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1.
Cell ; 187(3): 764-781.e14, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306985

RESUMO

Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.


Assuntos
Metabolômica , Gravidez , Animais , Feminino , Humanos , Gravidez/metabolismo , Corticosterona/metabolismo , Metaboloma/fisiologia , Placenta/metabolismo , Pré-Eclâmpsia , Primatas/metabolismo
2.
Cell ; 166(2): 451-467, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27419872

RESUMO

Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT.


Assuntos
Mesoderma/citologia , Transdução de Sinais , Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Coração/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Humanos , Mesoderma/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes/metabolismo , Linha Primitiva/citologia , Linha Primitiva/metabolismo , Análise de Célula Única , Somitos/metabolismo , Células-Tronco , Proteínas Supressoras de Tumor/metabolismo , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo
3.
Cell ; 155(4): 778-92, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24209617

RESUMO

Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics. PAPERCLIP:


Assuntos
Proteínas de Ligação a RNA/metabolismo , Cicatrização , Animais , Embrião de Mamíferos/metabolismo , Metabolismo Energético , Extremidades/fisiologia , Folículo Piloso/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , MicroRNAs/metabolismo , Regeneração
4.
Cell ; 148(1-2): 259-72, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22225612

RESUMO

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Transformação Celular Neoplásica , Glicina Desidrogenase (Descarboxilante)/metabolismo , Neoplasias Pulmonares/metabolismo , Sequência de Aminoácidos , Antígenos CD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteínas Fetais/metabolismo , Glicina/metabolismo , Humanos , Dados de Sequência Molecular , Neoplasias/enzimologia , Neoplasias/genética , Proteínas de Ligação a RNA , Alinhamento de Sequência , Serina/metabolismo , Thermus thermophilus/enzimologia , Transplante Heterólogo
5.
Cell ; 147(1): 81-94, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21962509

RESUMO

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.


Assuntos
Glucose/metabolismo , MicroRNAs/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina , Camundongos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Obesidade/genética , Obesidade/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
6.
Genes Dev ; 31(4): 336-346, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28314766

RESUMO

Advances in metabolomics have deepened our understanding of the roles that specific modes of metabolism play in programming stem cell fates. Here, we review recent metabolomic studies of stem cell metabolism that have revealed how metabolic pathways can convey changes in the extrinsic environment or their niche to program stem cell fates. The metabolic programming of stem cells represents a fine balance between the intrinsic needs of a cellular state and the constraints imposed by extrinsic conditions. A more complete understanding of these needs and constraints will afford us greater mastery over our control of stem cell fates.


Assuntos
Diferenciação Celular , Redes e Vias Metabólicas , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Meio Ambiente , Humanos , Metaboloma
7.
Mol Ther ; 31(5): 1418-1436, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37016578

RESUMO

Cancer cachexia is a multifactorial syndrome characterized by a significant loss of skeletal muscle, which negatively affects the quality of life. Inhibition of myostatin (Mstn), a negative regulator of skeletal muscle growth and differentiation, has been proven to preserve muscle mass in muscle atrophy diseases, including cachexia. However, myostatin inhibitors have repeatedly failed clinical trials because of modest therapeutic effects and side effects due to the poor efficiency and toxicity of existing delivery methods. Here, we describe a novel method for delivering Mstn siRNA to skeletal muscles using red blood cell-derived extracellular vesicles (RBCEVs) in a cancer cachectic mouse model. Our data show that RBCEVs are taken up by myofibers via intramuscular administration. Repeated intramuscular administrations with RBCEVs allowed the delivery of siRNAs, thereby inhibiting Mstn, increasing muscle growth, and preventing cachexia in cancer-bearing mice. We observed the same therapeutic effects when delivering siRNAs against malonyl-CoA decarboxylase, an enzyme driving dysfunctional fatty acid metabolism in skeletal muscles during cancer cachexia. We demonstrate that intramuscular siRNA delivery by RBCEVs is safe and non-inflammatory. Hence, this method is useful to reduce the therapeutic dose of siRNAs, to avoid toxicity and off-target effects caused by systemic administration of naked siRNAs at high doses.


