The potential role of 4-hydroxynonenal (HNE), a major product of membrane lipid peroxidation, in regulating glycogen synthase kinase-3beta (GSK3beta) activity was examined in human neuroblastoma IMR-32 cells. The inhibition of GSK3beta activity by HNE was observed by in vitro kinase assays with two substrates, the synthetic glycogen synthase peptide-2 and the human recombinant tau. GSK3beta activity is regulated by Ser9 (inhibitory) and Tyr216 (stimulatory) phosphorylation. By using specific activity-dependent phospho-antibodies, immunoblot analysis revealed that HNE induces an increase in phosphorylation of GSK3beta in Ser9, enhancing basal phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase 2 (ERK2) signalling pathways. Ser9-GSK3beta phosphorylation induced by HNE was abolished by treatment with LY294002 or U0126, two inhibitors of PI3K/AKT and ERK pathways, respectively. These experiments provide evidence for a crucial role of the PI3K/AKT and ERK2 pathways as intracellular targets of HNE that mediate the inhibition of GSK3beta activity in regulating cellular response to HNE in viable cells under conditions in which membrane lipid peroxidation occurs. These data support a key role for GSK3beta as a mediator of the signalling pathways activated by oxidative stress, and therefore it may be included among the redox-sensitive enzymes.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1111/j.1471-4159.2004.02413.x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Polysaccharides from Scrophularia ningpoensis Hemsl. Improve reserpine-induced depression-like behavior by inhibiting HTR2A/HTR2C mediated AKT/GSK3β/β-catenin/CBP/BDNF signaling.
Int J Biol Macromol
January 2025
College of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, PR China; College of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, PR China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, Shandong 272067, PR China; Jining Key Laboratory of Depression Prevention and Treatment, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address:
Scrophularia ningpoensis Hemsl. is a traditional Chinese medicine used to regulate blood sugar levels, immunity, etc. We previously isolated polysaccharides from S.
View Article and Find Full Text PDFThe chiisanoside derivatives present in the leaves of activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity.
Front Pharmacol
January 2025
College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China.
Introduction: Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from has abundant activity against CIO.
View Article and Find Full Text PDFPDE4 inhibitor rolipram represses hedgehog signaling via ubiquitin-mediated proteolysis of GLI transcription factors to regress breast cancer.
J Biol Chem
January 2025
Cell and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, Nadia, West Bengal, India, 741235. Electronic address:
Aberrant activation of the hedgehog (Hh) signaling pathway positively correlates with progression, invasion and metastasis of several cancers, including breast cancer. Although numerous inhibitors of the Hh signaling pathway are available, several oncogenic mutations of key components of the pathway, including Smoothened (Smo), have limited their capability to be developed as putative anti-cancer drugs. In this study, we have modulated the Hh signaling pathway in breast cancer using a specific FDA-approved phosphodiesterase 4 (PDE4) inhibitor rolipram.
View Article and Find Full Text PDFREDD1-dependent GSK3β signaling in podocytes promotes canonical NF-κB activation in diabetic nephropathy.
J Biol Chem
January 2025
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033. Electronic address:
Increasing evidence supports the role of an augmented immune response in the early development and progression of renal complications caused by diabetes. We recently demonstrated that podocyte-specific expression of stress response protein regulated in development and DNA damage response 1 (REDD1) contributes to activation of the pro-inflammatory transcription factor NF-κB in the kidney of diabetic mice. The studies here were designed to define the specific signaling events whereby REDD1 promotes NF-κB activation in the context of diabetic nephropathy.
View Article and Find Full Text PDFLncRNA-ANRIL regulates CDKN2A to promote malignant proliferation of Kasumi-1 cells.
Cell Div
January 2025
Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550004, China.
Objective: This study aimed to investigate the regulatory effects of long non-coding RNA-ANRIL on CDKN2A in the cell cycle of Kasumi-1 cells and elucidate the underlying molecular mechanisms.
Methods: ANRIL and CDKN2A expression levels were quantified using RT-qPCR in peripheral blood samples from acute myeloid leukemia (AML) patients. CDKN2A knockdown efficiency was validated via RT-qPCR, and cell cycle distribution was analyzed using flow cytometry.
Want 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!