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Apoptotic response and cell cycle transition in ataxia telangiectasia cells exposed to oxidative stress
P Formichi1, C Battisti, S A Tripodi
1U.O. Neurometabolic Diseases, Institute of Neurological Sciences, University of Siena, Italy.
Abstract:
The recently identified ATM gene plays a role in a signal transduction network activating multiple cellular functions in response to DNA damage. An attractive hypothesis is that the ATM protein is involved in a specialized antioxidant system responsible for detoxifying reactive oxygen intermediate and that the absence or dysfunction of this protein in AT cells would render them less capable of dealing with oxidative stress. In order to investigate the role of the ATM gene in cell cycle control and programmed cell death, Lymphoblastoid cell lines derived from four Ataxia-Telangiectasia (AT) patients and six controls have been analyzed. All cell lines were incubated with 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis through oxidative stress. The result showed an impaired response to dRib-induced apoptosis in AT cells, as well as a defect of cellular cycle arrest in G1/S phase and a normal expression of p53 protein. This indicate that the kinase activity of ATM gene product plays a very important role in the cellular response to oxidative stress. In conclusion the altered response of AT cells to oxidative stress and particularly their resistance to apoptotic cell death, could explain the high predisposition of these cells to progress toward malignant transformation.
Insights
Ataxia-Telangiectasia (AT) cells show impaired responses to oxidative stress due to ATM gene dysfunction. This resistance to apoptosis may increase cancer risk in AT patients.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The ATM gene is crucial for DNA damage response and signal transduction.
- ATM protein's role in antioxidant systems and oxidative stress response is hypothesized.
- Ataxia-Telangiectasia (AT) is a genetic disorder linked to ATM gene mutations.
Purpose of the Study:
- To investigate the role of the ATM gene in cell cycle control and apoptosis.
- To analyze the cellular response to oxidative stress induced by 2-deoxy-D-ribose (dRib) in AT cells.
Main Methods:
- Lymphoblastoid cell lines from AT patients and controls were analyzed.
- Cell lines were treated with 2-deoxy-D-ribose (dRib) to induce oxidative stress.
- Cell cycle progression and apoptosis were assessed, along with p53 protein expression.
Main Results:
- AT cells exhibited an impaired apoptotic response to dRib-induced oxidative stress.
- A defect in G1/S phase cell cycle arrest was observed in AT cells.
- p53 protein expression remained normal in AT cells despite the observed defects.
Conclusions:
- The kinase activity of the ATM gene product is vital for cellular response to oxidative stress.
- Altered oxidative stress response and resistance to apoptosis in AT cells may contribute to malignant transformation.
- ATM gene dysfunction impacts cell cycle regulation and apoptosis, potentially increasing cancer predisposition.