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Doctoraatsverdediging
Marcella Mori
Profiles of Gene Expression
induced by ionizing radiation in different human cell types
Ionizing radiation disrupts chemical bonds in biomolecules,
such as proteins and DNA, which result in important cellular damage. Exposure
to relatively
high doses of ionizing radiation such as those delivered to the tumor
in a radiotherapy protocol is generally lethal for the cell. However,
non-lethal dose of ionizing radiation can be delivered during radiotherapy
to the healthy tissue surrounding the tumor. Although the effects of ionizing
radiation at the cellular level are quite well established (cell cycle
arrest, senescence, apoptosis, mitotic catastrophe), questions remain
concerning the molecular pathways regulating these cellular responses,
including those differentiating the responses between tumor and normal
cells. In normal cells, the p53 protein plays a central role. However,
the efficacy of radiation treatments on tumor cells is often reduced because
of the frequent inactivation of the p53 protein in those cells. Our study
used the microarray technology to investigate the
molecular pathways induced by irradiation in transformed and non-transformed
human cells. Profiles of gene expression obtained with cDNA microarrays
were regarded as steps to characterize the general response to ionizing
radiation and, possibly also, differentiating the response between transformed
and non-transformed cells. Possible implications of such research include
the development of radiosensitizing (to maximize the effect of radiotherapeutic
irradiation) and of radioprotecting strategies. Transcriptional profiles
were investigated in transformed (Jurkat, HL60) and non-transformed (freshly
isolated lymphocyte subpopulations) cells of hematopoietic origin. Also,
because HeLa carcinoma-derived cells expressing human papilloma virus
(HPV) 18 derived E2 protein represent a reliable model to study the p53
pathway, which is normally activated in response to radiation, molecular
profiles were obtained to characterize this pathway in these cells.
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