule-associated protein 4 (MAP4), which is essential for maintaining microtubule acetylation and stabilization. Hsp90 depletion led to the decrease in MAP4, causing microtubule deacetylation and destabilization. Furthermore, in Hsp90-depleted cells, the Golgi apparatus was fragmented and anterograde vesicle trafficking was impaired, with phenotypes similar to those induced by silencing MAP4. These disruptive effects of Hsp90 depletion could be rescued by the expression of exogenous MAP4 or the treatment of trichostatin A that increases microtubule acetylation as well as stability. Thus, microtubule stability is an essential cellular event regulated by Hsp90.
基金This work was supported by the Royal Victoria Infirmary Breast Cancer Appeal(Reference number BH136312).
文摘It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.
基金This work was supported by the Agence Nationale de la Recherche(ANR-12-JSV1-0005)the Association Franc¸aise contre les Myopathies(14577,15882,and 16143)+4 种基金the CNM Project(www.labradorcnm.com)the Alliance program(22866ZM)the Myotubular Trust and Grants-in-Aid for Scientific Research(B)to A.K.from Japan Society for the Promotion of Science(23370057)J.B.was supported by the French Ministry of Research and Technologies and the Universite´Paris 6(Paris)V.G.,A.P.,and A.R.were supported by the ANR,N.B-G.and I.B.were supported by the AFM,and G.W.was supported by the BBSRC CASE and the Myotubular Trust.
文摘The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.
文摘Infertility is a problem faced by millions worldwide.In a recent paper published in Cell,Hayashi et al.(2011)provided a potential solution for male infertility through the generation of functional spermatozoa that can give rise to healthy offspring from embryonic stem cells and induced pluripotent stem cells.
基金funded by Deutsche Forschungsgemeinschaft(DFG,GermanResearch Foundation)under Germany's Excellence Strategy EXC2151390873048 of which E.B.,G.H.,and M.S.are memberssupported by other grants of DFG,including Project-ID 369799452 TRR237 to E.B.,G.H.,and M.S.,Project-ID 397484323 TRR259 to G.H.,GRK 2168 to E.B.and M.S.,and DFG SCHL1930/1-2+1 种基金funded by the Deutsche Krebshilfe through a Mildred Scheel Nachwuchszentrum(70113307)the recipient of a PhD scholarship from Bayer Pharma AG(40860128).
文摘Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.
基金supported by grants from the Ministry of Science and Technology of China(MOST,2017YFA0503600)the National Natural Science Foundation of China(NSFC,81630080,31621002,32090040,21922706,91854203,and 91853115)+1 种基金China Postdoctoral Science Foundation grant(2019M662181)the US National Institutes of Health(NIH,DK56292,DK115812,S21MD000101,and CA164133).
文摘Dear Editor,The hallmarks of cancer comprise several distinct biological characteristics acquired during the multistep development of human tumors with the unique feature of genomic instability(Shen,2011).These cancer characteristics include sustaining proliferative signaling,evading growth suppressors,resisting cell death,enabling replicative immortality,inducing angiogenesis,and activating invasion and metastasis(Chen et al.,2011;Song et al.,2018).Triple-negative breast cancer(TNBC),an aggressive disease with increased risks for visceral metastases,has a poor prognosis due to unavailable and viable therapeutic targets(Bianchini et al.,2016).A TNBC diagnosis indicates that cancer cells test negative for three key receptors:estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2(Bianchini et al.,2016).The absence of these three receptors renders existing hormone and targeted therapies ineffective.
文摘Recent trend on biological data at a molecular level is omics data analysis for both bulk and single cells, in eluding genomics, proteomics, metabolomics, and epigenetics data (Wang and Zhang, 2017;Zhang et al., 2017;Zhao and Li, 2017;Cheng and Leung, 2018). Rapid accumulation of such high-dimensional biological data is driving the system-level study from describing complex phenomena to understanding molecular mechanisms (Park et al., 2018;Sun et al., 2018) and from analyzi ng in dividual components to understanding their networks and systems (Chen et al., 2009;Chen, 2017).
基金This work was supported by grants from the Ministry of Science and Technology （2016YFA0101300）, the National Natural Science Foundation of China （81530042, 31210103905, 31371510, 31571529, 31571519, 31471250, and 31571390）, the Science and Technology Commission of Shanghai Municipality （15JC1403201）, and the Fundamental Research Funds for the Central Universities （2000219136 and 1500219106）.
基金supported by EU-FP7 CARE-MI,FWO(#G060612N,#G0A8813N,#G088715N),Opening the Future Campaign EJJ-OPTFUT-02010,and Rondoufonds voor Duchenne Onderzoek.D.C.has been supported by University of Turin.M.Q.is supported by FWO(Postdoctoral Fellowship#1263314N and Travel Grant#V448715N)and AFM(Trampoline Grant#18373).The D.H.lab is supported by a start-up grant of Erasmus MC.We also acknowledge infrastructural funding by the InfraMouse Grant from the Hercules Foundation(ZW09-03,to D.H.and A.Z.)and FWO-V G.0542.13(to A.Z.and D.H.).M.S.,D.H.,and A.Z.are supported by KU Leuven Research Council funding(OT-09/053 and GOA-11/012),the Belgian Agency for Science Policy(Belspo)network IUAPVII-07 DevRepair.
文摘Mesoangioblasts(MABs)are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration.Molecular circuits that regulate the myogenic commitment of MABs are still poorly characterized.The critical role of bone morphogenetic protein(BMP)signalling during proliferation and differentiation of adult myogenic precursors,such as satellite cells,has recently been established.Weevaluated whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in vivo.Addition of BMP inhibited MAB myogenic differentiation,whereas interference with the interactions between BMPs and receptor complexes induced differentiation.Similarly,siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin(DM)also improved myogenic differentiation,demonstrating a novel role of SMAD8.Moreover,using a transgenic mouse model of Smad8 deletion,we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation.Furthermore,once injected into a-Sarcoglycan(Sgca)-null muscles,DM-treated MABs were more efficacious to restore a-sarcoglycan(aSG)protein levels and re-establish functional muscle properties.Similarly,in acute muscle damage,DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated cells.Finally,SMADs also control the myogenic commitment of human MABs(hMABs).BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.
基金This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro to S.C.(AIRC IG5732,AIRC IG12075)S.Ci.was supported by a fellowship from Fondazione Umberto Veronesi(FUV).
文摘Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
