The tumor suppressor protein HBP1 is a novel c-myc-binding protein that negatively regulates c-myc transcriptional activity.

c-Myc is an important transcription factor that regulates cellular proliferation, cell growth, and differentiation. A number of transcriptional co-factors for c-Myc have been described that have binding sites within highly conserved regions of the c-Myc transactivational domain (TAD). Given the importance of the c-Myc TAD, we set out to identify new proteins that interact with this region using a yeast two-hybrid assay. HBP1 was identified in our screen as a protein that interacts with full-length c-Myc but not a c-Myc mutant lacking the TAD. HBP1 is a transcriptional repressor and has been shown to negatively regulate the cell cycle. A correlation between HBP1 under-expression and breast cancer relapse has been described, suggesting that HBP1 may be an important tumor suppressor protein. We have found that HBP1 binds c-Myc in cells, and expression of HBP1 inhibits c-Myc transactivational activity at least partly by preventing c-Myc binding to target gene promoters. c-Myc binds to the C terminus of HBP1, a region lost in some breast tumors, and some HBP1 mutants found in breast cancer weakly interact with and/or no longer negatively regulate c-Myc. This work adds to our understanding of c-Myc regulation and mechanisms of tumor suppression by HBP1.