Increased expression of UBF is a critical determinant for rRNA synthesis and hypertrophic growth of cardiac myocytes

Abstract

Recent evidence suggests that increased translational efficiency of existing ribosomes alone is insufficient to account for the hypertrophic growth of cardiomyocytes and that synthesis of new functional ribosomes must occur. The rate-limiting step in ribosome accumulation is the transcription of the ribosomal 45S genes (rDNA) by RNA polymerase I. Our previous studies have demonstrated that increases in the expression of the rDNA transcription factor UBF correlated with hypertrophy of neonatal cardiomyocytes. These studies expand this observation to examine directly the hypothesis that increased UBF levels are an essential requirement for the initiation of cardiac hypertrophy. We demonstrate that the introduction of UBF antisense RNA into myocytes, using adenovirus approaches, efficiently inhibits UBF accumulation during induction of cardiomyocyte hypertrophy. Moreover, this approach results in a significant reduction in rDNA transcription, rRNA levels, and protein accumulation, which are all the hallmarks of cardiac growth. Furthermore, UBF antisense RNA expression did not alter re-expression of the fetal gene program, which confirmed that the effect was specific for transcription by RNA polymerase I. These findings demonstrate that an increase in rRNA synthesis is required for hypertrophy of cardiomyocytes and also implicate UBF as a major regulatory factor in this process. Approaches that target UBF activity may be of therapeutic use in the regression of pathophysiological cardiac hypertrophy.

Phosphatidylinositol 3-Kinase and mTOR Signaling Pathways Regulate RNA Polymerase I Transcription in Response to IGF-1 and Nutrients

“…In yeast, it has recently been reported that the Tor signaling pathway regulates the Rrn3p-dependent recruitment of Pol I (60). Other studies have suggested various complementary scenarios affecting Pol I factors, further increasing the complexity and network of regulation, and these include regulated phosphorylation of UBF (51,56,(61)(62)(63), altered abundance of UBF (9,64,65), and the expression of an inhibitor of transcription (66).…”

RNA polymerase III transcription and cancer

“…Thus, a constitutively active TIF-IA mutant accelerated proliferation by 43%, whereas dominant negative TIF-IA produced a 33% slowing (Zhao et al, 2003). Similarly, the hypertrophic growth of rat cardiac myocytes can be blocked by specifically preventing a 37% increase in rRNA synthesis (Brandenburger et al, 2001). The magnitude of these changes compares closely with the B40% suppression of rRNA synthesis exerted by endogenous RB and its relative p130 in embryonic fibroblasts, as determined with knockout mice (Ciarmatori et al, 2001).…”

Inositol Polyphosphate 1-Phosphatase Is a Novel Antihypertrophic Factor

“…As described previously, contracting NCMs showed heightened expression of ANP and increased rDNA transcription (26,27). In experiments similar to those described above, INPP was overexpressed in arrested or contracting NCMs, and markers of ANP expression (ANP-luciferase) or rDNA transcription (pS-MECAT) were measured.…”

“…Transfection of CHO cells with pCR3.1-FLAG-INPP also increased INPP activity, which was measured as previously described (24) (Fig. 1A) (25)(26)(27). Control cells were contraction-arrested by the addition of 50 mM KCl to the medium to depolarize the cells.…”

“…6C). 2 Reduces rDNA Transcription-Increases in ribosomal gene transcription and ribosome biogenesis are a prerequisite for PE-mediated cardiac hypertrophy (26,27). In experiments similar to those described above, the effect of overexpression of INPP on rDNA transcription was assessed using pSMECAT, an accurate reporter for rDNA (26).…”