Related Experiment Videos
4-hydroxynonenal triggers multistep signal transduction cascades for suppression of cellular functions
Izumi Nakashima1, Wei Liu, Anwarul A Akhand
1Department of Immunology, Graduate School of Medicine, University of Nagoya, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. inakashi@med.nagoya-u.ac.jp
Abstract:
4-hydroxynonenal (HNE), an aldehyde product of membrane lipid peroxidation, has been suggested to mediate a number of oxidative stress-linked pathological events in humans, including cellular growth inhibition and apoptosis induction. Because HNE is potentially reactive to a number of both cell surface and intracellular proteins bearing sulfhydryl, amino and imidazole groups, it seems that there are multiple signal transduction cascades. Here we briefly review the HNE-triggered signal transduction cascades that lead to suppression of cellular functions and to cell death, based mainly on our own recent study results. We first showed that formation of HNE-cell surface protein adducts, which mimicked ligand-cell surface receptor binding, induced activation of receptor-type protein tyrosine kinases such as epithelial growth factor receptor (EGFR) and that this caused growth inhibition through a cascade of activation of EGFR, Shc and ERK. Next, we showed that HNE-mediated scavenging of cellular glutathione led to activation of caspases and to DNA fragmentation through a Fas-independent and mitochondria-linked pro-apoptotic signal pathway. More recently, we have obtained evidence that the HNE-triggered signal cascade for caspase activation encounters complex positive feedback regulatory mechanisms that are linked to the inhibition of anti-apoptotic signals and are dependent on caspase activity. Underlying multiple regulatory mechanisms, including mechanisms of activation of Akt-dephosphorylating PP2A activity, activities of protein tyrosine kinases have been shown to be biphasically controlled by HNE. In addition, we have obtained results suggesting that HNE inhibits phosphorylation of IkappaB, possibly by targeting some elements upstream of IkappaB, which might downregulate the NF-kappaB-mediated cellular responses, including serum deprivation-induced iNOS expression and generation of anti-apoptotic signals. These results suggest that HNE reacts with multiple cell surface and intracellular sites for triggering a network of signal transduction that is ultimately focused on suppression of cellular functions.
Insights
4-hydroxynonenal (HNE), a product of lipid peroxidation, triggers cell death and growth inhibition by activating multiple signaling pathways. HNE disrupts cellular functions through protein adducts and glutathione depletion, leading to apoptosis and altered kinase activity.
Area of Science:
- Biochemistry and Molecular Biology
- Cellular Signaling
- Oxidative Stress Research
Background:
- 4-hydroxynonenal (HNE) is a key aldehyde product of membrane lipid peroxidation implicated in oxidative stress-related human pathologies.
- HNE's reactivity with proteins suggests its involvement in multiple cellular signal transduction pathways.
- Understanding HNE's role is crucial for elucidating mechanisms of cellular dysfunction and death.
Purpose of the Study:
- To review and present recent findings on HNE-triggered signal transduction cascades.
- To elucidate how HNE leads to suppression of cellular functions and apoptosis.
- To explore the complex regulatory mechanisms involved in HNE-mediated signaling.
Main Methods:
- Investigated HNE-protein adduct formation mimicking ligand-receptor binding.
- Analyzed HNE-induced activation of receptor-type protein tyrosine kinases (e.g., EGFR).
- Examined HNE's effect on cellular glutathione levels and caspase activation pathways.
- Studied feedback mechanisms in HNE-triggered caspase activation.
- Assessed HNE's impact on protein phosphatases (PP2A) and kinases.
- Evaluated HNE's influence on IkappaB phosphorylation and NF-kappaB signaling.
Main Results:
- HNE-cell surface protein adducts activated EGFR, leading to growth inhibition via the EGFR-Shc-ERK cascade.
- HNE-induced glutathione depletion activated caspases and DNA fragmentation through a mitochondria-linked pathway.
- HNE-triggered caspase activation involves positive feedback loops and inhibition of anti-apoptotic signals.
- HNE biphasically controlled protein tyrosine kinase and Akt-dephosphorylating PP2A activities.
- HNE inhibited IkappaB phosphorylation, downregulating NF-kappaB-mediated responses like iNOS expression.
Conclusions:
- HNE initiates complex signaling networks by reacting with multiple cellular targets.
- These networks ultimately suppress cellular functions and promote cell death.
- HNE's multifaceted interactions highlight its significant role in oxidative stress pathology.