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Review
. 2019 Mar 1;11(3):231-244.
doi: 10.1093/jmcb/mjz007.

The long and the short of it: the MDM4 tail so far

Sue Haupt  1   2 , Javier Octavio Mejía-Hernández  1 , Reshma Vijayakumaran  1 , Simon P Keam  1 , Ygal Haupt  1   2   3   4
Affiliations
Review

The long and the short of it: the MDM4 tail so far

Sue Haupt et al. J Mol Cell Biol. .

Erratum in

Abstract

The mouse double minute 4 (MDM4) is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight, largely due to its therapeutic possibilities. MDM4 is a vital regulator of the tumor suppressor p53. It restricts p53 transcriptional activity and also, at least in development, facilitates MDM2's E3 ligase activity toward p53. These functions of MDM4 are critical for normal cell function and a proper response to stress. Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer. MDM4 tails are vital for its function, where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2. In this review, we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dysregulation in disease.

Keywords: MDM2; MDM4; MDM4-FL; MDM4-S; MDMX; cancer; p53.

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Figures

Figure 1
Figure 1
MDM4 regulates p53 at three key levels. (A) MDM4 binds to wt p53 and inhibits its transcriptional activity in normal cells and when MDM4 is elevated in cancers. (B) MDM4 promotes MDM2 E3 ligase activity towards p53 during development. (C) MDM4 and also MDM2 promote p53 translation from its IRES in response to stress.
Figure 2
Figure 2
MDM4 structure is subject to extensive post-transcriptionally modification. Human MDM4 is comprised of an N-terminal p53-binding domain, a central domain with an acidic region and a Zn finger, and a C-terminal RING domain. MDM4 undergoes post-transcriptional phosphorylations, which are designated by ‘P’, at either tyrosine ‘Y’ or serine ‘S’. The specific kinases (orange color) and phosphatase (mauve color) that modify MDM4 dictate its activity temporarily and spatially.
Figure 3
Figure 3
MDM4 is an emerging therapeutic target in cancer. Two primary approaches are to (A) interrupt its engagement of p53 using small molecules and stapled peptides and (B) reduce MDM4 expression levels by interfering with its splicing to force the expression of its unstable isoform MDM-S.
See this image and copyright information in PMC

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