Tissue-specific and age-dependent effects of global Mdm2 loss

Yun Zhang, Shunbin Xiong, Qin Li, Sophia Hu, Mehrnoosh Tashakori, Carolyn Van Pelt, Mingjian James You, Laura Pageon, Guillermina Lozano

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)380-391
Number of pages12
JournalJournal of Pathology
Volume233
Issue number4
DOIs
StatePublished - Aug 2014
Externally publishedYes

Keywords

  • cancer therapy
  • Mdm2
  • radio-insensitive tissues
  • Tp53

Fingerprint

Dive into the research topics of 'Tissue-specific and age-dependent effects of global Mdm2 loss'. Together they form a unique fingerprint.

Cite this