Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium.

摘要: INT6/EIF3E has been implicated in breast tumorigenesis, but its functional activities remain poorly defined. We found that, repressing INT6 expression induced transformed properties normal human mammary epithelium (MCF10A); contrast, Int6 silencing apoptosis HeLa cells. As fission yeast, cells was required for assembly of active proteasomes. A reverse-phase protein array screen identified SRC3/AIB1 as one oncoprotein the level and stability which increased when silenced MCF10A Our data further show that binds SRC3 ubiquitin ligase Fbw7, thus perhaps mediating interaction between SRC3–Fbw7 Consistent with this, did not increase levels cells, have low Fbw7 levels. It is surprising however, polyubiquitylated proteins do accumulate or may even decrease Int6-silenced contain defective Considering decreased might explain this observation control role a subunit eIF3 (eukaryote translation initiation factor 3), we reduced monoubiquitin levels, correlated shift mRNAs from larger polysomes to non-translating ribosomes. In many housekeeping change. This apparent reduction genes modest synthesis rate formation large polysomes. To determine whether can selectively translation, analyzed different 5′-untranslated region reporters indeed, loss had differential effects on these reporters. Together suggest depletion blocks ubiquitin-dependent proteolysis by decreasing both proteasome machinery, leading accumulation oncoproteins, such transform epithelium. also raise possibility fine-tune controlling specific mRNAs.