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1.
Appl Immunohistochem Mol Morphol ; 23(4): 266-72, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25839700

RESUMO

High-risk human papillomavirus (HPV) infection is a common cause of oropharyngeal squamous cell carcinoma, especially in young male nonsmokers. Accurately diagnosing HPV-associated oral cancers is important, because they have a better prognosis and may be treated differently than smoking-related oral carcinomas. Various methods have been validated to test for high-risk HPV in cervical tissue samples, and they are in routine clinical use to detect dysplasia before it progresses to invasive disease. Similarly, future screening for HPV-mediated oropharyngeal dysplasia may identify patients before it progresses. Our objective was to compare 4 of these methods in a retrospective series of 87 oral and oropharyngeal squamous cell carcinomas that had archived fresh-frozen and paraffin-embedded tissue for evaluation. Patient age, sex, smoking history, and tumor location were also recorded. DNA prepared from fresh-frozen tissue was tested for HPV genotypes by multiplex polymerase chain reaction analysis, and high-risk HPV screening was carried out using Hybrid Capture 2 and Cervista. Histologic sections were immunostained for p16. HPV-positive outcome was defined as agreement between at least 2 of the 3 genetic tests and used for χ analysis and calculations of diagnostic predictive value. As expected, high-risk HPV-positive oral cancers were most common in the tonsil and base of the tongue (oropharynx) of younger male (55 vs. 65 y) (P=0.0002) nonsmokers (P=0.01). Most positive cases were HPV16 (33/36, 92%). Hybrid Capture 2 and Cervista were as sensitive as polymerase chain reaction and had fewer false positives than p16 immunohistochemical staining.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Papillomavirus Humano 16/genética , Neoplasias Bucais , Neoplasias Otorrinolaringológicas , Infecções por Papillomavirus , Reação em Cadeia da Polimerase/métodos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/genética , Neoplasias Bucais/virologia , Neoplasias Otorrinolaringológicas/diagnóstico , Neoplasias Otorrinolaringológicas/genética , Neoplasias Otorrinolaringológicas/virologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/genética
2.
J Invest Dermatol ; 130(5): 1384-90, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20054338

RESUMO

Psoriasis is an inflammatory skin disorder with aberrant regulation of keratinocytes and immunocytes. Although it is well known that uncontrolled keratinocyte proliferation is largely driven by proinflammatory cytokines from the immunocytes, the functional role of keratinocytes in the regulation of immunocytes is poorly understood. Recently, we found that tripartite motif-containing protein 32 (Trim32), an E3-ubiquitin ligase, is elevated in the epidermal lesions of human psoriasis. We previously showed that Trim32 binds to the protein inhibitor of activated STAT-Y (Piasy) and mediates its degradation through ubiquitination. Interestingly, the Piasy gene is localized in the PSORS6 susceptibility locus on chromosome 19p13, and Piasy negatively regulates the activities of several transcription factors, including NF-kappaB, STAT, and SMADs, that are implicated in the pathogenesis of psoriasis. In this study, we show that Trim32 activates, and Piasy inhibits, keratinocyte production of CC chemokine ligand 20 (CCL20), a psoriatic chemokine essential for recruitment of DCs and T helper (Th)17 cells to the skin. Further, Trim32/Piasy regulation of CCL20 is mediated through Piasy interaction with the RelA/p65 subunit of NF-kappaB. As CCL20 is activated by Th17 cytokines, the upregulation of CCL20 production by Trim32 provides a positive feedback loop of CCL20 and Th17 activation in the self-perpetuating cycle of psoriasis.


Assuntos
Quimiocina CCL20/metabolismo , Queratinócitos/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Psoríase , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Quimiocina CCL20/genética , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Interleucina-17/metabolismo , Queratinócitos/citologia , Queratinócitos/imunologia , Camundongos , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas Inibidoras de STAT Ativados/genética , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Transfecção , Proteínas com Motivo Tripartido , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima/imunologia
3.
Cancer Biol Ther ; 3(11): 1102-8, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15467437

RESUMO

p53 is a unique DNA binding protein with two distinct DNA binding domains, the central domain for sequence-specific DNA binding and the C-terminal basic DNA binding domain (BD domain) for structure-specific DNA binding. In contrast to the apparent inhibitory effect of the BD domain on p53 binding to sequence-specific DNA in vitro, here we demonstrate that the BD domain enhances p53 binding to the endogenous p21(Waf1) promoter and mediates rapid transactivation of p21.(Waf1) This paradox is resolved by the observation that the BD domain is required for rapid binding to non-sequence-specific genomic DNA (NS-DNA) as evident from global chromatin immunoprecipitation analysis of p53 DNA binding in vivo. This finding provides the first in vivo evidence from a eukaryotic system to support binding to NS-DNA as an intermediate step in searching for specific sites as proposed by von Hippel and Berg. Furthermore, we speculate that binding to structure-specific DNA by the BD domain is a mechanism for p53 rapid binding to genomic DNA from its free state to facilitate the search for its target sites in the genome undergoing genotoxic stress.


Assuntos
Proteínas de Ciclo Celular/genética , DNA/metabolismo , Regiões Promotoras Genéticas/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/fisiologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Imunoprecipitação da Cromatina , Inibidor de Quinase Dependente de Ciclina p21 , DNA/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ligação Proteica
4.
Cancer Res ; 62(11): 3264-70, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12036943

RESUMO

Gene amplification accompanies tumor progression and is involved in the development of drug resistance. Previously, we reported (A. Albor et al., Cancer Res. 58: 2091-2094, 1998) that mutant p53 proteins conserve the capacity to interact with and activate topoisomerase I, and that this could be a mechanism for induction of genomic instability by mutant p53 proteins. To test this hypothesis, the effect of exogenous mutant p53 protein expression on genomic instability in human p53-/- Saos-2 cells was measured by the frequency of formation of N-(phosphoacetyl)-L-aspartate (PALA)-resistant (PALA(R)) colonies, mediated by gene amplification. Interaction of exogenous mutant p53 and topoisomerase I was confirmed by immunoprecipitation. Growth under continuous expression of mutant p53 proteins for 16-17 population doublings increased the frequency of appearance of PALA(R) colonies after subsequent exposure to PALA. Subtoxic concentrations of camptothecin (which stabilizes topoisomerase I cleavage complexes, mediating nonhomologous recombination) produced a dose-dependent increase in PALA(R) colonies, and combining expression of mutant p53 with exposure to camptothecin produced a greater than additive increase in PALA(R) colony formation. These results indicate that mutant p53 proteins promote gene amplification independently of their capacity to inactivate the wild-type p53 protein, and suggest that this effect is dependent on interaction of mutant p53 with topoisomerase I. Additional studies are needed to assess the potential of targeting mutant p53 interaction with topoisomerase I for the reduction of drug resistance development during chemotherapy.


Assuntos
Ácido Aspártico/análogos & derivados , Amplificação de Genes , Mutação , Ácido Fosfonoacéticos/análogos & derivados , Proteína Supressora de Tumor p53/genética , Ácido Aspártico/farmacologia , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Camptotecina/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores Enzimáticos/farmacologia , Amplificação de Genes/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Osteossarcoma/enzimologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fenótipo , Ácido Fosfonoacéticos/farmacologia , Estrutura Terciária de Proteína , Inibidores da Topoisomerase I , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/metabolismo
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