Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling
- Univ. of Nevada, Las Vegas, NV (United States)
The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental approaches to apply to these problems using confocal microscopy and flow cytometry to detail changes at low dose/dose-rate in order to understand individual cell responses, and will establish our mathematical models based on the experimental findings resulting from changes in DNA repair, apoptosis and proliferation.
- Research Organization:
- Univ. of Nevada, Las Vegas, NV (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- DOE Contract Number:
- SC0012640
- OSTI ID:
- 1335567
- Report Number(s):
- DoE-UNLV-SC0012640; TRN: US1700845
- Resource Relation:
- Related Information: Final Report
- Country of Publication:
- United States
- Language:
- English
Similar Records
Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases
P44/WDR77 restricts the sensitivity of proliferating cells to TGFβ signaling
Related Subjects
LYMPHOKINES
TRANSCRIPTION FACTORS
EPITHELIUM
DNA DAMAGES
RADIATION DOSES
SIGNALS
FIBROBLASTS
INTERACTIONS
DNA REPAIR
BIOLOGICAL RADIATION EFFECTS
OXYGEN
IONIZING RADIATIONS
APOPTOSIS
CARCINOGENESIS
LET
CELL PROLIFERATION
CELL CULTURES
CELL CYCLE
DOSE RATES
MATHEMATICAL MODELS
CONTROL
ETIOLOGY
BIOLOGICAL FUNCTIONS
MICROSCOPY
BIOLOGICAL PATHWAYS
Low dose
cancer risk
radiation protection
DNA damage response