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1.
Nat Immunol ; 19(12): 1427-1440, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374131

RESUMO

Multipotent progenitor cells confirm their T cell-lineage identity in the CD4-CD8- double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.


Assuntos
Linfopoese/imunologia , Células Precursoras de Linfócitos T/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Proteínas Repressoras/imunologia , Proteínas Supressoras de Tumor/imunologia , Animais , Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Proteína 2 Inibidora de Diferenciação/biossíntese , Proteína 2 Inibidora de Diferenciação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Precursoras de Linfócitos T/citologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia
2.
Cell ; 152(5): 1106-18, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23452856

RESUMO

In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21(-/-) mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3(-/-) mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock.


Assuntos
Relógios Circadianos , Criptocromos/metabolismo , Proteínas F-Box/metabolismo , Sequência de Aminoácidos , Animais , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Proteínas F-Box/genética , Fibroblastos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Complexos Multiproteicos , Alinhamento de Sequência , Ubiquitinação
3.
EMBO J ; 42(12): e112869, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37092320

RESUMO

Translation initiates when the eIF4F complex binds the 5' mRNA cap, followed by 5' untranslated region scanning for the start codon by scanning ribosomes. Here, we demonstrate that the ASC-1 complex (ASCC), which was previously shown to promote the dissociation of colliding 80S ribosomes, associates with scanning ribosomes to regulate translation initiation. Selective translation complex profiling (TCP-seq) analysis revealed that ASCC3, a helicase domain-containing subunit of ASCC, localizes predominantly to the 5' untranslated region of mRNAs. Ribo-seq, TCP-seq, and luciferase reporter analyses showed that ASCC3 knockdown impairs 43S preinitiation complex loading and scanning dynamics, thereby reducing translation efficiency. Whereas eIF4A, an RNA helicase in the eIF4F complex, is important for global translation, ASCC was found to regulate the scanning process for a specific subset of transcripts. Our results have thus revealed that ASCC is required not only for dissociation of colliding 80S ribosomes but also for efficient translation initiation by scanning ribosomes at a subset of transcripts.


Assuntos
Fator de Iniciação 4F em Eucariotos , Ribossomos , Fator de Iniciação 4F em Eucariotos/genética , Fator de Iniciação 4F em Eucariotos/metabolismo , Regiões 5' não Traduzidas , Ribossomos/genética , Ribossomos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Códon de Iniciação , Biossíntese de Proteínas , Iniciação Traducional da Cadeia Peptídica
4.
Immunity ; 48(6): 1119-1134.e7, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29924977

RESUMO

Transcription factors normally regulate gene expression through their action at sites where they bind to DNA. However, the balance of activating and repressive functions that a transcription factor can mediate is not completely understood. Here, we showed that the transcription factor PU.1 regulated gene expression in early T cell development both by recruiting partner transcription factors to its own binding sites and by depleting them from the binding sites that they preferred when PU.1 was absent. The removal of partner factors Satb1 and Runx1 occurred primarily from sites where PU.1 itself did not bind. Genes linked to sites of partner factor "theft" were enriched for genes that PU.1 represses despite lack of binding, both in a model cell line system and in normal T cell development. Thus, system-level competitive recruitment dynamics permit PU.1 to affect gene expression both through its own target sites and through action at a distance.


Assuntos
Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Linfopoese/fisiologia , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T/imunologia , Transativadores/imunologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/imunologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Linfopoese/imunologia , Proteínas de Ligação à Região de Interação com a Matriz/imunologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
5.
Cell ; 149(5): 1098-111, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22632973

RESUMO

Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Transformação Celular Neoplásica , Proteínas F-Box/metabolismo , Glicólise , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Neoplasias da Mama/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Receptor ErbB-2/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Trastuzumab , Ubiquitinação
6.
Development ; 150(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36633189

RESUMO

Adult neurogenesis is supported by multipotent neural stem cells (NSCs) with unique properties and growth requirements. Adult NSCs constitute a reversibly quiescent cell population that can be activated by extracellular signals from the microenvironment in which they reside in vivo. Although genomic imprinting plays a role in adult neurogenesis through dose regulation of some relevant signals, the roles of many imprinted genes in the process remain elusive. Insulin-like growth factor 2 (IGF2) is encoded by an imprinted gene that contributes to NSC maintenance in the adult subventricular zone through a biallelic expression in only the vascular compartment. We show here that IGF2 additionally promotes terminal differentiation of NSCs into astrocytes, neurons and oligodendrocytes by inducing the expression of the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), encoding the cell cycle inhibitor p57. Using intraventricular infusion of recombinant IGF2 in a conditional mutant strain with Cdkn1c-deficient NSCs, we confirm that p57 partially mediates the differentiation effects of IGF2 in NSCs and that this occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis and oligodendrogenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57 , Impressão Genômica , Fator de Crescimento Insulin-Like II , Células-Tronco Neurais , Neurogênese , Neurônios , Inibidor de Quinase Dependente de Ciclina p57/genética , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurogênese/genética , Fator de Crescimento Insulin-Like II/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL
7.
Mol Psychiatry ; 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38438524

RESUMO

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.

