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.

Public Health Relevance

): 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA049062-23
Application #
8693581
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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
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-κB, AP-1 and MAPK pathways in human proximal tubular cells. Arch Toxicol 90:2187-200
Hei, Tom K (2016) Response of Biological Systems to Low Doses of Ionizing Radiation. Health Phys 110:281-2
Panigrahi, Sunil K; Hopkins, Kevin M; Lieberman, Howard B (2015) Regulation of NEIL1 protein abundance by RAD9 is important for efficient base excision repair. Nucleic Acids Res 43:4531-46
Autsavapromporn, Narongchai; Plante, Ianik; Liu, Cuihua et al. (2015) Genetic changes in progeny of bystander human fibroblasts after microbeam irradiation with X-rays, protons or carbon ions: the relevance to cancer risk. Int J Radiat Biol 91:62-70
Brengues, Muriel; Gu, Jian; Zenhausern, Frederic (2015) Microfluidic module for blood cell separation for gene expression radiobiological assays. Radiat Prot Dosimetry 166:306-10
Wang, Tony J C; Wu, Cheng-Chia; Chai, Yunfei et al. (2015) Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions. PLoS One 10:e0136307
Gong, Xuezhong; Ivanov, Vladimir N; Davidson, Mercy M et al. (2015) Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death. Arch Toxicol 89:1057-70
Chen, Hongxin; Goodus, Matthew T; de Toledo, Sonia M et al. (2015) Ionizing Radiation Perturbs Cell Cycle Progression of Neural Precursors in the Subventricular Zone Without Affecting Their Long-Term Self-Renewal. ASN Neuro 7:
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

Showing the most recent 10 out of 211 publications