Protein stabilization: a common consequence of mutations in independently derived v-Myc alleles.
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.
Gavine
P R
PR
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Neil
J C
JC
Crouch
D H
DH
D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001354:Avian Leukosis Virus / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002472:Cell Transformation, Viral; D002642:Chick Embryo; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D016259:Genes, myc; D005256:Leukemia Virus, Feline / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009570:Nitriles; D016274:Oncogene Protein p55(v-myc); D011994:Recombinant Proteins; C113580:U 0126; D013912:Threonine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex