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Tissue‐specific and age‐dependent effects of global Mdm2 loss
Author(s) -
Zhang Yun,
Xiong Shunbin,
Li Qin,
Hu Sophia,
Tashakori Mehrnoosh,
Van Pelt Carolyn,
You Mingjian James,
Pageon Laura,
Lozano Guillermina
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4368
Subject(s) - mdm2 , tamoxifen , biology , senescence , ubiquitin ligase , cancer research , kidney , phenotype , suppressor , puma , antiestrogen , cancer , ubiquitin , pathology , medicine , endocrinology , breast cancer , apoptosis , microbiology and biotechnology , genetics , gene
Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2 FM , and a CAG–CreER tamoxifen‐inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2 FM /− ; CAG–CreER mice; both radio‐sensitive and radio‐insensitive tissues were impaired. Strikingly, a large number of radio‐insensitive tissues, including the kidney, liver, heart, retina and hippocampus, exhibited various pathological defects. Similar tamoxifen injections in older (16–18 month‐old) Mdm2 FM /− ; CAG–CreER mice yielded abnormalities only in the kidney. In addition, transcriptional activation of Cdkn1a ( p21 ), Bbc3 ( Puma ) and multiple senescence markers in young (2–4 month‐old) mice following loss of Mdm2 was dampened in older mice. All phenotypes were p53‐dependent, as Mdm2 FM /− ;Trp53 −/− ; CAG–CreER mice subjected to the same tamoxifen regimens were normal. Our findings implicate numerous possible toxicities in many normal tissues upon use of cancer therapies that aim to inhibit Mdm2 in tumours with wild‐type p53. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.