2017
DOI: 10.1073/pnas.1621436114
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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 wer… Show more

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Cited by 108 publications
(85 citation statements)
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“…Genes Sorbs1 and Stau1 found in our QTL analysis have been shown to be down-regulated in cells that have undergone p53-mediated immortalization and transformation as a direct or indirect result of Ras signaling activity [Boiko et al 2006]. Furthermore, another study showed through gene ontology analysis that p53 regulates various mitochondrial bioenergetic pathways including the up-regulation of our gene Cox15 involved in ATP synthesis [Mak et al 2017]. The same study also found that p53 regulates various genes involved in cardiac tissue function including the down-regulation of our gene Ran involved in major signal transduction pathways [Mak et al 2017].…”
Section: Discussionmentioning
confidence: 91%
See 1 more Smart Citation
“…Genes Sorbs1 and Stau1 found in our QTL analysis have been shown to be down-regulated in cells that have undergone p53-mediated immortalization and transformation as a direct or indirect result of Ras signaling activity [Boiko et al 2006]. Furthermore, another study showed through gene ontology analysis that p53 regulates various mitochondrial bioenergetic pathways including the up-regulation of our gene Cox15 involved in ATP synthesis [Mak et al 2017]. The same study also found that p53 regulates various genes involved in cardiac tissue function including the down-regulation of our gene Ran involved in major signal transduction pathways [Mak et al 2017].…”
Section: Discussionmentioning
confidence: 91%
“…Furthermore, another study showed through gene ontology analysis that p53 regulates various mitochondrial bioenergetic pathways including the up-regulation of our gene Cox15 involved in ATP synthesis [Mak et al 2017]. The same study also found that p53 regulates various genes involved in cardiac tissue function including the down-regulation of our gene Ran involved in major signal transduction pathways [Mak et al 2017]. P53 was further found to decrease the activity of mouse SA beta-Galactosidase protein (encoded by our gene Glb1) in mouse mesothelial cells as well as in mouse embryonic fibroblast cells [Pietruska et al 2007, Wang et al 2007.…”
Section: Discussionmentioning
confidence: 92%
“…Finally, we identify that HCM-associated ROS production leads to activation of p53. While p53 has been well studied in the context of cancer and other disorders, it has not been implicated in HCM pathogenesis to our knowledge, and only recently implicated in regulating the cardiac transcriptome 39 . Notably, p53 genetic ablation also protected against heart failure due to pressure-overload, but promoted age-associated cardiac dysfunction 39 .…”
Section: Discussionmentioning
confidence: 99%
“…While p53 has been well studied in the context of cancer and other disorders, it has not been implicated in HCM pathogenesis to our knowledge, and only recently implicated in regulating the cardiac transcriptome 39 . Notably, p53 genetic ablation also protected against heart failure due to pressure-overload, but promoted age-associated cardiac dysfunction 39 . Our results suggest that p53 ablation would be beneficial in HCM, and therefore molecular linkages between sarcomere variants, oxidative stress and p53 activation will need to be addressed in future studies with potential therapeutic implications.…”
Section: Discussionmentioning
confidence: 99%
“…This will provide the basis for further development strategies in preventing HF and focusing on these specific pathways at early stages of the disease for an individual treatment approach. The intracellular transcription factors TP53, HNF1B, HIF1A/ARNT and STAT6, which are not measured in our plasma protein panels, may complement the biomarker profile of patients at high risk for incident HF 65 , suggesting a combined multi-OMICS approach currently being investigated within the HOMAGE consortium.…”
Section: Metabolism Clustermentioning
confidence: 99%