TY - JOUR
T1 - Tissue-specific and age-dependent effects of global Mdm2 loss
AU - Zhang, Yun
AU - Xiong, Shunbin
AU - Li, Qin
AU - Hu, Sophia
AU - Tashakori, Mehrnoosh
AU - Van Pelt, Carolyn
AU - You, Mingjian James
AU - Pageon, Laura
AU - Lozano, Guillermina
PY - 2014/8
Y1 - 2014/8
N2 - Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2FM, 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 Mdm2FM/-;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) Mdm2FM/-;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 Mdm2FM/-;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.
AB - Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2FM, 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 Mdm2FM/-;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) Mdm2FM/-;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 Mdm2FM/-;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.
KW - Mdm2
KW - Tp53
KW - cancer therapy
KW - radio-insensitive tissues
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U2 - 10.1002/path.4368
DO - 10.1002/path.4368
M3 - Article
C2 - 24789767
AN - SCOPUS:84904267177
SN - 0022-3417
VL - 233
SP - 380
EP - 391
JO - Journal of Pathology
JF - Journal of Pathology
IS - 4
ER -