EFFECTS OF ONCOGENES ON THE RESISTANCE TO CIS-DIAMMINEDICHLOROPLATINUM(II) AND METALLOTHIONEIN GENE-EXPRESSION

Transformation of NIH3T3 cells with the ras, the sis, or the neu oncog ene rendered cells less susceptible to cis-diamminedichloroplatinum(II ). Since resistance to cis-diamminedichloroplatinum(II) is reported to be associated with increased levels of metallothionein, we examined e ffects of these oncogenes on metallothionein gene expression. NIH3T3 c ells were first transfected with the lacZ gene whose transcription is under the control of mouse metallothionein I promoter and then with th e uas, the sis, or the neu oncogene. The ras and the sis oncogenes inc reased beta-galactosidase activities which were induced either by meta l (cadmium and zinc) or by glucocorticoid (dexamethasone), whereas the neu oncogene repressed its activity. When SV40 early promoter was use d instead of metallothionein I promoter for the lacZ gene transcriptio n, the beta-galactosidase activities were not affected by metal, dexam ethasone, or any of these oncogenes. This result was coincident with t hat of reverse transcription polymerase chain reaction that metal-indu ced MT I mRNA was only detected in the sis- or the uas-transformed cel ls, whereas any of these oncogenes did not affect the metal-induced tr anscription of the MT II gene. These results demonstrate that the ras and the sis oncogenes upregulate the metal- or glucocorticoid-induced transcription from metallothionein I promoter, but the neu oncogene ne gatively regulates it. Thus, resistance to the chemotherapeutic agent by oncogenic transformation is partly associated with the metallothion ein gene expression, and MT I and MT II gene expressions are different ly controlled by different oncogenes. (C) 1995 Academic Press,Inc.