ATM-NF-kappaB connection as a target for tumor radiosensitization.
Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-kappaB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-kappaB leads to radiosensitization in radioresistant cancer cells. NF-kappaB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-kappaB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-kappaB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-kappaB in response to IR. Also, the association of ATM with the NF-kappaB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.
Ahmed
Kazi Mokim
KM
Division of Molecular Radiobiology, Purdue University School of Health Sciences, Purdue Cancer Center, West Lafayette, Indiana 47907, USA.
Li
Jian Jian
JJ
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011836:Radiation Tolerance; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
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; D017346:Protein Serine-Threonine Kinases