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.