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Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4

Shunbin Xiong1, Vinod Pant, Young-Ah Suh

  • 1Departments of Genetics and Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA.

Cancer Research
|August 26, 2010
PubMed

Insights

Mdm4 protein overexpression drives tumor development in mice, acting as an oncogene. It also accelerates cancer when p53 is partially lost, highlighting Mdm4 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • High Mdm4 levels are observed in tumors with wild-type p53, suggesting Mdm4 inactivates p53 during cancer development.
  • Mdm4 is a critical inhibitor of p53, a key tumor suppressor protein.

Purpose of the Study:

  • To investigate the in vivo role of Mdm4 in tumorigenesis.
  • To determine if Mdm4 overexpression cooperates with p53 heterozygosity in cancer induction.

Main Methods:

  • Generated transgenic mice with widespread Mdm4 expression (Mdm4(Tg1) and Mdm4(Tg15) lines).
  • Created Mdm4(Tg1) p53(+/-) mice to study the combined effects of Mdm4 overexpression and p53 heterozygosity.
  • Analyzed tumor development, spectrum, and p53 allele status in generated mouse models.

Main Results:

  • Mdm4 transgenic mice developed spontaneous tumors, primarily sarcomas.
  • Mdm4(Tg1) p53(+/-) mice exhibited accelerated tumorigenesis compared to controls.
  • Mdm4(Tg1) p53(+/-) mice showed a distinct tumor spectrum (more carcinomas, fewer lymphomas) with retention of the wild-type p53 allele in most tumors.

Conclusions:

  • Mdm4 functions as a bona fide oncogene in vivo.
  • Mdm4 cooperates with p53 heterozygosity to promote tumorigenesis.
  • The generated Mdm4 mouse models are valuable for preclinical studies of Mdm4 inhibitors.

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