Assuntos
Miostatina , Neoplasias , Camundongos , Animais , Miostatina/metabolismo , RNA Interferente Pequeno/metabolismo , Caquexia/etiologia , Caquexia/terapia , Caquexia/metabolismo , Qualidade de Vida , Músculo Esquelético/metabolismo , Neoplasias/complicações , Neoplasias/terapia , Neoplasias/metabolismo , Atrofia Muscular , RNA de Cadeia Dupla
8.
Mol Cell ; 62(1): 34-46, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27058786

RESUMO

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.


Assuntos
Melanoma/metabolismo , Fator B de Elongação Transcricional Positiva/genética , Pirimidinas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/patologia , Melanoma Experimental , Proteínas Oncogênicas/genética , Fatores de Transcrição , Transcrição Gênica , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
9.
Anal Bioanal Chem ; 415(14): 2819-2830, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37083759

RESUMO

We used deep neural networks to process the mass spectrometry imaging (MSI) data of mouse muscle (young vs aged) and human cancer (tumor vs normal adjacent) tissues, with the aim of using explainable artificial intelligence (XAI) methods to rapidly identify biomarkers that can distinguish different classes of tissues, from several thousands of metabolite features. We also modified classic neural network architectures to construct a deep convolutional neural network that is more suitable for processing high-dimensional MSI data directly, instead of using dimension reduction techniques, and compared it to seven other machine learning analysis methods' performance in classification accuracy. After ascertaining the superiority of Channel-ResNet10, we used a novel channel selection-based XAI method to identify the key metabolite features that were responsible for its learning accuracy. These key metabolite biomarkers were then processed using MetaboAnalyst for pathway enrichment mapping. We found that Channel-ResNet10 was superior to seven other machine learning methods for MSI analysis, reaching > 98% accuracy in muscle aging and colorectal cancer datasets. We also used a novel channel selection-based XAI method to find that in young and aged muscle tissues, the differentially distributed metabolite biomarkers were especially enriched in the propanoate metabolism pathway, suggesting it as a novel target pathway for anti-aging therapy.


Assuntos
Inteligência Artificial , Redes Neurais de Computação , Animais , Camundongos , Humanos , Idoso , Aprendizado de Máquina , Diagnóstico por Imagem , Processamento de Imagem Assistida por Computador
10.
Exp Dermatol ; 31(6): 906-917, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35119146

RESUMO

Androgenetic alopecia (AGA) is a prevalent hair loss condition in males that develops due to the influence of androgens and genetic predisposition. With the aim of elucidating genes involved in AGA pathogenesis, we modelled AGA with three-dimensional culture of keratinocyte-surrounded dermal papilla (DP) cells. We co-cultured immortalised balding and non-balding human DP cells (DPCs) derived from male AGA patients with epidermal keratinocyte (NHEK) using multi-interfacial polyelectrolyte complexation technique. We observed up-regulated mitochondria-related gene expression in balding compared with non-balding DP aggregates which indicated altered mitochondria metabolism. Further observation of significantly reduced electron transport chain complex activity (complexes I, IV and V), ATP levels and ability to uptake metabolites for ATP generation demonstrated compromised mitochondria function in balding DPC. Balding DP was also found to be under significantly higher oxidative stress than non-balding DP. Our experiments suggest that application of antioxidants lowers oxidative stress levels and improves metabolite uptake in balding DPC. We postulate that the observed up-regulation of mitochondria-related genes in balding DP aggregates resulted from an over-compensatory effort to rescue decreased mitochondrial function in balding DP through the attempted production of new functional mitochondria. In all, our three-dimensional co-culturing revealed mitochondrial dysfunction in balding DPC, suggesting a metabolic component in the aetiology of AGA.


