We tested the potential impact of tyrosine phosphorylation on the expression of the c-myc gene in two colon cancer cell lines, HCT8 and SW837. We found that the protein tyrosine kinase inhibitor genistein causes a decrease in the abundance of c-myc RNA and an inhibition of proliferation with a similar dose response. Geldanamycin, a mechanistically different tyrosine kinase inhibitor, also causes a decrease in both the expression of c-myc RNA and proliferation. Genistein has also been found to inhibit topoisomerase II, but the topoisomerase II inhibitor novobiocin did not lower the expression of c-myc. The most likely interpretation is that inhibition of protein tyrosine kinase activity caused a decrease in c-myc expression in these cells. The impact of tyrosine phosphorylation on the expression of the c-myc gene is further supported by the finding that inhibition of phosphotyrosine phosphatase using orthovanadate causes an increase in the level of c-myc RNA. The effect of genistein on HCT8 cells is not dependent on the synthesis of new protein and does not involve an alteration in the stability of the message. Analysis of transcription in the c-myc gene reveals a more complicated picture with a decrease in initiation and an increase in elongation but no net change in transcription. We speculate that the genistein induced reduction in myc expression is the result of a posttranscriptional intranuclear event(s).