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Ionizing radiation-inducible apoptosis in the absence of p53 linked to transcription factor EGR-1
M M Ahmed1, S F Sells, K Venkatasubbarao
1Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Abstract:
The tumor suppressor protein p53 is a pivotal regulator of apoptosis, and prostate cancer cells that lack p53 protein are moderately resistant to apoptotic death by ionizing radiation. Genes encoding the transcription factor early growth response-1 (EGR-1) and cytokine tumor necrosis factor-alpha (TNF-alpha) were induced upon irradiation of prostate cancer cells, and inhibition of EGR-1 function resulted in abrogation of both TNF-alpha induction and apoptosis. Induction of the TNF-alpha gene by ionizing radiation and EGR-1 was mediated via a GC-rich EGR-1-binding motif in the TNF-alpha promoter. Because TNF-alpha induces apoptosis in prostate cancer cells, these findings suggest that, in the absence of p53, ionizing radiation-inducible apoptosis is mediated by EGR-1 via TNF-alpha transactivation.
Insights
Prostate cancer cells lacking tumor suppressor p53 utilize the early growth response-1 (EGR-1) pathway to induce apoptosis via tumor necrosis factor-alpha (TNF-alpha) when exposed to ionizing radiation.
Area of Science:
- Molecular Biology
- Cancer Research
- Radiation Oncology
Background:
- The tumor suppressor protein p53 is crucial for regulating apoptosis.
- Prostate cancer cells deficient in p53 exhibit moderate resistance to ionizing radiation-induced apoptosis.
Purpose of the Study:
- To investigate the molecular mechanisms of apoptosis in p53-deficient prostate cancer cells following ionizing radiation.
- To identify key transcription factors and signaling pathways involved in radiation-induced cell death.
Main Methods:
- Irradiation of prostate cancer cell lines lacking p53.
- Analysis of gene expression for early growth response-1 (EGR-1) and tumor necrosis factor-alpha (TNF-alpha).
- Functional inhibition of EGR-1 to assess its role in apoptosis and TNF-alpha induction.
Main Results:
- Ionizing radiation induced EGR-1 and TNF-alpha in p53-deficient prostate cancer cells.
- Inhibition of EGR-1 abolished TNF-alpha induction and subsequent apoptosis.
- EGR-1 directly binds to a GC-rich motif in the TNF-alpha promoter, mediating its transactivation.
Conclusions:
- In p53-deficient prostate cancer cells, ionizing radiation triggers apoptosis through the EGR-1-mediated transactivation of TNF-alpha.
- EGR-1 acts as a critical mediator of radiation-induced apoptosis in the absence of functional p53.