Objective
This research proposal focuses on various aspects of the response of mammalian cells to ionizing radiation. The purpose will be to gain a better understanding of how radiation triggers signalling cascades and how these cascades culminate in cell-cycle control, and, at a later stage, may lead to such diverse phenomena as programmed cell death (apoptosis), initiation of oncogenic transformation and effects on the immune system. This proposal will address the mode of activation as well as the possible role of several intermediates of these ionizing radiation-induced signalling responses. In addition, it will be attempted to identify novel genes that are responsive to ionizing radiation and constituents of these signalling routes.
Firstly, this proposal concerns the activation by ionizing radiation of the transcription factors NFkB, KBFl and cJun/ATF2. These transcription factors are crucial targets of two well-known radiationactivated signal transduction pathways. Secondly, the radiationinduced stabilization of the transcription factor p53, a key component in activation of cell-cycle arrest and programmed cell death (apoptosis), will be investigated. Thirdly, ionizing radiation of mammalian cells seems to activate responses that lead not only to apoptosis but also to cellular protection. We want to get insight into these relatively unknown protective responses. In this respect we will study the activation and role of c-Fos and ornithine decarboxylase (ODC) upon ionizing radiation as depletion of any of these two proteins renders cells highly sensitive to radiation. Interestingly, both genes have been characterized as proto-oncogenes and play important roles at the Gl stage of the cell cycle. Fourthly, we will isolate human genes which are specifically activated by ionizing radiation via a signal transduction route which is probably independent of p53 and not shared by other DNA damaging agents. Similarly, we will isolate genes which are induced by ionizing radiation in a p53-dependent manner in tissues which will readily go into apoptosis. The identification of these genes and the analysis of their expression in normal and tumour tissue and in the tissues of individuals exposed to genotoxic agents has the potential to provide immense insight into the function of p53 and may identify many new genes of importance in human cancer.
Programme(s)
Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
2300 AL Leiden
Netherlands