Department of Medical and Molecular Genetics, Oregon Health and Science University, Portland, Oregon 97239, USA.
J Biol Chem. 2010 Feb 12;285(7):4847-58. doi: 10.1074/jbc.M109.074856. Epub 2009 Dec 11.
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.
c-Myc 是一种重要的转录因子，可调节细胞增殖、细胞生长和分化。已经描述了许多 c-Myc 的转录共因子，它们在 c-Myc 反式激活结构域（TAD）的高度保守区域内具有结合位点。鉴于 c-Myc TAD 的重要性，我们着手使用酵母双杂交测定法鉴定与该区域相互作用的新蛋白质。在我们的筛选中，HBP1 被鉴定为与全长 c-Myc 相互作用但不与缺乏 TAD 的 c-Myc 突变体相互作用的蛋白质。HBP1 是一种转录抑制剂，已被证明可负调控细胞周期。已经描述了 HBP1 低表达与乳腺癌复发之间的相关性，这表明 HBP1 可能是一种重要的肿瘤抑制蛋白。我们发现 HBP1 在细胞中与 c-Myc 结合，并且 HBP1 的表达通过阻止 c-Myc 与靶基因启动子结合至少部分抑制 c-Myc 的反式激活活性。c-Myc 结合到 HBP1 的 C 末端，一些乳腺癌中丢失了这一区域，一些在乳腺癌中发现的 HBP1 突变体与 c-Myc 的相互作用较弱，或者不再对 c-Myc 起负调控作用。这项工作增加了我们对 c-Myc 调控和 HBP1 肿瘤抑制机制的理解。
