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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine
S Rashi-Elkeles1, R Elkon, N Weizman
1The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics, Sackler School of Medicine, Tel Aviv, Israel.
Abstract:
The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia, is a master regulator of the cellular network induced by DNA double-strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combined gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation in murine lymphoid tissue. Cluster analysis revealed a prominent pattern characterizing dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of NF-kappaB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and antiapoptotic signals were simultaneously induced, with the proapoptotic pathway mediated by p53 targets, and the prosurvival pathway by NF-kappaB targets. These findings further elucidate the molecular network induced by IR, point to novel putative NF-kappaB targets, and suggest a mechanistic model for cellular balancing between pro- and antiapoptotic signals induced by IR in lymphoid tissues, which has implications for cancer management. The emerging model suggests that restoring the p53-mediated apoptotic arm while blocking the NF-kappaB-mediated prosurvival arm could effectively increase the radiosensitivity of lymphoid tumors.
Insights
The ATM protein kinase regulates DNA double-strand break responses. This study reveals ATM-dependent gene expression in lymphoid tissue, mediated by NF-kappaB and p53, balancing cell survival and death signals after irradiation.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- ATM protein kinase is crucial for DNA double-strand break repair and is often mutated in lymphoid cancers.
- Understanding the transcriptional response to DNA damage is vital for cancer therapy.
Purpose of the Study:
- To dissect the transcriptional response to ionizing radiation in murine lymphoid tissue.
- To identify key transcription factors involved in the ATM-dependent response.
- To elucidate the balance between pro- and anti-apoptotic signals.
Main Methods:
- Functional genomics approach combining gene expression profiling and computational promoter analysis.
- Cluster analysis to identify ATM-dependent gene expression patterns.
- Computational analysis of transcription factor binding sites in gene promoters.
Main Results:
- Identified dozens of genes with ATM-dependent responses to irradiation.
- Found significant enrichment of NF-kappaB and p53 binding sites in these promoters.
- Observed simultaneous induction of pro-apoptotic (p53-mediated) and pro-survival (NF-kappaB-mediated) signals.
Conclusions:
- NF-kappaB and p53 are major mediators of the ATM-dependent transcriptional response in irradiated lymphoid tissue.
- A mechanistic model for balancing pro- and anti-apoptotic signals by IR in lymphoid tissues was proposed.
- Targeting these pathways could enhance radiosensitivity in lymphoid tumors.
