Regulation of Transcription Factor SP1 by the ß-Catenin Destruction Complex Modulates Wnt Response.
Mol Cell Biol
; 38(22)2018 11 15.
Article
em En
| MEDLINE
| ID: mdl-30181396
ABSTRACT
The ubiquitous transcription factor specificity protein 1 (SP1) is heavily modified posttranslationally. These modifications are critical for switching its functions and modulation of its transcriptional activity and DNA binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidence that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In the absence of Wnt signaling, glycogen synthase kinase 3ß (GSK3ß)-mediated phosphorylation and ß-TrCP E3 ubiquitin ligase-mediated ubiquitination are required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in a ß-catenin-dependent manner. SP1 directly interacts with ß-catenin, and Wnt signaling induces the stabilization of SP1 by impeding its interaction with ß-TrCP and axin1, components of the destruction complex. Wnt signaling suppresses ubiquitination and subsequent proteosomal degradation of SP1. Furthermore, SP1 regulates Wnt-dependent stability of ß-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization, SP1 and ß-catenin cooccupy the promoters of TCFL2/ß-catenin target genes. Collectively, this study uncovers a direct link between SP1 and ß-catenin in the Wnt signaling pathway.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Transcrição Sp1
/
Beta Catenina
/
Complexo de Sinalização da Axina
/
Via de Sinalização Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Cell Biol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Índia