INVOLVEMENT OF HEAT-SHOCK FACTOR IN REGULATING TRANSCRIPTIONAL ACTIVATION OF MDR1 GENE IN MULTIDRUG-RESISTANT CELLS

The present study provides evidence that heat shock factor (HSF) may b e involved in a transacting factor modulating multidrug resistance 1 ( MDR1) gene. In conjunction with the presence of several heat shock ele ments (HSEs) in the 5' region of the MDR1 gene, we compared the level of HSF which binds to HSEs in multidrug-resistant P388/M and FM3A/M ce lls with that in their parental counterparts. Under unstressed conditi on, these multidrug-resistant cells showed constitutive HSF DNA-bindin g activity in the nucleus of the cells, whereas their parental counter parts did not show detectable HSF DNA-binding activity. We found that H-87, protein kinase A inhibitor, inhibited HSF DNA-binding activity i n heat-shocked P388/M cells and also suppressed the levels of hsp90 an d hsp70. These results demonstrated that HSF might be an important tra nscriptional regulator for inducing MDR1 gene, and modulation of HSF a ctivity might be a useful potential target for reversing MDR. (C) 1997 Elsevier Science Ireland Ltd.