AI Article Synopsis
Article Abstract
Aims/hypothesis: The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated.
Methods: The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66(Shc) was investigated using pancreatic islets from p66 (Shc-/-) mice and in INS-1E cells with knockdown of p66(Shc) or overexpression of wild-type and phosphorylation-defective p66(Shc). Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method.
Results: Palmitate induced a selective increase in p66(Shc) protein expression and phosphorylation on Ser(36) and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66(Shc) expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 (Shc-/-) mice and following p66 (Shc) knockdown in INS-1E cells; by contrast, overexpression of p66(Shc), but not that of the phosphorylation-defective p66(Shc) mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66(Shc) were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser(36) and associated with generation of ROS. p66(Shc) protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors.
Conclusions/interpretation: p53-dependent augmentation of p66(Shc) expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00125-015-3563-2 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Olaparib Enhances the Efficacy of Third-Generation Oncolytic Adenoviruses Against Glioblastoma by Modulating DNA Damage Response and p66shc-Induced Apoptosis.
CNS Neurosci Ther
November 2024
Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Aims: Patients with glioblastoma multiforme (GBM) do not benefit from current cancer treatments, and their prognosis is dismal. This study aimed to investigate the potential synergistic effects of TS-2021, a third-generation oncolytic adenovirus, combined with the PARP inhibitor olaparib in GBM.
Methods: TS-2021's impact on p66shc-induced apoptosis, DNA damage response, and poly (ADP-ribose) polymerase (PARP) activation was evaluated in GBM cells.
REGγ deficiency ameliorates hepatic ischemia and reperfusion injury in a mitochondrial p66shc dependent manner in mice.
Transl Gastroenterol Hepatol
October 2024
Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Article Synopsis
- Hepatic ischemia and reperfusion (I/R) injury is a significant issue for patients undergoing liver-related surgeries, and this study investigates the protein REGγ's role in this injury.* -
- Through experiments on mice, the study found that knocking out REGγ reduced liver damage, inflammation, and apoptosis, while also improving mitochondrial function.* -
- The findings suggest that REGγ is crucial in protecting the liver from I/R injury, potentially through the mitochondrial p66shc signaling pathway.*
p66shc deficiency attenuates high glucose-induced autophagy dysfunction in Schwann cells.
Korean J Physiol Pharmacol
October 2024
Department of Physiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 34134, Korea.
Schwann cells are the most abundant cells in the peripheral nervous system, maintaining the development, function and regeneration of peripheral nerves. Defects in these Schwann cells injury response potentially contribute to the pathogenesis of diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus. The protein p66shc is essential in regulating oxidative stress responses, autophagy induction and cell survival, and is also vital in the development of DPN.
View Article and Find Full Text PDFp66Shc 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 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!