8.
Mol Cell ; 68(4): 645-658.e5, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29149593

RESUMO

Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS.


Assuntos
Proteína 7 com Repetições F-Box-WD , Síndrome de Hajdu-Cheney , Mutação , Osteoporose , Proteólise , Receptor Notch2 , Animais , Linhagem Celular , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Síndrome de Hajdu-Cheney/genética , Síndrome de Hajdu-Cheney/metabolismo , Camundongos Knockout , Osteoporose/genética , Osteoporose/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Ubiquitinação/genética
9.
Cancer Sci ; 115(5): 1370-1377, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38413370

RESUMO

Cancer stem cells (CSCs) are a long-lived and self-renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5+ CSCs as well as quiescent Lgr5+ CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC.


Assuntos
Ciclo Celular , Plasticidade Celular , Neoplasias Colorretais , Células-Tronco Neoplásicas , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos , Diferenciação Celular , Receptores Acoplados a Proteínas G/metabolismo
10.
PLoS Genet ; 17(8): e1009686, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34351912

RESUMO

Although long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins by definition, some lncRNAs actually contain small open reading frames that are translated. TINCR (terminal differentiation-induced ncRNA) has been recognized as a lncRNA that contributes to keratinocyte differentiation. However, we here show that TINCR encodes a ubiquitin-like protein that is well conserved among species and whose expression was confirmed by the generation of mice harboring a FLAG epitope tag sequence in the endogenous open reading frame as well as by targeted proteomics. Forced expression of this protein promoted cell cycle progression in normal human epidermal keratinocytes, and mice lacking this protein manifested a delay in skin wound healing associated with attenuated cell cycle progression in keratinocytes. We termed this protein TINCR-encoded ubiquitin-like protein (TUBL), and our results reveal a role for TINCR in the regulation of keratinocyte proliferation and skin regeneration that is dependent on TUBL.


Assuntos
Queratinócitos/citologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Ciclo Celular , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Queratinócitos/metabolismo , Camundongos , Fases de Leitura Aberta , Proteômica , Ubiquitinas/genética , Ubiquitinas/metabolismo , Cicatrização
11.
Br J Cancer ; 128(12): 2206-2217, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37076565

RESUMO

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Proteômica , Aminoácidos de Cadeia Ramificada , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/genética , Transaminases
12.
Genes Cells ; 27(1): 61-71, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34897913

RESUMO

The CHD (chromodomain helicase DNA binding protein) family consists of nine chromatin remodeling factors that alter chromatin structure in an ATP-dependent manner. CHD4 contributes to the regulation of various cellular activities and processes including development through interaction with multiple proteins including formation of the NuRD (nucleosome remodeling and deacetylase activity) complex. Functions of CHD4 that appear not to be mediated by the NuRD complex or other known interactors have also been identified, however, suggesting the existence of unrecognized proteins that also associate with CHD4. We here generated HeLa-S3 and HEK293T cells with a knock-in allele for FLAG epitope-tagged CHD4 and used these cells to identify proteins that bind to CHD4 with the use of immunoprecipitation followed by liquid chromatography and tandem mass spectrometry. LCORL (ligand-dependent nuclear receptor corepressor like) and NOL4L (nucleolar protein 4 like) were reproducibly identified as novel CHD4 interactors. Furthermore, RNA-sequencing analysis of HEK293T cells depleted of CHD4, LCORL, or NOL4L revealed consistent up-regulation of genes related to the Notch signaling pathway. Our results thus suggest that both LCORL and NOL4L may cooperate with CHD4 to suppress the Notch pathway in mammalian cells.


Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Nucleossomos , Animais , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Proteínas
13.
Nature ; 541(7636): 228-232, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28024296

RESUMO

Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide 'small regulatory polypeptide of amino acid response' (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.


