RESUMO
The STAT6 (signal transducer and activator of transcription 6) protein facilitates T-helper cell 2 (Th2) mediated responses that control IgE-mediated atopic diseases such as asthma. We have identified compounds that bind to STAT6 and inhibit STAT6 tyrosine phosphorylation induced by IL-4. In the bronchial epithelial cell line BEAS-2B, compound (R)-84 inhibits the secretion of eotaxin-3, a chemokine eliciting eosinophil infiltration. (R)-84 appears to prevent STAT6 from assuming the active dimer configuration by directly binding the protein and inhibiting tyrosine phosphorylation.
Assuntos
Quimiocinas CC/metabolismo , Células Epiteliais/metabolismo , Indóis/química , Piridinas/química , Fator de Transcrição STAT6/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL26 , Dimerização , Humanos , Indóis/síntese química , Indóis/farmacologia , Interleucina-4/farmacologia , Fosforilação , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Interleucina-4/metabolismo , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacos , EstereoisomerismoRESUMO
When purified from persistent infections, the genomes of most human polyomaviruses contain single enhancers. However, when isolated from productively infected cells from immunocompromised individuals, the genomes of several polyomaviruses contain duplicated enhancers that promote a number of polyoma-based diseases. The mechanism(s) that gives rise to the duplicated enhancers in the polyomaviruses is, however, not known. Herein we propose a model for the duplication of the enhancers that is based on recent advances in our understanding of; 1) the initiation of polyomavirus DNA replication, 2) the formation of long flaps via displacement synthesis and 3) the subsequent generation of duplicated enhancers via double stranded break repair. Finally, we discuss the possibility that the polyomavirus based replication dependent enhancer duplication model may be relevant to the enhancer-associated rearrangements detected in human genomes that are associated with various diseases, including cancers.
Assuntos
Reparo do DNA/genética , DNA Viral/biossíntese , Polyomavirus/genética , Replicação Viral/genética , Animais , DNA/genética , Quebras de DNA de Cadeia Dupla , Elementos de DNA Transponíveis , Elementos Facilitadores Genéticos , Humanos , Modelos Genéticos , Infecções por Polyomavirus/virologiaRESUMO
The present treatment of childhood T-cell leukemias involves the systemic administration of prokaryotic L-asparaginase (ASNase), which depletes plasma Asparagine (Asn) and inhibits protein synthesis. The mechanism of therapeutic action of ASNase is poorly understood, as are the etiologies of the side-effects incurred by treatment. Protein expression from genes bearing Asn homopolymeric coding regions (N-hCR) may be particularly susceptible to Asn level fluctuation. In mammals, N-hCR are rare, short and conserved. In humans, misfunctions of genes encoding N-hCR are associated with a cluster of disorders that mimic ASNase therapy side-effects which include impaired glycemic control, dislipidemia, pancreatitis, compromised vascular integrity, and neurological dysfunction. This paper proposes that dysregulation of Asn homeostasis, potentially even by ASNase produced by the microbiome, may contribute to several clinically important syndromes by altering expression of N-hCR bearing genes. By altering amino acid abundance and modulating ribosome translocation rates at codon repeats, the microbiomic environment may contribute to genome decoding and to shaping the proteome. We suggest that impaired translation at poly Asn codons elevates diabetes risk and severity.