Assuntos
Alopecia , Androgênios , Trifosfato de Adenosina/metabolismo , Alopecia/patologia , Androgênios/metabolismo , Folículo Piloso/metabolismo , Humanos , Queratinócitos/metabolismo , Masculino , Mitocôndrias/metabolismo
11.
Nature ; 496(7443): 101-5, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23535601

RESUMO

Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.


Assuntos
Glutamina/metabolismo , Redes e Vias Metabólicas , Proteína Oncogênica p21(ras)/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas ras/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Aspartato Aminotransferases/deficiência , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclo do Ácido Cítrico , Glutamato Desidrogenase/metabolismo , Homeostase , Humanos , Ácidos Cetoglutáricos/metabolismo , Proteína Oncogênica p21(ras)/genética , Oncogenes/genética , Oxirredução , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Espécies Reativas de Oxigênio/metabolismo , Proteínas ras/genética
12.
Semin Cell Dev Biol ; 52: 110-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26851627

RESUMO

Mitochondria are the central hubs of cellular metabolism, equipped with their own mitochondrial DNA (mtDNA) blueprints to direct part of the programming of mitochondrial oxidative metabolism and thus reactive oxygen species (ROS) levels. In stem cells, many stem cell factors governing the intricate balance between self-renewal and differentiation have been found to directly regulate mitochondrial processes to control stem cell behaviors during tissue regeneration and aging. Moreover, numerous nutrient-sensitive signaling pathways controlling organismal longevity in an evolutionarily conserved fashion also influence stem cell-mediated tissue homeostasis during aging via regulation of stem cell mitochondria. At the genomic level, it has been demonstrated that heritable mtDNA mutations and variants affect mammalian stem cell homeostasis and influence the risk for human degenerative diseases during aging. Because such a multitude of stem cell factors and signaling pathways ultimately converge on the mitochondria as the primary mechanism to modulate cellular and organismal longevity, it would be most efficacious to develop technologies to therapeutically target and direct mitochondrial repair in stem cells, as a unified strategy to combat aging-related degenerative diseases in the future.


Assuntos
Mitocôndrias/fisiologia , Células-Tronco/fisiologia , Animais , Senescência Celular/genética , Senescência Celular/fisiologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
13.
Stem Cells ; 34(2): 277-87, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26676652

RESUMO

In recent years, the highly conserved promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16, ZNF145) has attracted attention as a multifunctional transcription factor involved in major biological processes during development. As a transcription factor, PLZF shows tight regulation in its cell-type-specific and stage-specific expression patterns. Emerging evidence shows that PLZF regulates the balance of self-renewal and differentiation in stem cells. However, the gene regulatory network of PLZF is only beginning to be understood. In this review, we discuss the diverse functions of PLZF, in particular its role in self-renewal versus differentiation of stem cells. We also discuss the current state of knowledge on the gene regulatory network of PLZF, in conjunction with its upstream factors, post-translational modifications and binding cofactors for multiprotein complexes. This review aims to provide the reader with an in-depth understanding of the molecular mechanisms underlying PLZF and the potential applications in tissue regeneration.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Células-Tronco/metabolismo , Animais , Humanos , Proteína com Dedos de Zinco da Leucemia Promielocítica , Células-Tronco/citologia
14.
Adv Exp Med Biol ; 1026: 233-249, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29282687

