Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue.
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.
Rashi-Elkeles
S
S
The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics, Sackler School of Medicine, Tel Aviv, Israel.
Elkon
R
R
Weizman
N
N
Linhart
C
C
Amariglio
N
N
Sternberg
G
G
Rechavi
G
G
Barzilai
A
A
Shamir
R
R
Shiloh
Y
Y
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000528:radiation effects*; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000528:radiation effects*; D005720:Gamma Rays; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000592:standards; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000528:radiation effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000592:standards; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000528:radiation effects*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases