A PATHWAY OF TUMOR SUPPRESSION

Summary

Principal Investigator: Guillermina Lozano
Affiliation: The University of Texas
Country: USA
Abstract: Cancer develops by the accumulation of numerous mutations that usurp signaling, proliferation, and apoptotic pathways. Specifically, the p53 pathway is disrupted in the majority of cancers. