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Dysfunction of the MDM2/p53 axis is linked to premature aging
Davor Lessel, … , Carol Prives, Christian Kubisch
Davor Lessel, … , Carol Prives, Christian Kubisch
Published August 28, 2017
Citation Information: J Clin Invest. 2017;127(10):3598-3608. https://doi.org/10.1172/JCI92171.
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Concise Communication Aging Genetics

Dysfunction of the MDM2/p53 axis is linked to premature aging

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Abstract

The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient’s primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation’s aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.

Authors

Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, Christian Kubisch

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Figure 5

Impaired function of the antiterminating Mdm2 mutation in a zebrafish model.

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Impaired function of the antiterminating Mdm2 mutation in a zebrafish mo...
Complementation assay in 10 hpf zebrafish embryos (tailbud stage). (A) Representative images of the lateral view of 10 hpf zebrafish embryos stained with TUNEL. Embryos were classified by the number of TUNEL-positive foci as follows: class I (0–10); class II (10–20); class III (20–40); and class IV (>40). (B and C) Percentage of TUNEL-positive foci of various apoptosis classes of embryos injected with 3 ng Mdm2 morpholino and coinjections of 40 pg mdm2 mRNAs and of embryos injected with p53 RNA and coinjections of 40 pg mdm2 mRNAs (right panel). NI, noninjected embryos; MO, embryos injected with Mdm2 morpholino; p53, embryos injected with p53 mRNA; + WT, coinjection of mdm2-WT; + MUT, coinjection of mdm2 bearing the antiterminating mutation. Data represent 3 independent experiments (2-sample Poisson tests).
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