RESUMO
Activating transcription factor 3 (ATF3) is a basic leucine zipper transcription factor that plays a regulatory role in inflammation, cell division, and apoptosis. Mast cells (MCs) initiate many inflammatory responses and have a central role in allergy and allergic diseases. We report here that ATF3 has a central role in MC development and function. Bone marrow-derived MC populations from ATF3-deficient mice are unresponsive to interleukin-3 (IL-3)-induced maturation signals, and this correlates with increased apoptosis, diminished activation of the Akt kinase, and decreased phosphorylation of the proapoptotic protein Bad. Furthermore, ATF3-null mice lacked MCs in the peritoneum and dermis, showing that the in vitro results are recapitulated in vivo. ATF3-null MCs also showed functional defects; high-affinity immunoglobulin E receptor-mediated degranulation was significantly inhibited, whereas IL-4 and IL-6 expression was enhanced. This dual role of ATF3 provides insight into the complex interplay between MC development and its subsequent physiologic role.
Assuntos
Fator 3 Ativador da Transcrição/imunologia , Apoptose/imunologia , Células da Medula Óssea/imunologia , Mediadores da Inflamação/imunologia , Mastócitos/imunologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Apoptose/genética , Células da Medula Óssea/metabolismo , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-3/biossíntese , Interleucina-3/genética , Interleucina-3/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-6/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Fosforilação/genética , Fosforilação/imunologia , Receptores de IgE/biossíntese , Receptores de IgE/genética , Receptores de IgE/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/imunologia , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
BACKGROUND: A prostate cancer (PCa) biomarker with improved specificity relative to PSA is a public health priority. Hypermethylated DNA can be detected in body fluids from PCa patients and may be a useful biomarker, although clinical performance varies between studies. We investigated the performance of candidate PCa DNA methylation biomarkers identified through a genome-wide search. METHODS: Real-time PCR was used to measure four DNA methylation biomarkers: GSTP1 and three previously unreported candidates associated with the genes RASSF2, HIST1H4K, and TFAP2E in sodium bisulfite-modified DNA. Matched plasma and urine collected prospectively from 142 patients referred for prostate biopsy and 50 young asymptomatic males were analyzed. RESULTS: Analysis of all biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers discriminated PCa from biopsy negative patients with AUCs ranging from 0.64 for HIST1H4K (95% CI 0.55-0.72, P < 0.00001) to 0.69 for GSTP1 (95% CI 0.60-0.77, P < 0.00001). All biomarkers showed minimal correlation with PSA. Multivariate analysis did not yield a panel that significantly improved performance over that of single biomarkers. All biomarkers showed greater sensitivity for PCa in urine than in plasma DNA. CONCLUSIONS: Analysis of the biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers provided information independent of PSA and may warrant inclusion in nomograms for predicting prostate biopsy outcome. The biomarkers' PCa sensitivity was greater for urine than plasma DNA. The biomarker performances in urine DNA should next be validated in formal training and test studies.
