Membrane-Derived Second Messenger Regulates X-Ray-Mediated Tumor Necrosis Factor α Gene Induction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 11; pp. 4897 - 4901
• Main Authors: Hallahan, Dennis E., Virudachalam, S., Kuchibhotla, J., Kufe, Donald W., Weichselbaum, Ralph R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 24.05.1994; National Acad Sciences
• Subjects: Amino Acid Sequence; Arachidonic Acids - biosynthesis; Cell Line; Cell Membrane - metabolism; DNA damage; Enzyme Activation; Fatty acids; Gene Expression Regulation - radiation effects; Gene induction; Hematopoietic stem cells; Humans; Hydrolysis; Ionizing radiation; Irradiation; Molecular Sequence Data; Nonesterified fatty acids; Phospholipases A - antagonists & inhibitors; Phospholipases A - metabolism; Phospholipases A2; Protein Kinase C - metabolism; RNA; Second Messenger Systems; Transcriptional Activation; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.11.4897

Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a signaling pathway involving the activation of phospholipase A2and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor α gene. Treatment of human cells with ionizing radiation or H2O2was associated with the production of arachidonic acid. Inhibition of phospholipase A2abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor α gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor α production.