The overall cellular response to ionizing radiation exposure is not limited to cells directly irradiated, but includes neighboring """"""""bystanders"""""""". Essentially every endpoint used routinely to test for changes in cells directly exposed to radiation, such as mutation, apoptosis, micronuclei formation or cell cycle checkpoints, has been studied in bystanders. This phenomenon has caused a paradigm shift in thinking about biological effects and associated health risks of radiafion exposure;the impacted cell population is larger than once believed. The mechanism regulating bystander effects is not well understood. However, certain gap junction proteins, i.e., Connexin 32, and proteins like Cox-2 control the overall process, whereas p21 just regulates the radiation-induced Gl to S checkpoint. We have shown that Rad9 regulates the bystander response to radiation, since Rad9 null enhances bystander apoptosis and micronuclei formation. Rad9 protein, which controls cell cycle checkpoints, DNA repair, apoptosis and transactivation of downstream target genes in directly irradiated cells, likely impacts on the bystander response via more than one pathway. In collaboration with investigators in Projects 2 and 3, we show that Rad9 is essential for bystander induction of Cox-2 and p21 (Project 2), and production of Connexin 32 in HeLa cells, which are normally devoid of the protein, increases bystander radiation resistance and levels of Rad9 as well as TCTP (Project 3), which both function in the bystander process. We also show that TCTP and Rad9 physically interact (Project 3). Our overarching hypothesis is that Rad9 plays an important role in radiation-induced bystander effects via mechanisms involving at least Cox-2, p2I, Connexin 32 and TCTP.
Specific aims to address this hypothesis are: I. Determine the activity of Rad9 in nuclear versus cytoplasmic irradiation-induced bystander effects;2. Analyze Rad9 functional domains and protein-protein interactions for roles in the bystander process;3. Establish the significance of Rad9-dependent bystander induction of Cox-2, p21 and other genes for bystander regulation;4. Determine if Rad9 is critical for bystander mutagenesis;and 5. Define the significance of junctional communication on the regulation and function of Rad9. These studies will reveal mechanisms by which Rad9 regulates radiation-induced bystander effects, and will impact on understanding the biological response to radiation exposure, with implications for improving radiotherapy and better defining health risk.
): It is now established that the effects of radiation exposure extend well beyond directly targeted cells or tissues, and involve neighboring bystanders. The molecular basis for this paradigm shift in thinking is not well understood, and is the focus of this proposal. Understanding the bystander response will impact on radiotherapy and health risk assessment, where radiation exposure is a crucial component.
|Wu, Jinhua; Zhang, Qin; Wuu, Yen-Ruh et al. (2017) Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase. Radiat Res 187:441-453|
|Liao, Wupeng; Hei, Tom K; Cheng, Simon K (2017) Radiation-Induced Dermatitis is Mediated by IL17-Expressing ?? T Cells. Radiat Res 187:454-464|
|Wu, Jinhua; Zhang, Bo; Wuu, Yen-Ruh et al. (2017) Targeted cytoplasmic irradiation and autophagy. Mutat Res 806:88-97|
|Chen, Hongxin; Chong, Zhao Zhong; De Toledo, Sonia M et al. (2016) Delayed activation of human microglial cells by high dose ionizing radiation. Brain Res 1646:193-198|
|Gong, Xuezhong; Ivanov, Vladimir N; Hei, Tom K (2016) 2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-?B, AP-1 and MAPK pathways in human proximal tubular cells. Arch Toxicol 90:2187-200|
|Azzam, Edouard I; Colangelo, Nicholas W; Domogauer, Jason D et al. (2016) Is Ionizing Radiation Harmful at any Exposure? An Echo That Continues to Vibrate. Health Phys 110:249-51|
|Hei, Tom K (2016) Response of Biological Systems to Low Doses of Ionizing Radiation. Health Phys 110:281-2|
|Ivanov, Vladimir N; Hei, Tom K (2015) Regulation of viability, differentiation and death of human melanoma cells carrying neural stem cell biomarkers: a possibility for neural trans-differentiation. Apoptosis 20:996-1015|
|Dong, Chen; He, Mingyuan; Tu, Wenzhi et al. (2015) The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation. Cancer Lett 363:92-100|
|Liu, Jing; Fang, Hongbo; Chi, Zhenfen et al. (2015) XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage. Nucleic Acids Res 43:5476-88|
Showing the most recent 10 out of 218 publications