AI Article Synopsis
Article Abstract
Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66(Shc) adaptor protein controls cellular responses to oxidative stress. Mice lacking p66(Shc) (p66(Shc-/-)) have increased resistance to ROS and prolonged life span. The present work was designed to investigate hyperglycemia-associated changes in endothelial function in a model of insulin-dependent diabetes mellitus p66(Shc-/-) mouse. p66(Shc-/-) and wild-type (WT) mice were injected with citrate buffer (control) or made diabetic by an i.p. injection of 200 mg of streptozotocin per kg of body weight. Streptozotocin-treated p66(Shc-/-) and WT mice showed a similar increase in blood glucose. However, significant differences arose with respect to endothelial dysfunction and oxidative stress. WT diabetic mice displayed marked impairment of endothelium-dependent relaxations, increased peroxynitrite (ONOO(-)) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66(Shc-/-) diabetic mice did not develop these high-glucose-mediated abnormalities. Furthermore, protein expression of the antioxidant enzyme heme oxygenase 1 and endothelial NO synthase were up-regulated in p66(Shc-/-) but not in WT mice. We report that p66(Shc-/-) mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66(Shc) adaptor protein is part of a signal transduction pathway relevant to hyperglycemia vascular damage and, hence, may represent a novel therapeutic target against diabetic vascular complications.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829289 | PMC |
| http://dx.doi.org/10.1073/pnas.0609656104 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Distribution of the p66Shc Adaptor Protein Among Mitochondrial and Mitochondria-Associated Membranes Fractions in Normal and Oxidative Stress Conditions.
Int J Mol Sci
November 2024
Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland.
Article Synopsis
- - p66Shc is an adaptor protein crucial for regulating cellular functions including signaling pathways, mitochondrial activity, and the production of reactive oxygen species (ROS), with its location shifting to mitochondria under oxidative stress.
- - The protein is also implicated in mitochondria-associated membranes (MAM), which play a role in key cellular processes like calcium balance, apoptosis (cell death), and autophagy (cell cleaning), suggesting p66Shc's involvement in determining cell fate.
- - This study investigates the distribution of p66Shc in different parts of mouse liver tissue and HepG2 cells, demonstrating a significant presence of p66Shc in MAM under both normal and oxidative stress conditions.
p66Shc Protein-Oxidative Stress Sensor or Redox Enzyme: Its Potential Role in Mitochondrial Metabolism of Human Breast Cancer.
Cancers (Basel)
September 2024
Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland.
This work presents a comprehensive evaluation of the role of p66Shc protein in mitochondrial physiology in MDA-MB-231 breast cancer cells. The use of human breast cancer cell line MDA-MB-231 and its genetically modified clones (obtained with the use of the CRISPR-Cas9 technique), expressing different levels of p66Shc protein, allowed us to demonstrate how the p66Shc protein affects mitochondrial metabolism of human breast cancer cells. Changes in the level of p66Shc (its overexpression, and overexpressing of its Serine 36-mutated version, as well as the knockout of p66Shc) exert different effects in breast cancer cells.
View Article and Find Full Text PDFBAG3 Mediated Down-regulation in Expression of p66shc has Ramifications on Cellular Proliferation, Apoptosis and Metastasis.
Cell Biochem Biophys
December 2024
Department of Biotechnology, University of Kashmir, Srinagar, Jammu & Kashmir, India.
Redundancy of cancer cells towards ROS-mediated apoptosis despite expressing proline-rich p66shc abundantly needs to be investigated properly. P66shc, an adapter protein, is indispensable both for initiating ROS-mediated apoptosis and subsequent ROS generation through Rac-1 activation. P66shc gets phosphorylated at Ser-36 that triggers its translocation to the mitochondria and subsequent release of Cytochrome c in response to oxidative stress.
View Article and Find Full Text PDFExploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.
Int J Mol Sci
March 2024
Department of Nutritional Sciences, College of Allied Health, University of Oklahoma Health Sciences, Oklahoma City, OK 73117, USA.
This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways.
View Article and Find Full Text PDFp66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation.
Front Cell Dev Biol
January 2024
Department of Life Sciences, University of Siena, Siena, Italy.
Escape from immunosurveillance is a hallmark of chronic lymphocytic leukemia (CLL) cells. In the protective niche of lymphoid organs, leukemic cells suppress the ability of T lymphocytes to form the immune synapse (IS), thereby hampering T-cell mediated anti-tumoral activities. By binding its cognate receptor PD-1 at the surface of T lymphocytes, the inhibitory ligand PD-L1, which is overexpressed in CLL cells, mediates the T-cell suppressive activities of CLL cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!