INFLUENCE OF PROTEIN-TYROSINE PHOSPHORYLATION ON THE EXPRESSION OF THE C-MYC ONCOGENE IN CANCER OF THE LARGE-BOWEL

We tested the potential impact of tyrosine phosphorylation on the expr ession of the c-myc gene in two colon cancer cell lines, HCT8 and SW83 7. We found that the protein tyrosine kinase inhibitor genistein cause s a decrease in the abundance of c-myc RNA and an inhibition of prolif eration with a similar dose response. Geldanamycin, a mechanistically different tyrosine kinase inhibitor, also causes a decrease in both th e expression of c-myc RNA and proliferation. Genistein has also been f ound to inhibit topoisomerase II, but the topoisomerase II inhibitor n ovobiocin did not lower the expression of c-myc. The most likely inter pretation is that inhibition of protein tyrosine kinase activity cause d a decrease in c-myc expression in these cells. The impact of tyrosin e phosphorylation on the expression of the c-myc gene is further suppo rted by the finding that inhibition of phosphotyrosine phosphatase usi ng orthovanadate causes an increase in the level of c-myc RNA. The eff ect of genistein on HCT8 cells is not dependent on the synthesis of ne w protein and does not involve an alteration in the stability of the m essage. Analysis of transcription in the c-myc gene reveals a more com plicated picture with a decrease in initiation and an increase in elon gation but no net change in transcription. We speculate that the genis tein induced reduction in myc expression is the result of a posttransc riptional intranuclear event(s). (C) 1995 Wiley-Liss, inc.