At the molecular level, cellular responses to ionizing radiation are determined by differential gene expression. Pathways of signal transduction cell cycle regulation, repair processes and programmed cell deathh (apoptosis), are all included in the events underlying radiation sensitivity or resistance. In this program project, our overall hypothesis that key proteins functioning in signal transduction pathways are associated with tumor cellular radiation sensitivity or resistance. We will investigate several of these proteins to determine mechanisms of action, as they relate to cellular responses to ionizing radiation. We have organized our investigations in seven projects and two cores. We will study the roles of NF-khib/ikhibalpha radiation sensitivity and programmed cell death in projects #1 and 2, respectively. Programmed cell death and poly (ADP- ribose) polymerase mechanisms will be investigated in projects #3 and 4. Radiation sensitivity of thymidine kinase deficient cells will be studied i project #5. Preclinical evaluation of antisense oligonucleotide to c-raf-1 ll be performed in human tumor xenograft model system, extending our previous laboratory observations with antisense RNA to this oncogene. Finally, a prospective clinical trial will be performed to determine the ro of ATM heterozygosity in breast cancer and acute radiation reactions. These projects run the gamut of investigations from basic science to clinical translation, centering on molecular mechanisms underlying cellular radiation responses. Data from these projects will enhance our understanding of radiation sensitivity, apoptosis, and may provide the basis for a clinical test to diagnose ATM heterozygotes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Subcommittee G - Education (NCI)
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Mahoney, Francis J
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Georgetown University
Schools of Medicine
United States
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Sakabe, Isamu; Hu, Rong; Jin, Lu et al. (2015) TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling. Breast Cancer Res Treat 153:285-97
Zhang, Chuanbo; Kallakury, Bhaskar V; Ross, Jeffrey S et al. (2013) The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence. Int J Cancer 133:31-42
Cheema, Amrita K; Varghese, Rency S; Timofeeva, Olga et al. (2013) Functional proteomics analysis to study ATM dependent signaling in response to ionizing radiation. Radiat Res 179:674-683
Jung, Mira; Timofeeva, Olga; Cheema, Amrita K et al. (2011) Human fibroblasts for large-scale ""omics"" investigations of ATM gene function. Adv Exp Med Biol 720:181-90
Cheema, Amrita K; Timofeeva, Olga; Varghese, Rency et al. (2011) Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism. J Proteome Res 10:2651-7
Konsoula, Zacharoula; Velena, Alfredo; Lee, Rachel et al. (2011) Histone deacetylase inhibitor: antineoplastic agent and radiation modulator. Adv Exp Med Biol 720:171-9
Hu, Zhang-Zhi; Huang, Hongzhan; Wu, Cathy H et al. (2011) Omics-based molecular target and biomarker identification. Methods Mol Biol 719:547-71
Varghese, Rency S; Cheema, Amrita; Cheema, Prabhdeep et al. (2010) Analysis of LC-MS data for characterizing the metabolic changes in response to radiation. J Proteome Res 9:2786-93
Broustas, Constantinos G; Ross, Jeffrey S; Yang, Qifeng et al. (2010) The proapoptotic molecule BLID interacts with Bcl-XL and its downregulation in breast cancer correlates with poor disease-free and overall survival. Clin Cancer Res 16:2939-48
Timofeeva, Olga A; Zhang, Xueping; Ressom, Habtom W et al. (2009) Enhanced expression of SOS1 is detected in prostate cancer epithelial cells from African-American men. Int J Oncol 35:751-60

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