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Involvement of p85 in p53-dependent apoptotic response to oxidative stress
Y Yin1, Y Terauchi, G G Solomon
1Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Abstract:
Reactive oxygen species have damaging effects on cellular components and so trigger defensive responses by the cell and even programmed cell death, although the mechanisms by which mammalian cells transmit signals in response to oxidative damage are unknown. We report here that the protein p85, a regulator of the signalling protein phosphatidyl-3-OH kinase (PI(3)K), participates in the cell death process that is induced in response to oxidative stress and that this role of p85 in apoptosis does not involve PI(3)K. We show that disruption of p85 by homologous recombination impairs the cellular apoptotic response to oxidative stress. Because the protein p53 is required for cell death induced by oxidative damage, we examined the relation between p85 and p53. Using a chimaeric p53 fusion protein with the oestrogen receptor (p53ER) to supply p53 (p53 is induced upon binding of p53ER to oestradiol) in a p53-deficient cell line, we found that p85 is upregulated by p53 and that its involvement in p53-mediated apoptosis is independent of PI(3)K. We propose that p85 acts as a signal transducer in the cellular response to oxidative stress, mediating cell death regulated by p53.
Insights
The protein p85 regulates cell death from oxidative stress independently of PI(3)K. P53 upregulates p85, which acts as a signal transducer in p53-mediated apoptosis during oxidative damage.
Area of Science:
- Cellular biology
- Molecular mechanisms of cell death
- Oxidative stress signaling
Background:
- Reactive oxygen species (ROS) damage cells, initiating defense responses and programmed cell death (apoptosis).
- Mechanisms of mammalian cell signaling in response to oxidative damage remain unclear.
- The protein p85, a regulator of phosphatidyl-3-OH kinase (PI(3)K), is implicated in cellular responses.
Purpose of the Study:
- To investigate the role of protein p85 in oxidative stress-induced apoptosis.
- To determine if p85's function in apoptosis involves PI(3)K.
- To elucidate the relationship between p85 and p53 in oxidative stress response.
Main Methods:
- Disruption of p85 using homologous recombination.
- Utilizing a p53-deficient cell line reconstituted with a chimeric p53-estrogen receptor fusion protein (p53ER).
- Assessing p85 upregulation and its role in p53-mediated apoptosis.
Main Results:
- Disruption of p85 impairs the cellular apoptotic response to oxidative stress.
- p85 mediates apoptosis independently of PI(3)K activity.
- p53 upregulates p85 expression.
Conclusions:
- p85 acts as a crucial signal transducer in the cellular response to oxidative stress.
- p85 plays a significant role in p53-regulated apoptosis.
- The p85-mediated apoptotic pathway in response to oxidative stress is independent of PI(3)K.