Overexpression of the transcription factor UBF1 is sufficient to increase ribosomal DNA transcription in neonatal cardiomyocytes: implications for cardiac hypertrophy.

Hannan, Ross D.; Stefanovsky, Victor Y.; Taylor, Laura; Moss, Tom; Rothblum, Lawrence I.

doi:10.1073/pnas.93.16.8750

Cited by 66 publications

(74 citation statements)

References 29 publications

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“…19 In agreement, we demonstrate that the increased binding of UBF to the rDNA promoter is associated with a similar increase in 18 s rRNA level. Markedly elevated, normal rRNA transcripts, seems a unique phenomenon and several consequences could be envisioned, including scavenging of RNA binding proteins, scavenging of RNA disposal machinery, or altered ribosome biogenesis.…”

supporting

confidence: 85%

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

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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supporting

confidence: 85%

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

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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“…It is possible that p8 can modulate the expression of genes associated with enhanced protein biosynthesis. Of note, both PE and ET-1 can trigger the expression of endogenous and reporter rRNA genes, and this induction contributes to cardiomyocyte hypertrophy (14).…”

Section: Discussionmentioning

confidence: 99%

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction

Goruppi

Patten

Force

et al. 2007

Molecular and Cellular Biology

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Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin-and ␣-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factorstimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13-MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.The progression to heart failure involves an initial phase of pathological cardiomyocyte hypertrophy, which develops as a consequence of excess hemodynamic work load and may be triggered by ␣-adrenergic agents, angiotensin II, and/or endothelin. Pathological cardiomyocyte hypertrophy is followed by left ventricular decompensation, characterized by cardiomyocyte loss, and interstitial fibrosis-direct contributors to adverse ventricular remodeling. Ultimately, the contractile properties of the heart are compromised, resulting in heart failure (17,18,27). The molecular components and cellular events required for heart failure remain incompletely understood, and few genes have been linked to both pathological hypertrophy of cardiomyocytes and matrix remodeling (9,17,18,27).Post-myocardial infarction, in addition to hypertrophy of surviving cardiomyocytes, remodeling of the extracellular matrix occurs, particularly within the territory of the infarct, as lost myocytes are replaced by fibrous tissue (22, 23). Key to this remodeling process is the production and release of matrix metalloproteases (MMPs) from both resident cells, especially cardiac fibroblasts, and infiltrating leukocytes. Inflammatory cytokine production (especially tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6 family members) by these cells is believed to be the major trigger for induction of MMP expression.Studies employing broad-spectrum inhibitors of MMPs have shown that cytokine (TNF)-stimulated upregulation of the expression of MMPs is a central factor leading to left ventricular dilation post-myocardial infarction, a harbinger of heart failure (28,32,48). Studies of mice with a targeted deletion of mmp9 clearly implicate this factor in not only left ventricular dilation but also in inhibition of neo-an...

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“…If UBF is not part of an autonomously initiating RPI enzyme, then how does one explain the ability of UBF to activate transcription in vivo (41,42). One possibility is that UBF might contribute to the regulation of transcription initiation, at least in part, by facilitating recruitment of the holoenzyme to the rRNA genes.…”

Section: Components Of the Dna Repair/replication System Are Associatmentioning

confidence: 99%

Identification of a mammalian RNA polymerase I holoenzyme containing components of the DNA repair/replication system

Hannan¹,

Cavanaugh²,

Hempel³

et al. 1999

Nucleic Acids Research

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Traditional models for transcription initiation by RNA polymerase I include a stepwise assembly of basic transcription factors/regulatory proteins on the core promoter to form a preinitiation complex. In contrast, we have identified a preassembled RNA polymerase I (RPI) complex that contains all the factors necessary and sufficient to initiate transcription from the rDNA promoter in vitro. The purified RPI holoenzyme contains the RPI homolog of TFIID, SL-1 and the rDNA transcription terminator factor (TTF-1), but lacks UBF, an activator of rDNA transcription. Certain components of the DNA repair/replication system, including Ku70/80, DNA topoisomerase I and PCNA, are also associated with the RPI complex. We have found that the holoenzyme supported specific transcription and that specific transcription was stimulated by the RPI transcription activator UBF. These results support the hypothesis that a fraction of the RPI exists as a preassembled, transcriptionally competent complex that is readily recruited to the rDNA promoter, i.e. as a holoenzyme, and provide important new insights into the mechanisms governing initiation by RPI.

show abstract

Overexpression of the transcription factor UBF1 is sufficient to increase ribosomal DNA transcription in neonatal cardiomyocytes: implications for cardiac hypertrophy.

Cited by 66 publications

References 29 publications

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

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

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction

Identification of a mammalian RNA polymerase I holoenzyme containing components of the DNA repair/replication system

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