The tumor suppressor p53 plays a prominent role in the protection against 
cancer. The activity of p53 is mainly controlled by the ubiquitin E3 ligase 
Mdm2, which targets p53 for proteasomal degradation. However, the regulation of 
Mdm2 remains not well understood. Here, we show that MARCH7, a RING 
domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is 
essential for maintaining the stability of Mdm2. MARCH7 catalyzes Lys63-linked 
polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and 
degradation, thereby leading to the stabilization of Mdm2. MARCH7 also promotes 
Mdm2-dependent polyubiquitination and degradation of p53. Furthermore, MARCH7 is 
able to regulate cell proliferation, DNA damage-induced apoptosis, and 
tumorigenesis via a p53-dependent mechanism. These findings uncover a novel 
mechanism for the regulation of Mdm2 and reveal MARCH7 as an important regulator 
of the Mdm2-p53 pathway.