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1.
Cell ; 146(6): 918-30, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21925315

RESUMO

Inhibitors of DNA binding (IDs) antagonize basic-helix-loop-helix (bHLH) transcription factors to inhibit differentiation and maintain stem cell fate. ID ubiquitination and proteasomal degradation occur in differentiated tissues, but IDs in many neoplasms appear to escape degradation. We show that the deubiquitinating enzyme USP1 promotes ID protein stability and stem cell-like characteristics in osteosarcoma. USP1 bound, deubiquitinated, and thereby stabilized ID1, ID2, and ID3. A subset of primary human osteosarcomas coordinately overexpressed USP1 and ID proteins. USP1 knockdown in osteosarcoma cells precipitated ID protein destabilization, cell-cycle arrest, and osteogenic differentiation. Conversely, ectopic USP1 expression in mesenchymal stem cells stabilized ID proteins, inhibited osteoblastic differentiation, and enhanced proliferation. Consistent with USP1 functioning in normal mesenchymal stem cells, USP1-deficient mice were osteopenic. Our observations implicate USP1 in preservation of the stem cell state that characterizes osteosarcoma and identify USP1 as a target for differentiation therapy.


Assuntos
Endopeptidases/metabolismo , Proteínas Inibidoras de Diferenciação/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Neoplásicas/citologia , Osteossarcoma/patologia , Animais , Proteínas de Arabidopsis , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteases Específicas de Ubiquitina , Ubiquitinação
2.
J Virol ; 86(18): 10093-102, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22787211

RESUMO

Intrinsic immunity is a first-line intracellular defense against virus infection, and viruses have evolved mechanisms to counteract it. During herpes simplex virus (HSV) infection, nuclear domain 10 (ND10) components localize adjacent to incoming viral genomes and generate a repressive environment for viral gene expression. Here, we found that the ND10 component, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) protein, is predicted to be a target of HSV-1 miR-H1 and HSV-2 miR-H6. These microRNAs (miRNAs) share a seed sequence and are abundant during lytic infection. Mimics of both miRNAs could deplete endogenous ATRX, and an miR-H1 mimic could repress the expression of a reporter linked to the 3' untranslated region of ATRX mRNA, identifying a cellular mRNA targeted by an HSV miRNA. Interestingly, ATRX protein and its mRNA were depleted in cells lytically infected with HSV, and ATRX protein was also depleted in cells infected with human cytomegalovirus. However, infection with an HSV-1 mutant lacking miR-H1 still resulted in ATRX depletion. This depletion was sensitive to a proteasome inhibitor and was largely ablated by a deletion of the gene encoding the immediate-early ICP0 protein. Additionally, a deletion of the gene encoding the tegument protein Vhs ablated most of the depletion of ATRX mRNA. Thus, HSV is equipped with multiple mechanisms to limit the expression of ATRX. As ATRX is implicated in repression of lytic viral gene expression, our results suggest roles for these different mechanisms during various phases of HSV infection.


Assuntos
DNA Helicases/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Simplexvirus/imunologia , Simplexvirus/patogenicidade , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Chlorocebus aethiops , DNA Helicases/genética , DNA Helicases/imunologia , Síndrome de Down , Células HEK293 , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 2/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteínas Imediatamente Precoces/metabolismo , MicroRNAs/genética , MicroRNAs/imunologia , MicroRNAs/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/imunologia , RNA Viral/fisiologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Proteínas Repressoras/fisiologia , Simplexvirus/genética , Simplexvirus/fisiologia , Transfecção , Ubiquitina-Proteína Ligases/metabolismo , Células Vero , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/fisiologia , Proteína Nuclear Ligada ao X
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