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1.
Development ; 150(20)2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37260407

RESUMO

Diet contributes to health at all stages of life, from embryonic development to old age. Nutrients, including vitamins, amino acids, lipids and sugars, have instructive roles in directing cell fate and function, maintaining stem cell populations, tissue homeostasis and alleviating the consequences of aging. This Review highlights recent findings that illuminate how common diets and specific nutrients impact cell fate decisions in healthy and disease contexts. We also draw attention to new models, technologies and resources that help to address outstanding questions in this emerging field and may lead to dietary approaches that promote healthy development and improve disease treatments.


Assuntos
Dieta , Nutrientes , Feminino , Gravidez , Humanos , Vitaminas , Diferenciação Celular , Envelhecimento/fisiologia
2.
Biochim Biophys Acta ; 1849(5): 469-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-24933113

RESUMO

The Myc oncoprotein is a key contributor to the development of many human cancers. As such, understanding its molecular activities and biological functions has been a field of active research since its discovery more than three decades ago. Genome-wide studies have revealed Myc to be a global regulator of gene expression. The identification of its DNA-binding partner protein, Max, launched an area of extensive research into both the protein-protein interactions and protein structure of Myc. In this review, we highlight key insights with respect to Myc interactors and protein structure that contribute to the understanding of Myc's roles in transcriptional regulation and cancer. Structural analyses of Myc show many critical regions with transient structures that mediate protein interactions and biological functions. Interactors, such as Max, TRRAP, and PTEF-b, provide mechanistic insight into Myc's transcriptional activities, while others, such as ubiquitin ligases, regulate the Myc protein itself. It is appreciated that Myc possesses a large interactome, yet the functional relevance of many interactors remains unknown. Here, we discuss future research trends that embrace advances in genome-wide and proteome-wide approaches to systematically elucidate mechanisms of Myc action. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.


Assuntos
Neoplasias/genética , Mapas de Interação de Proteínas/genética , Proteoma , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação da Expressão Gênica , Genoma Humano , Humanos , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/metabolismo
3.
bioRxiv ; 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38746230

RESUMO

Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.

4.
Ann N Y Acad Sci ; 1506(1): 55-73, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34414571

RESUMO

There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, "Metabolic Decisions in Development and Disease." The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism.


Assuntos
Congressos como Assunto/tendências , Desenvolvimento Humano/fisiologia , Doenças Metabólicas/fisiopatologia , Redes e Vias Metabólicas/fisiologia , Neoplasias/fisiopatologia , Relatório de Pesquisa , Animais , Epigênese Genética/fisiologia , Humanos , Doenças Metabólicas/genética , Neoplasias/genética , Transdução de Sinais/fisiologia
5.
Nat Commun ; 9(1): 3502, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158517

RESUMO

The c-MYC (MYC) oncoprotein is deregulated in over 50% of cancers, yet regulatory mechanisms controlling MYC remain unclear. To this end, we interrogated the MYC interactome using BioID mass spectrometry (MS) and identified PP1 (protein phosphatase 1) and its regulatory subunit PNUTS (protein phosphatase-1 nuclear-targeting subunit) as MYC interactors. We demonstrate that endogenous MYC and PNUTS interact across multiple cell types and that they co-occupy MYC target gene promoters. Inhibiting PP1 by RNAi or pharmacological inhibition results in MYC hyperphosphorylation at multiple serine and threonine residues, leading to a decrease in MYC protein levels due to proteasomal degradation through the canonical SCFFBXW7 pathway. MYC hyperphosphorylation can be rescued specifically with exogenous PP1, but not other phosphatases. Hyperphosphorylated MYC retained interaction with its transcriptional partner MAX, but binding to chromatin is significantly compromised. Our work demonstrates that PP1/PNUTS stabilizes chromatin-bound MYC in proliferating cells.


Assuntos
Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Eletroforese em Gel Bidimensional , Humanos , Immunoblotting , Imunoprecipitação , Espectrometria de Massas , Proteínas Nucleares/genética , Proteína Fosfatase 1/genética , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a RNA/genética
6.
Cancer Cell ; 34(4): 579-595.e8, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30300580

RESUMO

MYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.