Assuntos
Complexos Multiproteicos/metabolismo , Músculos/fisiologia , Peptídeos/metabolismo , RNA Longo não Codificante/genética , Regeneração/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Adenosina Trifosfatases/metabolismo , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Sistemas CRISPR-Cas/genética , Endossomos/metabolismo , Edição de Genes , Células HEK293 , Humanos , Lisossomos/enzimologia , Lisossomos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/agonistas , Músculos/lesões , Especificidade de Órgãos , Peptídeos/deficiência , Peptídeos/genética , Transdução de Sinais/efeitos dos fármacos
14.
Nucleic Acids Res ; 49(13): 7298-7317, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34226921

RESUMO

Although ribosome-profiling and translation initiation sequencing (TI-seq) analyses have identified many noncanonical initiation codons, the precise detection of translation initiation sites (TISs) remains a challenge, mainly because of experimental artifacts of such analyses. Here, we describe a new method, TISCA (TIS detection by translation Complex Analysis), for the accurate identification of TISs. TISCA proved to be more reliable for TIS detection compared with existing tools, and it identified a substantial number of near-cognate codons in Kozak-like sequence contexts. Analysis of proteomics data revealed the presence of methionine at the NH2-terminus of most proteins derived from near-cognate initiation codons. Although eukaryotic initiation factor 2 (eIF2), eIF2A and eIF2D have previously been shown to contribute to translation initiation at near-cognate codons, we found that most noncanonical initiation events are most probably dependent on eIF2, consistent with the initial amino acid being methionine. Comprehensive identification of TISs by TISCA should facilitate characterization of the mechanism of noncanonical initiation.


Assuntos
Códon de Iniciação , Fator de Iniciação 2 em Eucariotos/metabolismo , Iniciação Traducional da Cadeia Peptídica , Biologia Computacional/métodos , Fator de Iniciação 3 em Eucariotos/metabolismo , Células HEK293 , Humanos , Fases de Leitura Aberta , Pegadas de Proteínas , Proteômica , Análise de Sequência de RNA
15.
Hum Mol Genet ; 29(8): 1274-1291, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32142125

RESUMO

Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Neurogênese/genética , Fatores de Transcrição/genética , Animais , Transtorno do Espectro Autista/patologia , Montagem e Desmontagem da Cromatina/genética , Modelos Animais de Doenças , Haploinsuficiência/genética , Heterozigoto , Humanos , Camundongos , Mutação/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fenótipo
18.
Nature ; 537(7622): 675-679, 2016 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-27602517

RESUMO

Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD, with CHD8, a gene encoding a chromatin remodeller, being most frequently affected. Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Proteínas de Ligação a DNA/genética , Haploinsuficiência/genética , Animais , Ansiedade/complicações , Ansiedade/genética , Transtorno do Espectro Autista/complicações , Encéfalo/metabolismo , Proteínas de Ligação a DNA/deficiência , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Regulação para Baixo , Predisposição Genética para Doença , Heterozigoto , Masculino , Megalencefalia/complicações , Megalencefalia/genética , Camundongos , Camundongos Knockout , Mutação , Penetrância , Fenótipo , Proteínas Repressoras/metabolismo , Comportamento Social , Transcriptoma
19.
Bioessays ; 42(12): e2000169, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33165972

RESUMO

Carbon and nitrogen are essential elements for life. Glucose as a carbon source and glutamine as a nitrogen source are important nutrients for cell proliferation. About 100 years ago, it was discovered that cancer cells that have acquired unlimited proliferative capacity and undergone malignant evolution in their host manifest a cancer-specific remodeling of glucose metabolism (the Warburg effect). Only recently, however, was it shown that the metabolism of glutamine-derived nitrogen is substantially shifted from glutaminolysis to nucleotide biosynthesis during malignant progression of cancer-which might be referred to as a "second" Warburg effect. In this review, address the mechanism and relevance of this metabolic shift of glutamine-derived nitrogen in human cancer. We also examine the clinical potential of anticancer therapies that modulate the metabolic pathways of glutamine-derived nitrogen. This shift may be as important as the shift in carbon metabolism, which has long been known as the Warburg effect.


Assuntos
Glutamina , Neoplasias , Glutamina/metabolismo , Humanos , Redes e Vias Metabólicas , Nitrogênio , Nucleotídeos
20.
Semin Cancer Biol ; 67(Pt 2): 1-15, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32113998

RESUMO

FBXW7 (also known as Fbw7, Sel10, hCDC4, or hAgo) is a tumor suppressor and the most frequently mutated member of the F-box protein family in human cancers. FBXW7 functions as the substrate recognition component of an SCF-type E3 ubiquitin ligase. It specifically controls the proteasome-mediated degradation of many oncoproteins such as c-MYC, NOTCH, KLF5, cyclin E, c-JUN, and MCL1. In this review, we summarize the molecular and biological features of FBXW7 and its substrates as well as the impact of mutations of FBXW7 on cancer development. We also address the clinical potential of anticancer therapy targeting FBXW7.


Assuntos
Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Genes Supressores de Tumor , Mutação , Neoplasias/genética , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/patologia
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