UXT interacts with the transcriptional repressor protein EVI1 and suppresses cell transformation

The EVII transcriptional repressor is critical to the normal development of a variety of tissues and participates in the progression of acute myeloid leukaemias. The repressor domain (Rp) was used to screen an adult human kidney yeast two-hybrid library and a novel binding partner designated ubiquitously expressed transcript (UXT) was isolated. Enforced expression of UXT in Evil-expressing Rat1 fibroblasts suppresses cell transformation and UXT may therefore be a negative regulator of Evil biological activity. The Rp-binding site for UXT was determined and non-UXT-binding Evil mutants (Evil Delta 706-707) were developed which retain the ability to bind the corepressor mCtBP2. Evil Delta 706-707 transforms Rat1 fibroblasts, showing that the interaction is not essential for Evil-mediated cell transformation. However, EvilA706-707 produces an increased proportion of large colonies relative to wild-type, showing that endogenous UXT has an inhibitory effect on Evil biological activity. Exogenous UXT still suppresses Evi1 Delta 706-707-mediated cell transformation, indicating that it inhibits cell proliferation and/or survival by both Evil-dependent and Evil-independent mechanisms. These observations are consistent with the growth-suppressive function attributed to UXT in human prostate cancer. Our results show that UXT suppresses cell transformation and might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like Evil.