The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc

• DOI: 10.1038/emboj.2008.279
• Publication Date: 2009-01-08T16:19:47Z
• Authors: Hugh K Arnold; Xiaoli Zhang; Colin J Daniel; Deanne Tibbitts; Julie Escamilla-P...; Amy Farrell; Sara Tokarz; Charlie Morgan; Rosalie C Sears
• Keywords: Transcriptional Activation; Glycogen Synthase Kinase 3 beta; Tumor Suppressor Proteins; Ubiquitination; Peptidylprolyl Isomerase; Cell Line; Protein Structure, Tertiary; 3. Good health; NIMA-Interacting Peptidylprolyl Isomerase; Proto-Oncogene Proteins c-myc; Repressor Proteins; Glycogen Synthase Kinase 3; Axin Protein; E2F2 Transcription Factor; Humans; Protein Phosphatase 2; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Signal Transduction

Expression of the c-Myc proto-oncoprotein is tightly regulated in normal cells. Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62), regulates c-Myc protein stability. In cancer cells, c-Myc can become aberrantly stabilized associated with altered T58 and S62 phosphorylation. A complex signalling cascade involving GSK3beta kinase, the Pin1 prolyl isomerase, and the PP2A-B56alpha phosphatase controls phosphorylation at these sites. We report here a novel role for the tumour suppressor scaffold protein Axin1 in facilitating the formation of a degradation complex for c-Myc containing GSK3beta, Pin1, and PP2A-B56alpha. Although knockdown of Axin1 decreases the association of c-Myc with these proteins, reduces T58 and enhances S62 phosphorylation, and increases c-Myc stability, acute expression of Axin1 reduces c-Myc levels and suppresses c-Myc transcriptional activity. Moreover, the regulation of c-Myc by Axin1 is impaired in several tested cancer cell lines with known stabilization of c-Myc or loss of Axin1. This study provides critical insight into the regulation of c-Myc expression, how this can be disrupted in three cancer types, and adds to our knowledge of the tumour suppressor activity of Axin1.