Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 29, Pages 12001-12006Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1102309108
Keywords
knockin mouse model; p53 regulation
Categories
Funding
- National Natural Science Foundation of China [30871363, 81071666]
- New Century Excellent Talents in University
- Scientific Research Foundation for the Returned Overseas Chinese Scholars of State Education Ministry [NCET-08-0349]
- Ministry of Science and Technology of China [2006BAI23B02]
- E-Institutes of Shanghai Municipal Education Commission [E03003]
- National Institutes of Health [NCI R01 CA85679, RO1 CA125144]
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There are currently two distinct models proposed to explain why both MDM2 and MDMX are required in p53 control, with a key difference centered on whether these two p53 inhibitors work together or independently. To test these two competing models, we generated knockin mice expressing a point mutation MDMX mutant (C462A) that is defective in MDM2 binding. This approach allowed a targeted disassociation of the MDM2/MDMX heterocomplex without affecting the ability of MDMX to bind to p53, and while leaving the MDM2 protein itself completely untouched. Significantly, Mdmx(C462A/C462A) homozygous mice died at approximately day 9.5 of embryonic development, as the result of a combination of apoptosis and decreased cell proliferation, as shown by TUNEL and BrdU incorporation assays, respectively. Interestingly, even though the MDMX mutant protein abundance was found slightly elevated in the Mdmx(C462A/C462A) homozygous embryos, both the abundance and activity of p53 were markedly increased. A p53-dependent death was demonstrated by the finding that concomitant deletion of p53 completely rescued the embryonic lethality in Mdmx(C462A/C462A) homozygous mice. Our data demonstrate that MDM2 and MDMX function as an integral complex in p53 control, providing insights into the nonredundant nature of the function of MDM2 and MDMX.
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