Lessel, Davor ORCID: 0000-0003-4496-244X, Wu, Danyi, Trujillo, Carlos, Ramezani, Thomas ORCID: 0000-0003-4681-7844, Lessel, Ivana, Alwasiyah, Mohammad K., Saha, Bidisha, Hisama, Fuki M. ORCID: 0000-0001-7772-7855, Rading, Katrin, Goebel, Ingrid, Schuetz, Petra, Speit, Guenter, Hoegel, Josef, Thiele, Holger, Nuernberg, Gudrun, Nuernberg, Peter, Hammerschmidt, Matthias, Zhu, Yan, Tong, David R., Katz, Chen, Martin, George M., Oshima, Junko, Prives, Carol and Kubisch, Christian ORCID: 0000-0003-4220-0978 (2017). Dysfunction of the MDM2/p53 axis is linked to premature aging. J. Clin. Invest., 127 (10). S. 3598 - 3609. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lessel, DavorUNSPECIFIEDorcid.org/0000-0003-4496-244XUNSPECIFIED
Wu, DanyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trujillo, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramezani, ThomasUNSPECIFIEDorcid.org/0000-0003-4681-7844UNSPECIFIED
Lessel, IvanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alwasiyah, Mohammad K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saha, BidishaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hisama, Fuki M.UNSPECIFIEDorcid.org/0000-0001-7772-7855UNSPECIFIED
Rading, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebel, IngridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuetz, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speit, GuenterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoegel, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhu, YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tong, David R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katz, ChenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, George M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oshima, JunkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prives, CarolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
URN: urn:nbn:de:hbz:38-214606
DOI: 10.1172/JCI92171
Journal or Publication Title: J. Clin. Invest.
Volume: 127
Number: 10
Page Range: S. 3598 - 3609
Date: 2017
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UBIQUITIN LIGASE ACTIVITY; GENOMIC INSTABILITY; EMBRYONIC LETHALITY; MDM2-DEFICIENT MICE; TUMOR SUPPRESSION; WERNER-SYNDROME; P53 PROTEIN; STEM-CELLS; CANCER; MUTATIONSMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21460

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