Assuntos
Carcinogênese/genética , Expressão Gênica/genética , Histona Metiltransferases/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Epigênese Genética/genética , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Camundongos , Regiões Promotoras Genéticas/genética
7.
Genes (Basel) ; 8(6)2017 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-28587062

RESUMO

MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer.

8.
Genome Biol ; 17: 82, 2016 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-27139377

RESUMO

A cell's epigenome arises from interactions among regulatory factors-transcription factors and histone modifications-co-localized at particular genomic regions. We developed a novel statistical method, ChromNet, to infer a network of these interactions, the chromatin network, by inferring conditional-dependence relationships among a large number of ChIP-seq data sets. We applied ChromNet to all available 1451 ChIP-seq data sets from the ENCODE Project, and showed that ChromNet revealed previously known physical interactions better than alternative approaches. We experimentally validated one of the previously unreported interactions, MYC-HCFC1. An interactive visualization tool is available at http://chromnet.cs.washington.edu.


Assuntos
Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina/métodos , Cromatina/genética , Redes Reguladoras de Genes , Software , Cromatina/química , Cromatina/metabolismo , Histonas/metabolismo , Humanos , Fatores de Transcrição/metabolismo
9.
Cell Cycle ; 15(13): 1693-705, 2016 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-27267444

RESUMO

MYC is a key driver of cellular transformation and is deregulated in most human cancers. Studies of MYC and its interactors have provided mechanistic insight into its role as a regulator of gene transcription. MYC has been previously linked to chromatin regulation through its interaction with INI1 (SMARCB1/hSNF5/BAF47), a core member of the SWI/SNF chromatin remodeling complex. INI1 is a potent tumor suppressor that is inactivated in several types of cancers, most prominently as the hallmark alteration in pediatric malignant rhabdoid tumors. However, the molecular and functional interaction of MYC and INI1 remains unclear. Here, we characterize the MYC-INI1 interaction in mammalian cells, mapping their minimal binding domains to functionally significant regions of MYC (leucine zipper) and INI1 (repeat motifs), and demonstrating that the interaction does not interfere with MYC-MAX interaction. Protein-protein interaction network analysis expands the MYC-INI1 interaction to the SWI/SNF complex and a larger network of chromatin regulatory complexes. Genome-wide analysis reveals that the DNA-binding regions and target genes of INI1 significantly overlap with those of MYC. In an INI1-deficient rhabdoid tumor system, we observe that with re-expression of INI1, MYC and INI1 bind to common target genes and have opposing effects on gene expression. Functionally, INI1 re-expression suppresses cell proliferation and MYC-potentiated transformation. Our findings thus establish the antagonistic roles of the INI1 and MYC transcriptional regulators in mediating cellular and oncogenic functions.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína SMARCB1/metabolismo , Transcrição Gênica , Motivos de Aminoácidos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Montagem e Desmontagem da Cromatina , Sequência Conservada , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Zíper de Leucina , Ligação Proteica , Multimerização Proteica , Sequências Repetitivas de Aminoácidos , Proteína SMARCB1/química
10.
J Proteomics ; 118: 95-111, 2015 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-25452129

