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

The Journal of clinical investigation (2017-08-29)
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
RESUMEN

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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Anti-Actin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
Nutlin-3a, ≥98% (HPLC)
Sigma-Aldrich
Nutlin-3, ≥98% (HPLC), powder
Sigma-Aldrich
Anti-γ-Tubulin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Magnesium methyl carbonate solution, 2.0 M in DMF
Sigma-Aldrich
Monoclonal Anti-MDM2 antibody produced in mouse, clone SMP14, ascites fluid

Redes sociales

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon

Merck

Investigación. Desarrollo. Producción.

Somos un proveedor líder para la industria de Ciencias de la Vida con soluciones y servicios para investigación, desarrollo y producción biotecnológicos, y para desarrollo y producción de tratamientos farmacéuticos

© 2021 Merck KGaA, Darmstadt, Alemania y/o sus filiales. Todos los derechos reservados.

Queda estrictamente prohibida la reproducción sin permiso de cualquiera de los materiales de la página web.