FBXO46 negatively regulates p53 activity by stabilizing Mdm2.

The tumor suppressor p53 plays a central role in suppressing tumor formation. Mouse double minute 2 homolog (Mdm2) serves as the principal ubiquitin E3 ligase responsible for the ubiquitination and subsequent degradation of p53. However, the regulatory mechanisms governing the Mdm2-p53 pathway are not comprehensively understood. Here, we report that F-box only protein 46 (FBXO46) directly binds to Mdm2 and inhibits its self-ubiquitination and degradation, leading to Mdm2 stabilization and subsequent Mdm2-mediated ubiquitination and degradation of p53. Functionally, FBXO46 promotes cell proliferation, accelerates G1/S cell cycle progression, and increases anchorage-independent cell growth by inhibiting p53. Collectively, these findings reveal a critical role for FBXO46 in controlling Mdm2 stability and establish FBXO46 as an important regulator of the Mdm2-p53 pathway.