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1.
PLoS Pathog ; 10(7): e1004238, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25079227

RESUMO

Lyme disease spirochetes demonstrate strain- and species-specific differences in tissue tropism. For example, the three major Lyme disease spirochete species, Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii, are each most commonly associated with overlapping but distinct spectra of clinical manifestations. Borrelia burgdorferi sensu stricto, the most common Lyme spirochete in the U.S., is closely associated with arthritis. The attachment of microbial pathogens to cells or to the extracellular matrix of target tissues may promote colonization and disease, and the Lyme disease spirochete encodes several surface proteins, including the decorin- and dermatan sulfate-binding adhesin DbpA, which vary among strains and have been postulated to contribute to strain-specific differences in tissue tropism. DbpA variants differ in their ability to bind to its host ligands and to cultured mammalian cells. To directly test whether variation in dbpA influences tissue tropism, we analyzed murine infection by isogenic B. burgdorferi strains that encode different dbpA alleles. Compared to dbpA alleles of B. afzelii strain VS461 or B. burgdorferi strain N40-D10/E9, dbpA of B. garinii strain PBr conferred the greatest decorin- and dermatan sulfate-binding activity, promoted the greatest colonization at the inoculation site and heart, and caused the most severe carditis. The dbpA of strain N40-D10/E9 conferred the weakest decorin- and GAG-binding activity, but the most robust joint colonization and was the only dbpA allele capable of conferring significant joint disease. Thus, dbpA mediates colonization and disease by the Lyme disease spirochete in an allele-dependent manner and may contribute to the etiology of distinct clinical manifestations associated with different Lyme disease strains. This study provides important support for the long-postulated model that strain-specific variations of Borrelia surface proteins influence tissue tropism.


Assuntos
Artrite Infecciosa/imunologia , Proteínas de Bactérias/metabolismo , Borrelia burgdorferi/classificação , Decorina/metabolismo , Dermatan Sulfato/metabolismo , Doença de Lyme/imunologia , Miocardite/imunologia , Animais , Artrite Infecciosa/metabolismo , Artrite Infecciosa/microbiologia , Proteínas de Bactérias/genética , Borrelia burgdorferi/imunologia , Dicroísmo Circular , Feminino , Citometria de Fluxo , Humanos , Doença de Lyme/metabolismo , Doença de Lyme/microbiologia , Camundongos , Camundongos Endogâmicos C3H , Mutação/genética , Miocardite/metabolismo , Miocardite/microbiologia , Ligação Proteica , Proteínas Recombinantes/metabolismo , Especificidade da Espécie , Ressonância de Plasmônio de Superfície , Tropismo
2.
Cancer Cell ; 35(1): 46-63.e10, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30581152

RESUMO

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner. This p62-RBP interaction distinguishes melanoma from other tumors where p62 controls autophagy or oxidative stress. The relevance of these data is emphasized by follow-up analyses of patient prognosis revealing p62 and FERMT2 as adverse determinants of disease-free survival.


Assuntos
Melanoma/metabolismo , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/química , Proteínas de Ligação a RNA/metabolismo , Proteína Sequestossoma-1/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Proteínas de Membrana/química , Camundongos , Proteínas de Neoplasias/química , Transplante de Neoplasias , Mapas de Interação de Proteínas , Proteômica/métodos , Estabilidade de RNA , Análise Serial de Tecidos
3.
Nat Commun ; 7: 13418, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857118

RESUMO

Nuclear 3'-end-polyadenylation is essential for the transport, stability and translation of virtually all eukaryotic mRNAs. Poly(A) tail extension can also occur in the cytoplasm, but the transcripts involved are incompletely understood, particularly in cancer. Here we identify a lineage-specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma. CPEB4 is upregulated early in melanoma progression, as defined by computational and histological analyses. Melanoma cells are distinct from other tumour cell types in their dependency on CPEB4, not only to prevent mitotic aberrations, but to progress through G1/S cell cycle checkpoints. RNA immunoprecipitation, sequencing of bound transcripts and poly(A) length tests link the melanoma-specific functions of CPEB4 to signalling hubs specifically enriched in this disease. Essential in these CPEB4-controlled networks are the melanoma drivers MITF and RAB7A, a feature validated in clinical biopsies. These results provide new mechanistic links between cytoplasmic polyadenylation and lineage specification in melanoma.


Assuntos
Melanoma/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Melanoma/genética , Camundongos , Neoplasias Experimentais , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética
4.
Oncotarget ; 6(14): 11848-62, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-26008978

RESUMO

Derailed endolysosomal trafficking is emerging as a widespread feature of aggressive neoplasms. However, the oncogenic signals that alter membrane homeostasis and their specific contribution to cancer progression remain unclear. Understanding the upstream drivers and downstream regulators of aberrant vesicular trafficking is distinctly important in melanoma. This disease is notorious for its inter- and intra-tumoral heterogeneity. Nevertheless, melanomas uniformly overexpress a cluster of endolysosomal genes, being particularly addicted to the membrane traffic regulator RAB7. Still, the underlying mechanisms and temporal determinants of this dependency have yet to be defined. Here we addressed these questions by combining electron microscopy, real time imaging and mechanistic analyses of vesicular trafficking in normal and malignant human melanocytic cells. This strategy revealed Class I PI3K as the key trigger of a hyperactive influx of macropinosomes that melanoma cells counteract via RAB7-mediated lysosomal degradation. In addition, gain- and loss-of-function in vitro studies followed by histopathological validation in clinical biopsies and genetically-engineered mouse models, traced back the requirement of RAB7 to the suppression of premature cellular senescence traits elicited in melanocytes by PI3K-inducing oncogenes. Together, these results provide new insight into the regulators and modes of action of RAB7, broadening the impact of endosomal fitness on melanoma development.


Assuntos
Melanoma/metabolismo , Melanoma/patologia , Pinocitose/fisiologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Linhagem Celular Tumoral , Imunofluorescência , Xenoenxertos , Humanos , Immunoblotting , Camundongos , Microscopia Eletrônica de Transmissão , Fosfatidilinositol 3-Quinases/metabolismo , Transfecção , proteínas de unión al GTP Rab7
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