Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation.

Given that expression of c-Myc is up-regulated in many human malignancies, targeted inactivation of this oncoprotein is a potentially effective strategy for cancer treatment. The ubiquitin-proteasome pathway of protein degradation is highly specific and can be engineered to achieve the elimination of undesirable proteins such as oncogene products. We have ...
now generated a fusion protein (designated Max-U) that is composed both of Max, which forms a heterodimer with c-Myc, and of CHIP, which is a U box-type ubiquitin ligase (E3). Max-U physically interacted with c-Myc in transfected cells and promoted the ubiquitylation of c-Myc in vitro. It also reduced the stability of c-Myc in vivo, resulting in suppression of transcriptional activity dependent on c-Myc. Expression of Max-U reduced both the abundance of endogenous c-Myc in and the proliferation rate of a Burkitt lymphoma cell line. Furthermore, expression of Max-U but not that of a catalytically inactive mutant thereof markedly inhibited both the anchorage-independent growth in vitro of NIH 3T3 cells that overexpress c-Myc as well as tumor formation by these cells in nude mice. These findings indicate that the targeted destruction of c-Myc by an artificial E3 may represent an effective therapeutic strategy for certain human malignancies.
Mesh Terms:
Animals, Burkitt Lymphoma, Cell Transformation, Neoplastic, Cloning, Molecular, Hela Cells, Humans, Mice, Mice, Nude, NIH 3T3 Cells, Protein Engineering, Proto-Oncogene Proteins c-myc, Recombinant Fusion Proteins, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
Cancer Res.
Date: Sep. 01, 2005
Download Curated Data For This Publication
Switch View:
  • Interactions 2