An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation

AUTOR(ES)

Fernandez-Zapico, Martin E.

FONTE

Oxford University Press

RESUMO

KLF11 is a biochemical paradigm for a subset of proteins that repress transcription via a Mad1-like mSin3A interacting domain (SID). The biological role of these proteins and the significance of their biochemical activity, however, remain to be established. We report that KLF11 is downregulated in human cancers, inhibits cell growth in vitro and in vivo, and suppresses neoplastic transformation. Transgenic mice for KLF11 display a downregulation of genes encoding the oxidative stress scavengers SOD2 and Catalase1. Chromatin immunoprecipitation assays confirm that, indeed, these genes are bonafide targets of KLF11. KLF11 expression renders cells more sensitive to oxidative drugs, an effect that is rescued by infection with recombinant adenoviruses expressing SOD2 and Catalase1. KLF11-regulated functions require the Mad1-like SID, indicating that these target genes involved in these phenomena are regulated via this corepressor system. These results demonstrate that SID-containing KLF repressor proteins can inhibit cell growth and neoplastic transformation, and outline for the first time cellular and molecular mechanisms by which these functions may be achieved.

Documentos Relacionados

• Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a
• A Conserved α-Helical Motif Mediates the Interaction of Sp1-Like Transcriptional Repressors with the Corepressor mSin3A
• mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival
• Signaling disrupts mSin3A binding to the Mad1-like Sin3-interacting domain of TIEG2, an Sp1-like repressor
• Identification and Characterization of Three New Components of the mSin3A Corepressor Complex