RESUMO

The BioID proximity-based biotin labeling technique was recently developed for the characterization of protein-protein interaction networks [1]. To date, this method has been applied to a number of different polypeptides expressed in cultured cells. Here we report the adaptation of BioID to the identification of protein-protein interactions surrounding the c-MYC oncoprotein in human cells grown both under standard culture conditions and in mice as tumor xenografts. Notably, in vivo BioID yielded >100 high confidence MYC interacting proteins, including >30 known binding partners. Putative novel MYC interactors include components of the STAGA/KAT5 and SWI/SNF chromatin remodeling complexes, DNA repair and replication factors, general transcription and elongation factors, and transcriptional co-regulators such as the DNA helicase protein chromodomain 8 (CHD8). Providing additional confidence in these findings, ENCODE ChIP-seq datasets highlight significant coincident binding throughout the genome for the MYC interactors identified here, and we validate the previously unreported MYC-CHD8 interaction using both a yeast two hybrid analysis and the proximity-based ligation assay. In sum, we demonstrate that BioID can be utilized to identify bona fide interacting partners for a chromatin-associated protein in vivo. This technique will allow for a much improved understanding of protein-protein interactions in a previously inaccessible biological setting. BIOLOGICAL SIGNIFICANCE: The c-MYC (MYC) oncogene is a transcription factor that plays important roles in cancer initiation and progression. MYC expression is deregulated in more than 50% of human cancers, but the role of this protein in normal cell biology and tumor progression is still not well understood, in part because identifying MYC-interacting proteins has been technically challenging: MYC-containing chromatin-associated complexes are difficult to isolate using traditional affinity purification methods, and the MYC protein is exceptionally labile, with a half-life of only ~30 min. Developing a new strategy to gain insight into MYC-containing protein complexes would thus mark a key advance in cancer research. The recently described BioID proximity-based labeling technique represents a promising new complementary approach for the characterization of protein-protein interactions (PPIs) in cultured cells. Here we report that BioID can also be used to characterize protein-protein interactions for a chromatin-associated protein in tumor xenografts, and present a comprehensive, high confidence in vivo MYC interactome. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Acetiltransferases/metabolismo , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Xenoenxertos , Histona Acetiltransferases/genética , Humanos , Lisina Acetiltransferase 5 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Neoplasias Experimentais/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição/genética
11.
Methods Mol Biol ; 1012: 51-64, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24006057

RESUMO

In this chapter, we discuss in detail two essential methods used to evaluate the interaction of Myc with another protein of interest: co-immunoprecipitation (Co-IP) and in vitro pull-down assays. Co-IP is a method that, by immunoaffinity, allows the identification of protein-protein interactions within cells. We provide methods to conduct Co-IPs from whole-cell extracts as well as cytoplasmic and nuclear-enriched fractions. By contrast, the pull-down assay evaluates whether a bait protein that is bound to a solid support can specifically interact with a prey protein that is in solution. We provide methods to conduct in vitro pull-downs and further detail how to use this assay to distinguish whether a protein-protein interaction is direct or indirect. We also discuss methods used to screen for Myc interactors and provide an in silico strategy to help prioritize hits for further validation using the described Co-IP and in vitro pull-down assays.


Assuntos
Proteínas de Transporte/metabolismo , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fracionamento Celular/métodos , Imunoprecipitação/métodos , Ligação Proteica , Mapeamento de Interação de Proteínas/métodos
12.
Cancer Res ; 73(21): 6504-15, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24030976

RESUMO

Despite its central role in human cancer, MYC deregulation is insufficient by itself to transform cells. Because inherent mechanisms of neoplastic control prevent precancerous lesions from becoming fully malignant, identifying transforming alleles of MYC that bypass such controls may provide fundamental insights into tumorigenesis. To date, the only activated allele of MYC known is T58A, the study of which led to identification of the tumor suppressor FBXW7 and its regulator USP28 as a novel therapeutic target. In this study, we screened a panel of MYC phosphorylation mutants for their ability to promote anchorage-independent colony growth of human MCF10A mammary epithelial cells, identifying S71A/S81A and T343A/S344A/S347A/S348A as more potent oncogenic mutants compared with wild-type (WT) MYC. The increased cell-transforming activity of these mutants was confirmed in SH-EP neuroblastoma cells and in three-dimensional MCF10A acini. Mechanistic investigations initiated by a genome-wide mRNA expression analysis of MCF10A acini identified 158 genes regulated by the mutant MYC alleles, compared with only 112 genes regulated by both WT and mutant alleles. Transcriptional gain-of-function was a common feature of the mutant alleles, with many additional genes uniquely dysregulated by individual mutant. Our work identifies novel sites of negative regulation in MYC and thus new sites for its therapeutic attack.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Glândulas Mamárias Humanas/patologia , Mutação/genética , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Western Blotting , Adesão Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Células Cultivadas , Imunoprecipitação da Cromatina , Ensaio de Unidades Formadoras de Colônias , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Glândulas Mamárias Humanas/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Consumo de Oxigênio , Fosforilação , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Sequências Reguladoras de Ácido Nucleico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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