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1.
Nat Rev Cancer ; 18(12): 744-757, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30425336

RESUMO

Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.

2.
Am J Hum Genet ; 102(4): 557-573, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576218

RESUMO

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

3.
Nat Commun ; 8(1): 290, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28819139

RESUMO

The mitochondrial proteome comprises ~1000 (yeast)-1500 (human) different proteins, which are distributed into four different subcompartments. The sublocalization of these proteins within the organelle in most cases remains poorly defined. Here we describe an integrated approach combining stable isotope labeling, various protein enrichment and extraction strategies and quantitative mass spectrometry to produce a quantitative map of submitochondrial protein distribution in S. cerevisiae. This quantitative landscape enables a proteome-wide classification of 986 proteins into soluble, peripheral, and integral mitochondrial membrane proteins, and the assignment of 818 proteins into the four subcompartments: outer membrane, inner membrane, intermembrane space, or matrix. We also identified 206 proteins that were not previously annotated as localized to mitochondria. Furthermore, the protease Prd1, misannotated as intermembrane space protein, could be re-assigned and characterized as a presequence peptide degrading enzyme in the matrix.Protein localization plays an important role in the regulation of cellular physiology. Here the authors use an integrated proteomics approach to localize proteins to the mitochondria and provide a detailed map of their specific localization within the organelle.


Assuntos
Proteínas Mitocondriais/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Proteínas de Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Humanos , Immunoblotting , Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Espectrometria de Massas em Tandem
4.
Mol Biol Cell ; 28(8): 997-1002, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28228553

RESUMO

Approximately 70% of mitochondrial precursor proteins are imported from the cytosol via N-terminal presequences, which are cleaved upon exposure to the mitochondrial processing protease MPP in the matrix. Cleaved presequence peptides then need to be efficiently degraded, and impairment of this clearance step, for example, by amyloid ß peptides, causes feedback inhibition of MPP, leading ultimately to accumulation of immature precursor proteins within mitochondria. Degradation of mitochondrial peptides is performed by Cym1 in yeast and its homologue, PreP, in humans. Here we identify the novel mitochondrial matrix protease Ste23 in yeast, a homologue of human insulin-degrading enzyme, which is required for efficient peptide degradation. Ste23 and Cym1 tightly cooperate to ensure the correct functioning of the essential presequence processing machinery.


Assuntos
Metaloendopeptidases/metabolismo , Mitocôndrias/metabolismo , Produtos Finais de Degradação Proteica/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Humanos , Metaloproteases/metabolismo , Mitocôndrias/enzimologia , Peptídeos/metabolismo , Precursores de Proteínas/metabolismo , Proteólise , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo
5.
Nat Commun ; 7: 10498, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26876920

RESUMO

Early dissemination, metastasis and therapy resistance are central hallmarks of aggressive cancer types and the leading cause of cancer-associated deaths. The EMT-inducing transcriptional repressor ZEB1 is a crucial stimulator of these processes, particularly by coupling the activation of cellular motility with stemness and survival properties. ZEB1 expression is associated with aggressive behaviour in many tumour types, but the potent effects cannot be solely explained by its proven function as a transcriptional repressor of epithelial genes. Here we describe a direct interaction of ZEB1 with the Hippo pathway effector YAP, but notably not with its paralogue TAZ. In consequence, ZEB1 switches its function to a transcriptional co-activator of a 'common ZEB1/YAP target gene set', thereby linking two pathways with similar cancer promoting effects. This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in breast cancer, indicating the clinical relevance of our findings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Fosfoproteínas/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Imunofluorescência , Células HCT116 , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Imunoprecipitação , Técnicas In Vitro , Células MCF-7 , Fosfoproteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo , Ativação Transcricional/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco
6.
Cell Metab ; 20(4): 662-9, 2014 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-25176146

RESUMO

Most mitochondrial proteins possess N-terminal presequences that are required for targeting and import into the organelle. Upon import, presequences are cleaved off by matrix processing peptidases and subsequently degraded by the peptidasome Cym1/PreP, which also degrades Amyloid-beta peptides (Aß). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, Aß inhibits degradation of presequence peptides by PreP, resulting in accumulation of mitochondrial preproteins and processing intermediates. Dysfunctional preprotein maturation leads to rapid protein degradation and an imbalanced organellar proteome. Our findings reveal a general mechanism by which Aß peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Metaloproteases/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Serina Endopeptidases/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Humanos , Metaloproteases/antagonistas & inibidores , Metaloproteases/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/genética , Superóxido Dismutase/metabolismo
7.
Biochim Biophys Acta ; 1819(9-10): 1098-106, 2012 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22172993

RESUMO

Mitochondrial proteins are synthesized as precursor proteins on either cytosolic or mitochondrial ribosomes. The synthesized precursors from both translation origins possess targeting signals that guide the protein to its final destination in one of the four subcompartments of the organelle. The majority of nuclear-encoded mitochondrial precursors and also mitochondrial-encoded preproteins have an N-terminal presequence that serves as a targeting sequence. Specific presequence peptidases that are found in the matrix, inner membrane and intermembrane space of mitochondria proteolytically remove the signal sequence upon import or sorting. Besides the classical presequence peptidases MPP, IMP and Oct1, several novel proteases have recently been described to possess precursor processing activity, and analysis of their functional relevance revealed a tight connection between precursor processing, mitochondrial dynamics and protein quality control. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.


Assuntos
Mitocôndrias , Proteínas Mitocondriais/genética , Peptídeo Hidrolases , Processamento de Proteína Pós-Traducional , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/biossíntese , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Biossíntese de Proteínas , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional/genética , Sinais Direcionadores de Proteínas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
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