The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer.
The RNA polymerase I (Pol I) transcription machinery in the nucleolus is the key convergence point that collects and integrates a vast array of information from cellular signaling cascades to regulate ribosome production that in turn guides cell growth and proliferation. Cancer cells commonly harbor mutations that inactivate tumor suppressors, hyperactivate oncogenes, and upregulate protein kinases, all of which promote Pol I transcription and drive cell proliferation. The intimate balance between Pol I transcription and growth-factor signaling is perturbed in cancer cells, indicating that upregulation of rRNA synthesis is mandatory for all tumors. Though the emerging picture of transcriptional regulation reveals an unexpected level of complexity, we are beginning to understand the multiple links between rRNA biogenesis and cancer. In this review, we discuss experimental data and potential strategies to downregulate rRNA synthesis and induce an antiproliferative response in cancer cells.
Drygin
Denis
D
Cylene Pharmaceuticals, San Diego, California, USA. ddrygin@cylenepharma.com
Rice
William G
WG
Grummt
Ingrid
I
D000818:Animals; D017209:Apoptosis; D002466:Cell Nucleolus / Q000502:physiology / Q000648:ultrastructure; D004275:DNA, Ribosomal / Q000235:genetics; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009857:Oncogenes; D035463:Pol1 Transcription Initiation Complex Proteins / Q000502:physiology; D011499:Protein Processing, Post-Translational; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000502:physiology; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects*
D004275:DNA, Ribosomal; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C428423:RRN3 protein, human; D012318:RNA Polymerase I