RESUMO
The Myc basic helix-loop-helix zipper domain determines dimerization with Max and binding to the DNA E-box, both of which play a critical role in Myc regulation of growth, proliferation, tumorigenesis, and apoptosis. The mutant basic helix-loop-helix zipper domain, Omomyc, dimerizes with Myc, sequestering it in complexes unable to bind the E-box, and so acting as a potential dominant negative. Consistent with this, Omomyc reverses Myc-induced cytoskeletal disorganization in C2C12 myoblasts. Surprisingly, however, Omomyc strongly potentiates Myc-induced apoptosis in a manner dependent on Myc expression level. Expression analysis of known Myc target genes indicates that Omomyc inhibits transcriptional activation but enhances repression. These findings suggest that Omomyc can selectively trigger apoptosis in cells overexpressing Myc, possibly through the transcriptional repression of specific genes.
Assuntos
Apoptose/fisiologia , Zíper de Leucina/fisiologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fatores de Transcrição de Zíper de Leucina Básica , Linhagem Celular , Citoesqueleto/fisiologia , Proteínas de Ligação a DNA/metabolismo , Elementos E-Box/fisiologia , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologiaRESUMO
Neurotrophins support neuronal survival, development, and plasticity through processes requiring gene expression. We studied how vgf target gene transcription is mediated by a critical promoter region containing E-box, CCAAT and cAMP response element (CRE) sites. The p300 acetylase was present in two distinct protein complexes bound to this region. One complex, containing HEB (ubiquitous basic helix-loop-helix (bHLH)), bound the promoter in non-neuronal cells and was involved in repressing vgf expression. Neurotrophin-dependent transcription was mediated by the second complex, specific for neuronal cells, which included CRE binding protein and MASH1 (neuro-specific bHLH), bound the CCAAT motif, and was target of neurotrophin signalling. The interaction, mediated by p300, of different transcription factors may add specificity to the neurotrophin response.