C-MYC TRANSCRIPTIONAL REPRESSION IN CELL TRANSFORMATION

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (Applicant's Description): Deregulated expression of the c-Myc oncoprotein occurs in many human malignancies, yet the mechanisms by which c-Myc promotes tumorigenesis remain ambiguous. There is some evidence that c-Myc could effect cell transformation by functioning as a transcriptional activator of genes presumably involved in cell proliferation. Its ability to transactivate reporter genes through upstream specific DNA binding sites (CACGTG, also referred to as E-boxes) has been well-documented by several investigators. The study of c-Myc oncoprotein function has been clouded by reports of c-Myc mediated transcriptional repression, an activity of unknown biological significance. Preliminary evidence from the investigators' laboratory demonstrates that c-Myc can repress the adenoviral major late promoter through the initiation (Inr), a pyrimidine-rich promoter element that is present in many TATA-less genes. They have also observed that a portion of the amino-terminal c-Myc transactivation domain is required for the repressive activity through the Inr. A lymphoma-derived Myc mutant that bears a substitution (115-Phe) within the domain necessary for transcriptional repression is a stronger repressor of the adML promoter and confers a greater potential for anchorage-independent cell growth than wild-type c-Myc, suggesting that transcriptional repression may play a role in c-Myc mediated cell transformation in vivo. This proposal will further delineate the link between c-Myc mediated transcriptional repression through Inr and cell transformation. Several lymphoma-derived Myc proteins that contain mutations within the region required for transcriptional repression through the Inr will be examined with regard to their transcriptional activity and transformation ability. Investigation of c-Myc interaction in vivo with two putative target genes, ornithine decarboxylase (ODC) and albumin will be pursued because ODC, a growth-regulated gene, has been reported to be transactivated by c-Myc through its E-boxes whereas albumin, a gene expressed in differentiated cells, has been reported to be repressed by c-Myc through its Inr. To further establish c-Myc function in vivo, the technique of representational difference analysis will be applied to identify novel target genes that are either transactivated or repressed by c-Myc in regenerating liver, an in vivo model of cell proliferation.