Identification of kinase inhibitors that target transcription initiation by RNA polymerase II

José M. Morachis, Ruo Huang, Beverly Emerson

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Our current understanding of eukaryotic transcription has greatly benefited from use of small molecule inhibitors that have delineated multiple regulatory steps in site-specific initiation and elongation of RNA synthesis by multiple forms of RNA polymerase (RNAP). This class of " transcription" drugs is also of therapeutic interest and under evaluation in clinical trials. However, to date very few small molecules that directly abolish transcription have been identified, particularly those that act at the level of RNAP II initiation. Using a biochemical assay that measures transcription from recombinant, natural p53-responsive promoters and an artificial " super" promoter, we have identified three distinct small molecules that inhibit mRNA synthesis in vitro. Unexpectedly, these are kinase inhibitors, Hypericin, Rottlerin, and SP600125, with known substrates, which we find also strongly impair transcriptional initiation (IC50s = μM range) by targeting specific components of the RNAP II pre-initiation complex. When measured before and during transcription in vitro, one common target of inhibition by all three compounds is modification of the TATA Binding Protein (TBP) within the RNAP II holocomplex as it converts to an active transcribing enzyme. On this basis, by blocking the critical step of TBP modification, transcriptional initiation is effectively abolished even on structurally distinct core promoters.

Original languageEnglish (US)
Pages (from-to)18-28
Number of pages11
JournalOncotarget
Volume2
Issue number1-2
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

TATA-Box Binding Protein
RNA Polymerase II
Phosphotransferases
DNA-Directed RNA Polymerases
Clinical Trials
RNA
Messenger RNA
Enzymes
Pharmaceutical Preparations
In Vitro Techniques
Therapeutics
anthra(1,9-cd)pyrazol-6(2H)-one
rottlerin
hypericin

Keywords

  • Core promoters
  • Fas/APO1
  • Kinase inhibitors
  • P21
  • P53
  • RNA polymerase II
  • Transcription therapy

ASJC Scopus subject areas

  • Oncology

Cite this

Identification of kinase inhibitors that target transcription initiation by RNA polymerase II. / Morachis, José M.; Huang, Ruo; Emerson, Beverly.

In: Oncotarget, Vol. 2, No. 1-2, 01.01.2011, p. 18-28.

Research output: Contribution to journalArticle

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