The Molecular Mechanisms Of The Regulation Of P53 By REGγ And Its Role In Tumor Development

The proteasome activator REGγhas been demonstrated to mediate a shortcut to destruction of intact mammalian proteins. Yet the biological roles of REGy and underlying mechanisms are not fully understood. Here we provide evidence, in vitro and in cells, that REGy regulates p53 cellular distribution by facilitating multiple monoubiquitination of p53. While p53 get the Mdm2-dependent monoubiquitination promotes canonical nuclear export and subsequent degradation, inhibition of p53 tetramerization by REGγmay further enhance cytoplasmic relocation of p53 and reduce p53 activity in nucleus. Furthermore, multiple monoubiquitination of p53 enhances its physical interaction with Mdm2 and likely facilitates subsequent polyubiquitination of p53, suggesting a role of monoubiquitination as asignal for p53 degradation. Depletion of REGy sensitizes cells to stress-induced apoptosis, validating its critical role in the control of apoptosis likely through regulating p53 function. Using a mouse xenograft model, we show that REGy knockdown results in a significant reduction of tumor growth, suggesting an important role for REGγin tumor development. Taken together, our study demonstrates REGγ-mediated inactivation of p53 as one of the mechanisms in cancer progression.