Regulation of the Mdm2–p53 pathway by the ubiquitin E3 ligase MARCH 7

Jan 4, 2018EMBO reports

Control of the Mdm2-p53 protein system by the cellular regulator MARCH7

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Abstract

MARCH7 is essential for maintaining the stability of the Mdm2 protein, which regulates the tumor suppressor p53.

MARCH7 interacts physically with Mdm2, a key regulator of p53.
MARCH7 catalyzes the addition of chains of ubiquitin to Mdm2, preventing its self-destruction.
The stabilization of Mdm2 by MARCH7 results in enhanced degradation of p53.
MARCH7 influences cell growth, responses to DNA damage, and the development of tumors through a mechanism involving p53.
These findings suggest a novel regulatory role for MARCH7 in the Mdm2-p53 pathway.

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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 Lys-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. 63

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