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Role of 4-hydroxynonenal in stress-mediated apoptosis signaling
Yogesh C Awasthi1, Rajendra Sharma, J Z Cheng
1Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, 551 Basic Science Building, Galveston, TX 77555-0647, USA. ycawasth@utmb.ca
Abstract:
In this mini review we summarize recent studies from our laboratory, which show the involvement of 4-hydroxynonenal (4-HNE) in cell cycle signaling. We demonstrate 4-HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase and caspase-3 activation. Cells exposed to mild, transient, heat or oxidative stress acquire capacity to exclude intracellular 4-HNE at a faster rate by inducing hGST5.8 which conjugate 4-HNE to GSH, and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4-HNE. The cells preconditioned with mild transient stress acquire resistance to H(2)O(2) and 4-HNE induced apoptosis by excluding intracellular 4-HNE at an accelerated pace. Furthermore, a decrease in intracellular concentration of 4-HNE achieved by transfecting cells with mGSTA4-4 or hGSTA4-4 results in a faster growth rate. These studies strongly suggest a role of 4-HNE in stress mediated signaling.
Insights
This study reveals 4-hydroxynonenal (4-HNE) involvement in cell cycle signaling and stress responses. Mild stress enhances cellular defense against 4-HNE, promoting resistance to apoptosis and faster cell growth.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- 4-hydroxynonenal (4-HNE) is a key cytotoxic aldehyde implicated in cellular damage.
- Cellular signaling pathways are complex and influenced by oxidative stress.
- Understanding lipid peroxidation byproducts is crucial for cell health.
Purpose of the Study:
- To investigate the role of 4-HNE in cell cycle signaling.
- To elucidate the mechanisms of cellular defense against 4-HNE.
- To explore the impact of 4-HNE modulation on cell proliferation and stress resistance.
Main Methods:
- Utilized various cell lines exposed to oxidative and heat stress.
- Analyzed the activation of c-Jun-N-terminal kinase and caspase-3.
- Investigated the expression and function of glutathione S-transferases (GSTs) and RLIP76.
- Employed gene transfection techniques to alter intracellular 4-HNE levels.
Main Results:
- 4-HNE induces apoptosis, associated with c-Jun-N-terminal kinase and caspase-3 activation.
- Mild stress enhances cellular exclusion of 4-HNE via hGST5.8 and RLIP76.
- Preconditioned cells exhibit resistance to H2O2 and 4-HNE-induced apoptosis.
- Reduced intracellular 4-HNE levels (via mGSTA4-4/hGSTA4-4) correlate with accelerated cell growth.
Conclusions:
- 4-HNE plays a significant role in stress-mediated cell signaling.
- Cellular preconditioning enhances protective mechanisms against 4-HNE toxicity.
- Modulating 4-HNE levels impacts cell proliferation and stress resilience.