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

Sue Haupt,Simon P Keam,Ygal Haupt,Javier Octavio Mejía-Hernández,Reshma Vijayakumaran

doi:10.1093/jmcb/mjz007

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.

Highlights

mouse double minute 4 (MDM4) regulation of p53 The pioneering discovery of MDM4 was made in mice by the Jochemsen group (Shvarts et al, 1996)
MDM4 was identified by its engagement with the major tumor suppressor protein p53 and named through its structural similarity with MDM2; with the two forming a family (Shvarts et al, 1996). p53 is a transcription factor that acts as a fundamental determinant of cell fate in response to cellular stress (Kastenhuber and Lowe, 2017). p53 activities were originally shown to be strictly controlled by its major E3 ligase MDM2 (Haupt et al, 1997; Kubbutat et al, 1997; Honda and Yasuda, 2000)
Evidence that MDM4 critically influences p53 function during development was provided by the demonstration that its absence causes embryo lethality, which is rescued by elimination of p53

Summary

Introduction

MDM4 regulation of p53 The pioneering discovery of MDM4 was made in mice by the Jochemsen group (Shvarts et al, 1996). These studies identify p53 translation as a chronologically early response to increase levels of newly synthesized p53 protein, in a process critically regulated by MDM4, in conjunction with MDM2 (Malbert-Colas et al, 2014). The 75-kDa isoform, which inhibits p53 transcriptional activity, would be predicted to pose a particular cancer risk in a wt p53 context.

Results

Conclusion