Cardiac hypertrophy occurs normally in neonatal hearts and, in adult hearts, is induced by various physiological and pathological conditions such as ischemia, hypertension, and thyrotoxicosis. During this process the cardiac muscle cells increase in size but not in number. Our central hypothesis is that the determination of the mechanisms regulating ribosomal RNA synthesis in cardiomyocytes will provide targets for intervention and illuminate the signal transduction pathways that lead to hypertrophy. The hallmark of cardiomyocyte hypertrophy is the accumulation of total protein. Ribosome accumulation 1) is a key adaptive change that always occurs during hypertrophy, regardless of the stimulus, 2) is the primary mechanism for accelerating the rate of protein synthesis, and 3) results from an increased rate of transcription of the ribosomal RNA genes (rDNA). We have examined the regulation of rDNA transcription in several models of neonatal and adult cardiomyocyte hypertrophy. We found that in several models, including aortic coarctation, the amount of the rDNA transcription factor UBF increased in the cardiomyocytes. The increase in UBF mass parallels the increased rate of rDNA transcription and resulted from increased expression of the UBF gene. One goal of this project is to test the hypothesis that the increase in UBF protein is necessary for hypertrophic growth. Our results suggest that at least one signal transduction pathway that regulates rDNA transcription in cardiomyocytes targets the UBF gene. Our goal is to define the pathway by mapping the cis-acting elements of the UBF gene responsible for increased expression of the gene in response to either adrenergic agents or pressure overload. The results of these experiments will increase our understanding of the signal transduction pathway(s) that lead to the process of cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL077814-03
Application #
7509303
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2008-02-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$318,200
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Rothblum, Lawrence I; Rothblum, Katrina; Chang, Eugenie (2017) PAF53 is essential in mammalian cells: CRISPR/Cas9 fails to eliminate PAF53 expression. Gene 612:55-60
Penrod, Yvonne; Rothblum, Katrina; Cavanaugh, Alice et al. (2015) Regulation of the association of the PAF53/PAF49 heterodimer with RNA polymerase I. Gene 556:61-7
Rothblum, Katrina; Hu, Qiyue; Penrod, Yvonne et al. (2014) Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3. Mol Cancer Res 12:1586-96
Stepanchick, Ann; Zhi, Huijun; Cavanaugh, Alice H et al. (2013) DNA binding by the ribosomal DNA transcription factor rrn3 is essential for ribosomal DNA transcription. J Biol Chem 288:9135-44
Hannan, K M; Sanij, E; Rothblum, L I et al. (2013) Dysregulation of RNA polymerase I transcription during disease. Biochim Biophys Acta 1829:342-60
Penrod, Yvonne; Rothblum, Katrina; Rothblum, Lawrence I (2012) Characterization of the interactions of mammalian RNA polymerase I associated proteins PAF53 and PAF49. Biochemistry 51:6519-26
DuRose, Jenny B; Scheuner, Donalyn; Kaufman, Randal J et al. (2009) Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. Mol Cell Biol 29:4295-307
Cavanaugh, Alice H; Evans, Ann; Rothblum, Lawrence I (2008) Mammalian Rrn3 is required for the formation of a transcription competent preinitiation complex containing RNA polymerase I. Gene Expr 14:131-47
Sanij, Elaine; Poortinga, Gretchen; Sharkey, Kerith et al. (2008) UBF levels determine the number of active ribosomal RNA genes in mammals. J Cell Biol 183:1259-74
Cheung, Joseph Y; Rothblum, Lawrence I; Moorman, J Randall et al. (2007) Regulation of cardiac Na+/Ca2+ exchanger by phospholemman. Ann N Y Acad Sci 1099:119-34