RESUMO

Wasting of adipose tissue and skeletal muscle is a hallmark of metastatic cancer and a major cause of death. Like patients with cachexia caused by other chronic infections or inflammatory diseases, the cancer subject manifests both malnutrition and metabolic stress. Both carbohydrate utilization and amino acid incorporation are decreased in the muscles of cancer cachexia patients. Cancer cells affect host metabolism in two ways: (a) their own metabolism of nutrients into other metabolites and (b) circulating factors they secrete or induce the host to secrete. Accelerated glycolysis and lactate production, i.e., the Warburg effect and the resultant increase in Cori cycle activity, are the most widely discussed metabolic effects. Meanwhile, although a large number of pro-cachexia circulating factors have been found, such as TNFa, IL-6, myostatin, and PTHrp, none have been shown to be a dominant factor that can be targeted singly to treat cancer cachexia in humans. It is possible that given the complex multifactorial nature of the cachexia secretome, and the personalized differences between cancer patients, targeting any single circulating factor would always be insufficient to treat cachexia for all patients. Here we review the metabolic changes that occur in response to tumor growth and tumor-secreted factors during cachexia.


Assuntos
Caquexia/fisiopatologia , Metabolismo Energético , Redes e Vias Metabólicas/genética , Neoplasias/fisiopatologia , Caquexia/complicações , Caquexia/metabolismo , Glicólise/genética , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Metabolismo dos Lipídeos/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miostatina/genética , Miostatina/metabolismo , Neoplasias/complicações , Neoplasias/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Genes Dev ; 23(7): 862-76, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19293287

RESUMO

The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 3' untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with gamma-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica , Genes p53/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/metabolismo , Animais , Apoptose/fisiologia , Sequência de Bases , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Embrião não Mamífero/metabolismo , Teste de Complementação Genética , Humanos , Dados de Sequência Molecular , Ligação Proteica , Estresse Fisiológico/fisiologia , Peixe-Zebra
16.
Development ; 140(12): 2535-47, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23715547

RESUMO

Recent advances in metabolomics and computational analysis have deepened our appreciation for the role of specific metabolic pathways in dictating cell fate. Once thought to be a mere consequence of the state of a cell, metabolism is now known to play a pivotal role in dictating whether a cell proliferates, differentiates or remains quiescent. Here, we review recent studies of metabolism in stem cells that have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of adult stem cells, and during the reprogramming of somatic cells to pluripotency. These insights promise to inform strategies for the directed differentiation of stem cells and to offer the potential for novel metabolic or pharmacological therapies to enhance regeneration and the treatment of degenerative disease.


Assuntos
Blastocisto/metabolismo , Senescência Celular , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Blastocisto/citologia , Diferenciação Celular , Proliferação de Células , Desenvolvimento Embrionário , Epigênese Genética , Glicólise , Humanos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Células-Tronco Pluripotentes/citologia
18.
Stem Cells ; 31(8): 1563-73, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23666760

RESUMO

LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of Lin28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of Lin28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal Lin28b acts at least in part via mTORC1 signaling.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Glucose/metabolismo , Proteínas de Ligação a RNA/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Nanismo/genética , Nanismo/metabolismo , Feminino , Feto/metabolismo , Expressão Gênica , Glucose/genética , Crescimento e Desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores Sexuais , Transdução de Sinais
19.
PLoS Genet ; 7(9): e1002242, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21935352

RESUMO

MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA-target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Regiões 3' não Traduzidas , Células 3T3 , Animais , Linhagem Celular , Proliferação de Células , Células HEK293 , Humanos , Camundongos , MicroRNAs/genética , Microinjeções , Peixe-Zebra
20.
Artigo em Inglês | MEDLINE | ID: mdl-39122601

RESUMO

Pregnancy is associated with physiological adaptations that affect virtually all organs, enabling the mother to support the growing fetus and placenta while withstanding the demands of pregnancy. As a result, mammalian pregnancy is a unique state that exerts paradoxical effects on maternal health. On one hand, the metabolic stress induced by pregnancy can accelerate aging and functional decline in organs. On the other hand, pregnancy activates metabolic programming and tissue regenerative responses that can reverse age-related impairments. In this sense, the oocyte-to-blastocyst transition is not the only physiological reprogramming event in the mammalian body, as pregnancy-induced regeneration could constitute a second physiological reprogramming event. Here, we review findings on how pregnancy dualistically leads to aging and rejuvenation in the maternal body.

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