The promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, induces cellular resistance to oncogenic transformation by diverse oncoproteins. Two point mutants of PLZF that have lost the antioncogenic activity of the wild-type protein are oncogenic in chicken embryo fibroblasts; this activity is correlated with differential effects on Myc. Wild-type PLZF represses Myc transcription without affecting total Myc protein levels and reduces the levels of phosphorylated Myc. The PLZF mutants do not alter Myc transcription or protein expression but increase the levels of phosphorylated Myc. These modifications of Myc are correlated with PLZF-induced changes in Akt and the mitogen-activated protein kinase (MAPK) pathway. Wild-type PLZF downregulates the MAPK pathway and activates Akt, resulting in reduced phosphorylation on serine 62 of Myc by Erk and on threonine 58 by glycogen synthase kinase 3beta. The mutants fail to activate Akt and only slightly downregulate phospho-Erk. We postulate that the 2 PLZF mutants are oncogenic, because they function as dominant negatives of wild-type PLZF, enhancing Myc phosphorylation and increasing Myc transcriptional and oncogenic activity. In support of this suggestion, a specific inhibitor of Myc is able to revert the transformed phenotype of PLZF mutant-expressing cells.