[Molecular mechanism of the stress induction of MDR1 gene]

MDR1 promoter activity increases in response to various environmental stimuli, including anticancer drugs and in a manner that is dependent on the inverted CCAAT box. The binding activity of a nuclear factor MDR-NF1 that interacts with this promoter region was augmented when the nuclear extract was prepared from cells that had been treated with either UV or anticancer drugs. In an attempt to understand the molecular basis for the stress-dependent induction of MDR1 promoter activity, the cDNA for MDR-NF1 have been cloned. The amino acid sequence encoded by the cloned cDNA was identical to that of YB-1. The human Y-Box binding protein (YB-1) is a member of a DNA-binding protein family with a structurally and functionally conserved cold shock domain. YB-1 was found to be much higher in all cisplatin-resistant cell lines than that in the respective drug-sensitive parental counterparts. Two transfectants with a YB-1 antisense construct showed increased sensitivity to cisplatin, mitomycin C and UV irradiation, but not to vincristine, doxorubicin, camptothecin or etoposide. Thus, YB-1 may protect cells from the cytotoxic effects of agents that induce cross-linking of DNA, suggesting a novel function of this ancestor DNA binding protein. Regulatory mechanism of the YB-1 gene expression and the cellular functions of YB-1 are currently under investigation in relation to drug resistance.