Regulation of Ribosomal Gene Expression in Cancer

Abstract

The ability of a cell to undergo malignant transformation is both associated with and dependent on a concomitant increase in protein synthesis due to increased cell division rates and biosynthetic activities. Protein synthesis, in turn, depends upon the synthesis of ribosomes and thus ultimately on the transcription of ribosomal RNA by RNA polymerase I that occurs in the nucleolus. Enlargement of nucleoli has long been considered a hallmark of the malignant cell, but it is only recently that the rate of synthesis of rRNA in the nucleolus has been recognized as both a critical regulator of cellular proliferation and a potential target for therapeutic intervention. As might be expected, the factors regulating rRNA synthesis are both numerous and complex. It is the objective of this review to highlight recent advances in understanding how rRNA synthesis is perturbed in transformed mammalian cells and to consider the impact of these findings on the development of new approaches to the treatment of malignancies. In-depth analysis of the process of rRNA transcription itself may be found in several recently published reviews (Drygin et al., 2010, Annu Rev Pharmacol Toxicol 50:131-156; Bywater et al., 2013,Cancer Cell 22: 51-65; Hein et al., 2013,Trends Mol Med 19:643-654).

Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells

“…Ribosomal RNA synthesis is a prerequisite for cellular proliferation and is tightly regulated in response to diverse growth and inhibitory stimuli (reviewed in 10,11). It requires the recruitment of RNA polymerase I (Pol I) and several transcription initiation factors including Transcription Initiation Factor I (TIF-IA), upstream binding factor (UBF), and the TATA-binding protein (TBP)-containing factor TIF-IB/SL1 to the ribosomal DNA (rDNA) promoter to generate a productive transcription initiation complex.…”

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

“…Such a dysregulation would have a profound impact, since rDNA heterochromatin status is tightly regulated during differentiation and has a broader effect on heterochromatin formation throughout the nucleus. 17,28 Obviously, the data and the consequent assumptions should be regarded as preliminary, because all derived from a single cell line of an affected individual and one healthy control.…”

Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury–Induced Neointimal Hyperplasia

“…An adequate rate of ribosome biogenesis is essential for cell proliferation to meet the increased demand for protein synthesis. 8,9 The nucleolus is the site where ribosomal biogenesis occurs. In the nucleolus, RNA polymerase I (Pol I) transcribes rDNA genes to the 47S pre-rRNA, which undergoes multiple steps of processing to generate the mature 18S, 5.8S, and 28S rRNAs; these rRNA transcripts are then assembled with ribosomal proteins to form the large (60S) and small (40S) subunits of the ribosome.…”

“…9,10 Indeed, overactivation of the Pol I activity has been recognized as a hallmark of certain cancer cells. 8,10,11 In eukaryotes, disruption of the normal nucleolar functions, such as inhibiting rDNA transcription with actinomycin D or inhibiting rRNA processing with 5-fluorouracil, induces a unique cellular stress response called nucleolar stress (or ribosomal stress), which results in stabilization of p53 protein by repressing p53 degradation by the E3 ubiquitin ligase MDM2. 9,12,13 CX-5461 is a novel, first-in-class selective Pol I inhibitor.…”

“…18,19 In addition, it is clear that mammalian target of rapamycin is an important positive regulator of rDNA transcription, and the rate of rRNA synthesis is sensitive to rapamycin. 8 Therefore, the potent cytostatic effect of rapamycin in VSMCs suggests the possibility that inhibiting rRNA synthesis may reduce the proliferating capability of the cell. Based on these liners of information, in the present study, we hypothesized that specific inhibition of Pol I with CX-5461 might be effective in blocking the development of proliferative neointimal lesions.…”