Involvement multiple factors in p53-dependent gene regulation in response to low-dose radiation

Elucidation of how living organisms respond to ionizing radiation of doses lower than 0.5Gy is critical for establishment of a scientifically-justified risk assessment. It has been revealed that low-dose radiation causes distinct biological responses, such as adaptive responses, bystander effects and induction of genomic instability, which were not observed in experiments using lethal dose of radiation. There is accumulating evidence showing that p53 plays a pivotal role in these low-dose radiation-distinct responses. In fact, p53 is activated by a faint damage of the genome, and its target genes, such as p21WAF1/CIP1, GADD45a and MDM2, are induced by low-dose radiation. We have observed 8-fold increase in p21 gene transcription and 5-fold increase in GADD45a gene transcription after 0.5Gy of X rays in human myeloblastic leukemia cell line ML1. However activation of p53 by radiation is not limited in a low-dose range. Therefore, as yet determined mechanisms involving p53 must be operating in inducing the low-dose radiation-distinct biological responses. In this regard, it is noteworthy that a lot of nuclear factors have been demonstrated to associate with p53, modulating its function in regulation of the downstream genes. For examples, transcription factors Sp1, gut-enriched kruppel-like factor (GKLF), Ets1, and interferon regulatory factor-1 (1RF-1) have been shown to be involved in the p53-dependent transcriptional activation. BRCA1 has also been shown to play a role in both p53-dependent and p53-independent transcriptional activation of the GADD45a gene. Histone acetyl transferase p300/CBP and PHD-finger motif proteins ING family are the cofactors, modulating p53 function through chromatin remodeling. Based on these observations, it may be hypothesized that a specific combination of cooperating transcription factors and cofactors is activated by low-dose radiation, and it causes a distinct biological response. We attempt here to review recent data, including ours, concerning nuclear factors participating in transcriptional regulation by p53The Fifth Japan-France Workshop on Radiobiology and Medical Imagin