Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells.
Rapid Myc protein turnover is critical for maintaining basal levels of Myc activity in normal cells and a prompt response to changing growth signals. We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), ... which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus. TRPC4AP/TRUSS suppresses Myc-mediated transactivation and transformation in a dose-dependent manner. Finally, we found that TRPC4AP/TRUSS expression is strongly down-regulated in most cancer cell lines, leading to Myc protein stabilization. These studies identify a novel pathway targeting Myc degradation that is suppressed in cancer cells.
Mesh Terms:
Cell Line, Tumor, Cullin Proteins, DNA-Binding Proteins, Down-Regulation, Hela Cells, Humans, Multiprotein Complexes, Neoplasms, Protein Stability, Proto-Oncogene Proteins c-myc, Sequence Deletion, TRPC Cation Channels, Ubiquitin-Protein Ligases
Cell Line, Tumor, Cullin Proteins, DNA-Binding Proteins, Down-Regulation, Hela Cells, Humans, Multiprotein Complexes, Neoplasms, Protein Stability, Proto-Oncogene Proteins c-myc, Sequence Deletion, TRPC Cation Channels, Ubiquitin-Protein Ligases
Genes Dev.
Date: Jun. 15, 2010
PubMed ID: 20551172
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