Muscle and non-muscle cell RNA polymerase activity during the development of myocardial hypertrophy

Cutilletta, Anthony F.; Rudnik, Margaret; Zak, Radovan

doi:10.1016/0022-2828(78)90403-0

Cited by 40 publications

(8 citation statements)

References 20 publications

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“…Of those quantitated, we failed to find a difference between the sham and AS rat groups for 10 TPs; however, eight other TPs significantly changed with the induction of hypertrophy. TPs 18,22,23, and 28 all increased in predominance with the induction of hypertrophy. TPs 27,39,41 b , and 75 all decreased with cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 91%

Cardiac response to pressure overload in the rat: the selective alteration of in vitro directed RNA translation products.

Boheler

Dillmann

1988

Circulation Research

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As cardiac hypertrophy develops, total cardiac RNA and protein synthesis increase significantly. We have identified specific messenger RNAs that change in predominance with the induction of pressure-overload-stimulated cardiac hypertrophy. Total cardiac RNA was isolated from rats either undergoing cardiac hypertrophy secondary to subdiaphragmatic aortic constriction or subjected to sham surgery. The products translated in vitro were separated by two-dimensional gel electrophoresis and quantitated. The translation of four proteins decreased while the translation of four others increased in preparations from hypertrophied hearts compared with those from sham-treated rats. Two isoforms of creatine kinase M were translated in vitro. Only one of these isoforms decreased with cardiac hypertrophy, suggesting that the transcriptional or translational control for creatine kinase is much more complex than previously believed. Finally, since only eight of over 700 different translation products changed in relative predominance with cardiac hypertrophy, we conclude that the accumulation of existing RNA and protein products is the primary adaptive process responsible for cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 91%

Cardiac response to pressure overload in the rat: the selective alteration of in vitro directed RNA translation products.

Boheler

Dillmann

1988

Circulation Research

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“…While the involvement of RNA pol II in cardiac hypertrophy has been established in earlier studies 1, 3, 13, 29 , including alpha 1-adrenergic-induced hypertrophy 4 , the details of its involvement and how, in particular, it regulates the expression of housekeeping genes, and their incremental increase in parallel with cell size, has not been determined. We expect that the mechanism presented in our pressure-induced hypertrophy model, with respect to the dichotomous effect of pol II and TFIID on transcriptional dynamics, to be similar in other forms of hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Acute Targeting of General Transcription Factor IIB Restricts Cardiac Hypertrophy via Selective Inhibition of Gene Transcription

Sayed

Yang

et al. 2015

Circ: Heart Failure

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Background We previously reported that specialized and housekeeping genes are differentially regulated via de novo recruitment and pause-release of RNA polymerase II (pol II), respectively, during cardiac hypertrophy. However, the significance of this finding remains to be examined. Therefore, the purpose of this study was to determine the mechanisms that differentially regulate these gene groups and exploit them for therapeutic targeting. Methods and Results Here we show that general transcription factor IIB (TFIIB) and cyclin-dependent kinase 9 are upregulated during hypertrophy, both targeted by miR-1, and play preferential roles in regulating those two groups of genes. Chromatin immunoprecipitation-sequencing reveals that TFIIB is constitutively bound to all paused, housekeeping, promoters, whereas, de novo recruitment of TFIIB and pol II is required for specialized genes that are induced during hypertrophy. We exploited this dichotomy to acutely inhibit induction of the latter set, which encompasses cardiomyopathy, immune reaction, and extracellular matrix genes, using locked nucleic acid (LNA)-modified antisense TFIIB oligonucleotide treatment. This resulted in suppression of all specialized genes, while sparing the housekeeping ones, and, thus, attenuated pathological hypertrophy. Conclusions The data for the first time reveal distinct general transcription factor IIB dynamics that regulate specialized vs. housekeeping genes during cardiac hypertrophy. Thus, by acutely targeting TFIIB we were able to selectively inhibit the former set of genes and ameliorate pressure overload hypertrophy. We also demonstrate the feasibility of acutely and reversibly targeting cardiac mRNA for therapeutic purposes using LNA-modified antisense oligonucleotides.

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“…Cell were plated on glass coverslips coated with gelatin. Forty-eight hours after virus delivery, the cells were fixed with 3% paraformaldehyde plus 0.3% Triton X-100 for 5 min, and then with 3% paraformaldehyde for 20 min, in CB buffer (10 H]phenylalanine per ml for 24 h. Total RNA was isolated by using a Qiagen RNA/DNA extraction kit, which also allowed simultaneous extraction of DNA from each sample. Subsequently, poly(A) RNA was extracted from the total RNA by using a Qiagen Oligotex extraction kit.…”

Section: Construction Of Adenovirusesmentioning

confidence: 99%

“…Cardiac hypertrophy is accompanied by enhanced activity of RNA polymerase I (pol I) (38,39), pol II, and pol III (10), which regulate synthesis of rRNA, mRNA, and tRNA, respectively, as well as by enhanced p70 S6K (49) and eukaryotic translation initiation factor 4E (eIF-4E) (61) phosphorylation and activities, which each contribute to the regulation of overall protein synthesis. However, the precise signaling pathways involved in mediating these events are still largely unknown.…”

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confidence: 99%

A Ras-Dependent Pathway Regulates RNA Polymerase II Phosphorylation in Cardiac Myocytes: Implications for Cardiac Hypertrophy

Abdellatif¹,

Packer²,

Michael³

et al. 1998

Molecular and Cellular Biology

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Cardiac hypertrophy, in response to mechanical load or growth factors, characteristically entails the induction of a socalled fetal program of cardiac gene expression, superimposed on a generalized increase in cellular RNA and protein content. Signaling pathways leading to the transcription of fetal genes have been extensively studied (19,26,32,35,45,47,48,50,(56)(57)(58)(59), but information is still lacking for the underlying molecular mechanisms that augment total protein content. Despite evidence from gene transfer in vitro and in vivo implicating the proto-oncoprotein Ras in cardiac hypertrophy (1,24,56,57), there is only meager information on the exact mechanism(s) by which this GTP-binding molecule might augment cardiac growth.Our previous finding that Ras can enhance expression of a generalized set of promoters, including constitutive ones, led us to speculate that Ras may be a candidate molecule that regulates global gene expression during cardiac hypertrophy (1). In support of this inference, a transgenic mouse expressing activated Ras in the heart manifested cardiac hypertrophy (23,24), although the exact mechanism for Ras-dependent growth was not established, and an indirect effect, inherent with a chronic model, cannot be excluded. Through mutational analysis of the effector domain of Ras, we have shown that a GTPase-activating protein (GAP) binding site is necessary for Ras-dependent gene induction in the ventricular myocytes, suggesting that GAP predominantly exercises an effector role in the cardiac cells (2). This conclusion was corroborated by the fact that full-length GAP and the N-terminal region of GAP (nGAP) both mimicked the global effect of Ras on cardiac gene expression.While GAP may thus mediate the generalized effects of Ras on gene expression, one Ras effector protein, Raf, has been implicated more specifically in the regulation of fetal genes that are reexpressed during ventricular hypertrophy, such as ANF and MLC-2 (56). A possible dissociation between the signaling pathways that lead to an increase in total cellular protein and the fetal phenotype was recently suggested in connection with angiotensin II (AII) stimulation (49): rapamycin blocked the increase in ribosomal p70 kinase (S6K) activity, and consequently the increase in total cell protein, but did not impair the reactivation of fetal genes (skeletal ␣-actin gene and ANF) or the increase in mitogenactivated protein kinase activity.An increase in total protein per cell (the sine qua non of hypertrophy) is itself a complex process that involves regulation of multiple cellular functions. Cardiac hypertrophy is accompanied by enhanced activity of RNA polymerase I (pol I) (38, 39), pol II, and pol III (10), which regulate synthesis of rRNA, mRNA, and tRNA, respectively, as well as by enhanced p70 S6K (49) and eukaryotic translation initiation factor 4E (eIF-4E) (61) phosphorylation and activities, which each contribute to the regulation of overall protein synthesis. However, the precise signaling pathways involved in mediating t...

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Muscle and non-muscle cell RNA polymerase activity during the development of myocardial hypertrophy

Cited by 40 publications

References 20 publications

Cardiac response to pressure overload in the rat: the selective alteration of in vitro directed RNA translation products.

Cardiac response to pressure overload in the rat: the selective alteration of in vitro directed RNA translation products.

Acute Targeting of General Transcription Factor IIB Restricts Cardiac Hypertrophy via Selective Inhibition of Gene Transcription

A Ras-Dependent Pathway Regulates RNA Polymerase II Phosphorylation in Cardiac Myocytes: Implications for Cardiac Hypertrophy

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