Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

Bywater, M. J., Poortinga, G., Sanij, E., Hein, N., Peck, A., Cullinane, C., Wall, M., Cluse, L., Drygin, D., Anderes, K., Huser, N., Proffitt, C., Bliesath, J., Haddach, M., Schwaebe, M. K., Ryckman, D. M., Rice, W. G, Schmitt, C., Lowe, Scott W, Johnstone, R. W., Pearson, R. B., McArthur, G. A., Hannan, R. D. (July 2012) Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53. Cancer Cell, 22 (1). pp. 51-65. ISSN 1535-6108

URL: http://www.ncbi.nlm.nih.gov/pubmed/22789538
DOI: 10.1016/j.ccr.2012.05.019

Abstract

Summary Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > RNA polymerase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 15 July 2012
Date Deposited: 31 Jan 2013 20:56
Last Modified: 31 Jan 2013 20:56
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26912

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