Transcriptional tools: Small molecules for modulating CBP KIX-dependent transcriptional activators

Caleb A. Bates, William C. Pomerantz, Anna K. Mapp

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Previously it was demonstrated that amphipathic isoxazolidines are able to functionally replace the transcriptional activation domains of endogenous transcriptional activators. In addition, in vitro binding studies suggested that a key binding partner of these molecules is the CREB Binding Protein (CBP), more specifically the KIX domain within this protein. Here we show that CBP plays an essential role in the ability of isoxazolidine transcriptional activation domains to activate transcription in cells. Consistent with this model, isoxazolidines are able to function as competitive inhibitors of the activators MLL and Jun, both of which utilize a binding interaction with KIX to up-regulate transcription. Further, modification of the N2 side chain produced three analogs with enhanced potency against Jun-mediated transcription, although increased cytotoxicity was also observed. Collectively these small KIX-binding molecules will be useful tools for dissecting the role of the KIX domain in a variety of pathological processes.

Original languageEnglish (US)
Pages (from-to)17-23
Number of pages7
JournalBiopolymers
Volume95
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Domain
  • Isoxazolidine
  • Jun
  • MLL
  • Transcriptional activation
  • Transcriptional activator

Fingerprint

Dive into the research topics of 'Transcriptional tools: Small molecules for modulating CBP KIX-dependent transcriptional activators'. Together they form a unique fingerprint.

Cite this