Protein stabilization : a common consequence of mutations in independently derived v-Myc alleles

• Published in: Oncogene Vol. 18; no. 52; pp. 7552 - 7558
• Main Authors: GAVINE, P. R, NEIL, J. C, CROUCH, D. H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 09.12.1999; Nature Publishing Group
• Subjects: Alleles; Amino Acid Motifs; Animals; Avian Leukosis Virus - genetics; Biological and medical sciences; Butadienes - pharmacology; c-myc gene; c-Myc protein; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Viral; Chick Embryo; Cysteine Endopeptidases - metabolism; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fos protein; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene rearrangement; Genes, myc; Jun protein; Leukemia Virus, Feline - genetics; MAP Kinase Signaling System - drug effects; Molecular and cellular biology; Multienzyme Complexes - metabolism; Mutation; Myb protein; Myc gene; Myc protein; Nitriles - pharmacology; Oncogene Protein p55(v-myc) - genetics; Oncogene Protein p55(v-myc) - metabolism; Phenotypes; Phosphorylation; Proteasome Endopeptidase Complex; Proteasomes; Protein turnover; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Threonine - metabolism; Tumors; Ubiquitin; V-myc gene; V-Myc protein; Stabilization; Retroviridae; V-Onc gene; Carcinogenesis; Virus; Vertebrata; Cell line; Tumor progression; Avian leukosis virus; Avian type C retrovirus; Chicken; Mutation; Aves; Transcription factor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203102

Myc is overexpressed in many cancers as a result of gene rearrangement or amplification, but coding sequence changes which cluster in the N-terminal transactivation domain also appear to play a role in tumour progression. The prototypic v-Myc gene of MC29 virus differs from avian c-Myc by a series of mutations, including a change at a regulatory phosphorylation site within the mutational hotspot (thr-61) which is known to potentiate transformation in vitro. We now show that the mutation at thr-61 stabilizes the v-Myc protein (turnover difference) and that this single mutation is both necessary and sufficient for the phenotype. A major involvement of the proteasome in Myc degradation was confirmed, but surprisingly, a dilysine motif adjacent to thr-61 proved not to be the ubiquitin target. Two other v-Myc genes which carry a mutation at thr-61 (avian MH2) or a large deletion encompassing this domain (feline T17) were found to be stabilized to a similar extent as MC29, showing that stabilization is a common feature of independently derived Myc oncogenes. These results suggest a common selective process in the genesis of these three viral oncoproteins and a mechanistic link with Jun, Fos and Myb oncoproteins which are also stabilized relative to their cellular counterparts.