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p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.
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http://dx.doi.org/10.1038/s41467-021-25390-0 | DOI Listing |
Aging Cell
December 2024
Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies due to their self-renewal and differentiation capabilities. Pathological microenvironments expose MSCs to senescence-inducing factors such as reactive oxygen species (ROS), resulting in MSC functional decline and loss of stemness. Oxidative stress leads to mitochondrial dysfunction, a hallmark of senescence, and is prevalent in aging tissues characterized by elevated ROS levels.
View Article and Find Full Text PDFStem Cells
December 2024
Department of Obstetrics, the Affiliated Hospital of Qingdao University, Qingdao, China.
Background: Amniotic mesenchymal stem cells (AMSCs) have been demonstrated as effective in tissue repair and regeneration. Trophoblast dysfunction is associated with several types of pregnancy complications. The aim of this study is to investigate the effects of AMSCs on the biological activities of human trophoblasts, as well as their molecular mechanisms.
View Article and Find Full Text PDFJ Med Chem
December 2024
Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB, F-33607 Pessac, France.
Combining helical foldamers with α-peptides can produce α-helix mimetics with a reduced peptide character and enhanced resistance to proteolysis. Previously, we engineered a hybrid peptide-oligourea sequence replicating the N-terminal α-helical domain of p53 to achieve high affinity binding to hDM2. Here, we further advance this strategy by combining the foldamer approach with side chain cross-linking to create more constrained cell-permeable inhibitors capable of effectively engaging the target within cells.
View Article and Find Full Text PDFJ Am Heart Assoc
December 2024
Department of Cardiology, Pulmonology, and Nephrology Yamagata University School of Medicine Yamagata Japan.
Background: Doxorubicin-induced cardiotoxicity is still an important medical problem associated with a high mortality rate in cancer survivors. p53 plays a key role in doxorubicin-induced cardiotoxicity. Diacylglycerol kinase ζ (Dgkζ), a 130-kDa enzyme abundant in cardiomyocytes, regulates the p53 protein expression level in neurons.
View Article and Find Full Text PDFBiochem Genet
December 2024
College of Pharmacy, The Islamic University, Najaf, Iraq.
The long non-coding RNA Growth Arrest-Specific 5 (GAS5) is pivotal in modulating key signaling pathways by functioning as a molecular sponge for microRNAs (miRNAs). GAS5 is notably recognized for its antitumor properties, primarily through its ability to sequester oncogenic miRNAs, thereby influencing critical pathways such as p53, Wnt/β-catenin, and PI3K/Akt, all of which are integral to cell proliferation, apoptosis, and metastasis. The disruption of GAS5-miRNA interactions has been implicated in various malignancies, reinforcing its potential as both a biomarker and a therapeutic target.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!