Rabring7 degrades c-Myc through complex formation with MM-1

Abstract

We have reported that a novel c-Myc-binding protein, MM-1, repressed E-box-dependent transcription and transforming activities of c-Myc and that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. MM-1 also binds to the ubiquitin-proteasome system, leading to degradation of c-Myc. In this study, we identified Rabring7, a Rab7-binding and RING finger-containing protein, as an MM-1-binding protein, and we found that Rabring7 mono-ubiquitinated MM-1 in the cytoplasm without degradation of MM-1. Rabring7 was also found to bind to c-Myc and to ubiquitinate c-Myc in a threonine 58-dependent manner. When c-Myc was co-transfected with MM-1 and Rabring7, c-Myc was degraded. Furthermore, it was found that c-Myc was stabilized in MM-1-knockdown cells even when Rabring7 was transfected and that Rabring7 was bound to and co-localized with MM-1 and c-Myc after MM-1 and Rabring7 had been translocated from the cytoplasm to the nucleus. These results suggest that Rabring7 stimulates c-Myc degradation via mono-ubiquitination of MM-1. © 2012 Narita et al.