TRANSACTIVATION OF THE HUMAN P53 TUMOR-SUPPRESSOR GENE BY C-MYC MAX CONTRIBUTES TO ELEVATED MUTANT P53 EXPRESSION IN SOME TUMORS/

Elevated levels of mutant forms of the p53 tumor suppressor are a hall mark of many transformed cells. Multiple mechanisms such as increased stability of the protein and increased transcription of the gene can a ccount for elevated p53 expression. Recent findings indicate that c-My c/Max heterodimers can bind to an essential CA(C/T)GTG-containing site in the p53 promoter and elevate its expression. We have addressed the possibility that elevated mutant p53 expression is due to deregulated c-Myc expression. Here we demonstrate that the human p53 promoter is transactivated by high c-Myc expression and repressed by high Max expr ession. In examining the relative levels of c-Myc and p53 in human Bur kitt's lymphomas and other B-lymphoid lines, we found that there is a correlation between the levels of c-Myc protein and p53 mRNA expressio n. In particular, cells that express very low levels of c-Myc protein also express low levels of p53 mRNA, while cells that express high lev els of c-Myc tend to express high levels of p53 mRNA. To determine whe ther the p53 gene can be a target for c-Myc in vivo, we assayed the ef fects of antisense c-myc RNA on the levels of endogenous p53 mRNA. The results indicate that the presence of antisense c-myc RNA leads to a reduction in the levels of c-Myc protein, p53 mRNA, and expression fro m the p53 promoter. Taken together, our findings support a direct role for c-Myc in elevating expression of the mutant p53 gene in some tumo rs.