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Open Access Highly Accessed Research article

Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes

Michal Mikula13, Karolina Hanusek2, Agnieszka Paziewska2, Artur Dzwonek1, Tymon Rubel1, Karol Bomsztyk3 and Jerzy Ostrowski12*

Author Affiliations

1 Department of Gastroenterology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

2 Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland

3 UW Medicine Lake Union, University of Washington, Seattle, USA

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BMC Molecular Biology 2010, 11:4  doi:10.1186/1471-2199-11-4

Published: 15 January 2010

Abstract

Background

Aberrant activation of protein kinases is one of the essential oncogenic driving forces inherent to the process of tumorigenesis. The protein kinase CK2 plays an important role in diverse biological processes, including cell growth and proliferation as well as in the governing and transduction of prosurvival signals. Increased expression of CK2 is a hallmark of some cancers, hence its antiapoptotic properties may be relevant to cancer onset. Thus, the designing and synthesis of the CK2 inhibitors has become an important pursuit in the search for cancer therapies.

Results

Using a high-throughput microarray approach, we demonstrate that two potent inhibitors of CK2, 4,5,6,7-tetrabromo-benzimidazole (TBBz) and 2-Dimethyloamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), blocked mitogen induced mRNA expression of immediate early genes. Given the impact of these inhibitors on the process of transcription, we investigated their effects on RNA Polymerase II (RNAPII) elongation along the mitogen inducible gene, EGR1 (early growth response 1), using chromatin immunoprecipitation (ChIP) assay. ChIP analysis demonstrated that both drugs arrest RNAPII elongation. Finally, we show that CDK9 kinase activity, essential for the triggering of RNAPII elongation, was blocked by TBBz and to lesser degree by DMAT.

Conclusions

Our approach revealed that small molecules derived from halogenated imidazole compounds may decrease cell proliferation, in part, by inhibiting pathways that regulate transcription elongation.