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.
Choi
Seung H
SH
Department of Genetics, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA.
Wright
Jason B
JB
Gerber
Scott A
SA
Cole
Michael D
MD
D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017384:Sequence Deletion; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D050052:TRPC Cation Channels; C550321:TRPC4AP protein, human; D044767:Ubiquitin-Protein Ligases