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

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Dysfunction of the MDM2/p53 axis is linked to premature aging. / Lessel, Davor; Wu, Danyi; Trujillo, Carlos; Ramezani, Thomas; Lessel, Ivana; Alwasiyah, Mohammad K; Saha, Bidisha; Hisama, Fuki M; Rading, Katrin; Goebel, Ingrid; Schütz, Petra; Speit, Günter; Högel, Josef; Thiele, Holger; Nürnberg, Gudrun; Nürnberg, Peter; Hammerschmidt, Matthias; Zhu, Yan; Tong, David R; Katz, Chen; Martin, George M; Oshima, Junko; Prives, Carol; Kubisch, Christian.

in: J CLIN INVEST, Jahrgang 127, Nr. 10, 02.10.2017, S. 3598-3608.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Lessel, D, Wu, D, Trujillo, C, Ramezani, T, Lessel, I, Alwasiyah, MK, Saha, B, Hisama, FM, Rading, K, Goebel, I, Schütz, P, Speit, G, Högel, J, Thiele, H, Nürnberg, G, Nürnberg, P, Hammerschmidt, M, Zhu, Y, Tong, DR, Katz, C, Martin, GM, Oshima, J, Prives, C & Kubisch, C 2017, 'Dysfunction of the MDM2/p53 axis is linked to premature aging', J CLIN INVEST, Jg. 127, Nr. 10, S. 3598-3608. https://doi.org/10.1172/JCI92171

APA

Lessel, D., Wu, D., Trujillo, C., Ramezani, T., Lessel, I., Alwasiyah, M. K., Saha, B., Hisama, F. M., Rading, K., Goebel, I., Schütz, P., Speit, G., Högel, J., Thiele, H., Nürnberg, G., Nürnberg, P., Hammerschmidt, M., Zhu, Y., Tong, D. R., ... Kubisch, C. (2017). Dysfunction of the MDM2/p53 axis is linked to premature aging. J CLIN INVEST, 127(10), 3598-3608. https://doi.org/10.1172/JCI92171

Vancouver

Lessel D, Wu D, Trujillo C, Ramezani T, Lessel I, Alwasiyah MK et al. Dysfunction of the MDM2/p53 axis is linked to premature aging. J CLIN INVEST. 2017 Okt 2;127(10):3598-3608. https://doi.org/10.1172/JCI92171

Bibtex

@article{062450b11ec545d085f1d779ebca82c3,
title = "Dysfunction of the MDM2/p53 axis is linked to premature aging",
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.",
keywords = "Journal Article",
author = "Davor Lessel and Danyi Wu and Carlos Trujillo and Thomas Ramezani and Ivana Lessel and Alwasiyah, {Mohammad K} and Bidisha Saha and Hisama, {Fuki M} and Katrin Rading and Ingrid Goebel and Petra Sch{\"u}tz and G{\"u}nter Speit and Josef H{\"o}gel and Holger Thiele and Gudrun N{\"u}rnberg and Peter N{\"u}rnberg and Matthias Hammerschmidt and Yan Zhu and Tong, {David R} and Chen Katz and Martin, {George M} and Junko Oshima and Carol Prives and Christian Kubisch",
year = "2017",
month = oct,
day = "2",
doi = "10.1172/JCI92171",
language = "English",
volume = "127",
pages = "3598--3608",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

RIS

TY - JOUR

T1 - Dysfunction of the MDM2/p53 axis is linked to premature aging

AU - Lessel, Davor

AU - Wu, Danyi

AU - Trujillo, Carlos

AU - Ramezani, Thomas

AU - Lessel, Ivana

AU - Alwasiyah, Mohammad K

AU - Saha, Bidisha

AU - Hisama, Fuki M

AU - Rading, Katrin

AU - Goebel, Ingrid

AU - Schütz, Petra

AU - Speit, Günter

AU - Högel, Josef

AU - Thiele, Holger

AU - Nürnberg, Gudrun

AU - Nürnberg, Peter

AU - Hammerschmidt, Matthias

AU - Zhu, Yan

AU - Tong, David R

AU - Katz, Chen

AU - Martin, George M

AU - Oshima, Junko

AU - Prives, Carol

AU - Kubisch, Christian

PY - 2017/10/2

Y1 - 2017/10/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/JCI92171

DO - 10.1172/JCI92171

M3 - SCORING: Journal article

C2 - 28846075

VL - 127

SP - 3598

EP - 3608

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 10

ER -