Molecular Switches and Dose-Response Relationships

A.L. Brooks (Washington State University Tri-Cities)

To evaluate the shape of radiation dose-response relationships it is essential to understand the molecular basis of cellular responses to radiation. It has been well established that cells detect biological alterations following very low doses of ionizing radiation. The number and type of genes activated by radiation exposure is dependent on dose, with a different set of genes being activated by low doses of radiation than are observed following high radiation doses. Radiation-induced DNA damage has been demonstrated to result in a variety of cell signaling events that alter the responses directed to either increase DNA repair capability or to trigger pathways that lead to apoptosis. The balance between error-free repair, error-prone repair and cell killing seems to be an important part of low dose-response relationships that can influence risk. Other cellular responses have been demonstrated that may be related to the signaling from the damaged cells. These signals are capable of activating a number of molecular mechanisms that act as switches to produce on/off biological responses. These seem to produce "bystander effects" in non-exposed cells and activate signals that are involved in triggering DNA damage repair. Recent research has demonstrated that some DNA repair genes are up and down regulated in a time related cyclic manner in response to DNA damage and that this regulation is a function of the level of damage and the radiation dose. Research to understand the impact of these molecular processes on cell transformation and ultimately on cancer is underway. This research funded by grant #DE-FG03-99ER62787 from U.S. Department of Energy, Office of Biological and Environmental Research to Washington State University.

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