MDM4, also known as MDMX or HDMX, is a crucial negative regulator of the tumor suppressor p53 [5,6,7]. It restricts p53 transcriptional activity and, at least in development, aids MDM2's E3 ligase activity towards p53, which is vital for normal cell function and the stress response [6]. Its dysregulation is associated with cancer due to its role in cell proliferation, DNA repair, and apoptosis regulation [1].

MDM4 overexpression and amplification can lead to cancer formation, metastasis, and poor prognosis [1]. It is frequently amplified and upregulated in human cancers, blocking the expression of p53 pathway downstream target genes to promote overgrowth and inhibit apoptosis [2]. Some MDM4 SNPs in non-coding regions can disrupt microRNA binding in the 3'UTR, affecting its regulation, though studies on the association between MDM4 SNPs and cancer risk in different populations have had conflicting results [1]. MDM4 also inhibits ferroptosis in p53 mutant colon cancer by regulating TRIM21/GPX4 expression, promoting cancer progression [3]. Additionally, pharmacological inhibition of MDM4 alleviates pulmonary fibrosis, as the inhibitor XI-011 reduces MDM4 expression and increases p53 expression in relevant models [4].

In summary, MDM4 is a key negative regulator of p53, and its dysregulation is involved in cancer and pulmonary fibrosis. Research on MDM4, including through studies of its SNPs and inhibition, provides insights into disease mechanisms and potential therapeutic strategies for these conditions.

References:

1. Almeida, Gabriela Mattevi, Castilho, Ana Clara, Adamoski, Douglas, Braun-Prado, Karin. 2022. MDM4: What do we know about the association between its polymorphisms and cancer? In Medical oncology (Northwood, London, England), 40, 61. doi:10.1007/s12032-022-01929-z. https://pubmed.ncbi.nlm.nih.gov/36566308/

2. Wu, Jin, Lu, Guanting, Wang, Xinjiang. 2021. MDM4 alternative splicing and implication in MDM4 targeted cancer therapies. In American journal of cancer research, 11, 5864-5880. doi:. https://pubmed.ncbi.nlm.nih.gov/35018230/

3. Liu, Jie, Wei, Xujin, Xie, Yixuan, Zheng, Xiaoling, Huang, Qingling. 2024. MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression. In Cell death & disease, 15, 825. doi:10.1038/s41419-024-07227-y. https://pubmed.ncbi.nlm.nih.gov/39543140/

4. Mei, Qianru, Yang, Zhenhua, Xiang, Zhengkai, Zhou, Yong, Qu, Jing. 2023. Pharmacological inhibition of MDM4 alleviates pulmonary fibrosis. In Theranostics, 13, 2787-2799. doi:10.7150/thno.81993. https://pubmed.ncbi.nlm.nih.gov/37284444/

5. Markey, Michael P. 2011. Regulation of MDM4. In Frontiers in bioscience (Landmark edition), 16, 1144-56. doi:. https://pubmed.ncbi.nlm.nih.gov/21196223/

6. Haupt, Sue, Mejía-Hernández, Javier Octavio, Vijayakumaran, Reshma, Keam, Simon P, Haupt, Ygal. . The long and the short of it: the MDM4 tail so far. In Journal of molecular cell biology, 11, 231-244. doi:10.1093/jmcb/mjz007. https://pubmed.ncbi.nlm.nih.gov/30689920/

7. Mancini, F, Di Conza, G, Monti, O, Pontecorvi, A, Moretti, F. 2010. Puzzling over MDM4-p53 network. In The international journal of biochemistry & cell biology, 42, 1080-3. doi:10.1016/j.biocel.2010.04.010. https://pubmed.ncbi.nlm.nih.gov/20417304/