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1.
Oncogene ; 36(1): 97-109, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27270431

RESUMO

As a transcription factor, localization to the nucleus and the recruitment of cofactors to regulate gene transcription is essential. Nuclear localization and nucleosome remodeling and histone deacetylase (NuRD) complex binding are required for the zinc-finger transcription factor CASZ1 to function as a neuroblastoma (NB) tumor suppressor. However, the critical amino acids (AAs) that are required for CASZ1 interaction with NuRD complex and the regulation of CASZ1 subcellular localization have not been characterized. Through alanine scanning, immunofluorescence cell staining and co-immunoprecipitation, we define a critical region at the CASZ1 N terminus (AAs 23-40) that mediates the CASZ1b nuclear localization and NuRD interaction. Furthermore, we identified a nuclear export signal (NES) at the N terminus (AAs 176-192) that contributes to CASZ1 nuclear-cytoplasmic shuttling in a chromosomal maintenance 1-dependent manner. An analysis of CASZ1 protein expression in a primary NB tissue microarray shows that high nuclear CASZ1 staining is detected in tumor samples from NB patients with good prognosis. In contrast, cytoplasmic-restricted CASZ1 staining or low nuclear CASZ1 staining is found in tumor samples from patients with poor prognosis. These findings provide insight into mechanisms by which CASZ1 regulates transcription, and suggests that regulation of CASZ1 subcellular localization may impact its function in normal development and pathologic conditions such as NB tumorigenesis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neuroblastoma/metabolismo , Sinais de Exportação Nuclear , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Espaço Intracelular/metabolismo , Mutação , Neuroblastoma/genética , Ligação Proteica , Transporte Proteico , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Transcrição Gênica , Transcriptoma , Proteínas Supressoras de Tumor/química
2.
J Pediatric Infect Dis Soc ; 4(1): e1-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26407369

RESUMO

Human adenovirus (HAdV) is one of the most feared infections among immunocompromised patients. In particular, in liver transplant patients, HAdV has been implicated in acute liver failure with resultant mortality. The development of current molecular techniques and surveillance testing protocols have provided tools for early detection of HAdV infection, prior to or at the early onset of HAdV disease. Although reduction in immune suppression is the mainstay of therapy, many researchers have also advocated for early administration of antiviral therapy. In multiple reports, cidofovir treatment has been associated with declines in HAdV viral loads or clinical improvement in solid organ and bone marrow transplant recipients. However, there have also been case reports that raise questions about the effectiveness of antiviral therapy in controlling systemic HAdV disease. We report a case of a 26-month-old male recipient of a liver transplantation for hepatoblastoma who developed adenoviremia with an associated hepatitis and gastroenteritis. He recovered with reduced immune suppression but without antiviral therapy, thus avoiding potential toxicities associated with cidofovir therapy. This case a contrast to previous reports, and it highlights the ambiguity regarding which patients should receive HAdV-specific antiviral therapy. Additional knowledge regarding specific pediatric host factors and HAdV factors that predict poor outcomes are needed. Such information would allow clinicians to better stratify patients by risk at the time of adenoviremia detection so that low-risk patients are not unnecessarily exposed to medications with potential toxicities.


Assuntos
Infecções por Adenovirus Humanos/terapia , Adenovírus Humanos/fisiologia , Imunossupressores/administração & dosagem , Transplante de Fígado , Linfopenia/terapia , Neutropenia/terapia , Viremia/terapia , Infecções por Adenovirus Humanos/complicações , Infecções por Adenovirus Humanos/metabolismo , Infecções por Adenovirus Humanos/virologia , Pré-Escolar , Hepatoblastoma/complicações , Hepatoblastoma/metabolismo , Hepatoblastoma/cirurgia , Humanos , Hospedeiro Imunocomprometido , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Linfopenia/etiologia , Linfopenia/metabolismo , Masculino , Neutropenia/etiologia , Neutropenia/metabolismo , Carga Viral , Viremia/complicações , Viremia/metabolismo
3.
Oncogene ; 16(16): 2115-22, 1998 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-9572492

RESUMO

p53 is a transcriptional activator that plays a key role in the integration of signals inducing cell division arrest and programmed cell death. Moreover, p53 is a tumor suppressor gene, mutations of which are the most commonly detected mutations in diverse malignancies. In order to better understand the significance of p53 mutations to human cancer, we isolated mutant alleles of p53 that had lost transcription factor activity in yeast. These mutant alleles were evaluated for their precise changes, their activity against three different p53 responsive enhancers and their ability to act in a transdominant fashion to the wild type allele. While many of the mutations isolated in yeast resembled those found in human tumors, consistent with the importance of transcription factor activity for p53 in mammalian cells, the mutational spectrum obtained was dependent upon the p53 enhancer employed for the selection. Some mutations specifically inactivated p53 in yeast for a single enhancer element. Virtually all missense mutations tested had a dominant inhibitory effect on wild type p53 in yeast. Since some of these transdominant mutations are virtually unknown in human tumors we conclude that transdominance, per se, fails to predict which mutations occur frequently in cancer.


Assuntos
Mutagênese , Proteínas Nucleares , Fatores de Transcrição/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/genética , Alelos , Creatina Quinase/genética , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/genética , Elementos Facilitadores Genéticos , Humanos , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-mdm2 , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Leveduras/metabolismo
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