We have investigated the mechanisms of oncogenes regulation in human malignancies. Deregulation of the c-myc gene accompanies all cases of human Burkitt's lymphoma (BL) and therefore the mechanism underlying the transcriptional regulation of the c-myc gene in lymphoid tumors is of great importance. We have discovered a cis element located in the intron I of the human c-myc gene which binds a novel nuclear protein and we showed that this binding was abolished by point mutation present in the corresponding region in most BL DNA. We have purified and identified this Myc Intron Factor (designated M]IF-1) to be a 138 kD protein. We have also demonstrated that the 138 kD MIF-1 is a phosphoprotein and that phosphorylation of MIF-1 is required for the interaction with its recognition sequence. Functional analysis of MIF- 1 led as to the identification of additional cis element adjacent to MIF-1 binding site. We showed that the interaction between these two regions and its binding factors may be important in the control of c-myc expression and it may be perturbed in BL due to mutations frequently observed in MIF-1 binding site. Our results suggest that the intron I cis elements, the binding factors MIF- 1 and MIF-2 and the kineses which phosphorylates MIF-1 may comprise and important physiological circuit, alteration of which may perturb c-myc expression and may have malignant consequences. In addition we have studied the effect of conventional and novel cancer agents as well as differentiating agents on the function of transcription factors which regulate expression of the c-myc gene. We have shown that treatment of cells with certain pharmacological agents alters dramatically MIF-I binding pattern to the intron I cis element Understanding the process by which transcription factors regulate gene expression will allow development of reagents which could turn off uncontrolled expression of genes implicated in malignant transformation.
