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A Strategy for Direct Chemical Activation of the Retinoblastoma Protein.

Authors
  • Cr, Pye
  • Wm, Bray
  • Er, Brown
  • Jr, Burke
  • Rs, Lokey
  • Seth Rubin
Type
Published Article
Journal
ACS Chemical Biology
Publisher
American Chemical Society
Volume
11
Issue
5
Pages
1192–1197
Identifiers
DOI: 10.1021/acschembio.6b00011
Source
UCSC Cancer biomedical-ucsc
License
Unknown

Abstract

The retinoblastoma (Rb) tumor suppressor protein negatively regulates cell proliferation by binding and inhibiting E2F transcription factors. Rb inactivation occurs in cancer cells upon cyclin-dependent kinase (Cdk) phosphorylation, which induces E2F release and activation of cell cycle genes. We present a strategy for activating phosphorylated Rb with molecules that bind Rb directly and enhance affinity for E2F. We developed a fluorescence polarization assay that can detect the effect of exogenous compounds on modulating affinity of Rb for the E2F transactivation domain. We found that a peptide capable of disrupting the compact inactive Rb conformation increases affinity of the repressive Rb-E2F complex. Our results demonstrate the feasibility of discovering novel molecules that target the cell cycle and proliferation through directly targeting Rb rather than upstream kinase activity.

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