Document Type

Article

Publication Date

3-25-2026

Identifier

DOI: 10.3390/cancers18071059; PMCID: PMC13072321

Abstract

MDM4 (Murine Double Minute 4), also known as MDMX, is a crucial negative regulator of the tumor suppressor p53. MDM4 heterodimerizes with MDM2 to enhance MDM2-mediated ubiquitination and degradation of p53, thereby promoting tumorigenesis. Beyond its canonical role in inhibiting p53 activity, recent studies have revealed diverse p53-independent functions. MDM4 interacts with various proteins, including p73, E2F1, casein kinase 1α, PPARα, and TRIM21 to regulate cell cycle progression, β-catenin-mediated pre-leukemic progression, and ferroptosis independent of p53. In addition, MDM4 functions independently of both p53 and MDM2 by interacting with proteins, such as SMAD family members 3/4, retinoblastoma protein (pRB), p21, Nbs1 (also known as Nibrin), mTOR complex 1 (mTORC1), and the Polycomb Repressive Complexes (PRCs) complex, to control cell proliferation and survival, as well as protein degradation, double-strand break (DSB) repair, and replication fork progression. Intriguingly, multiple studies suggest that MDM4 exhibits oncogenic activity independent of p53; however, other reports highlight a potential tumor-suppressive role for MDM4 in the absence of p53. Thus, MDM4's functions extend well beyond the canonical p53-MDM2 axis. A deeper understanding of MDM4 biology may facilitate the development of novel targeted therapies for various cancers.

Journal Title

Cancers (Basel)

Volume

18

Issue

7

PubMed ID

41976281

Keywords

MDM2; MDM4; ferroptosis; independent; p53; replication fork progression; tumorigenesis

Comments

Grants and funding

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Publisher's Link: https://www.mdpi.com/2072-6694/18/7/1059

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