title: p53 regulates the cardiac transcriptome.
abstract: The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP-mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9; phyllis.billia@uhn.ca tmak@uhnres.utoronto.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Toronto General Research Institute, Toronto, ON, Canada M5G 1L7.
authors.forename: Ludger
authors.initials: L
authors.lastname: Hauck
authors.affiliation: Toronto General Research Institute, Toronto, ON, Canada M5G 1L7.
authors.forename: Daniela
authors.initials: D
authors.lastname: Grothe
authors.affiliation: Toronto General Research Institute, Toronto, ON, Canada M5G 1L7; phyllis.billia@uhn.ca tmak@uhnres.utoronto.ca.|Division of Cardiology, University Health Network, Toronto, ON, Canada M5G 2C4.|Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 1A8.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5G 1A8.
authors.forename: Filio
authors.initials: F
authors.lastname: Billia
mesh_terms: D000818:Animals; D017209:Apoptosis; D001696:Biomechanical Phenomena; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013314:Stress, Mechanical; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: cardiac hypertrophy; cardiomyopathy; heart failure; transcriptome; tumor suppressor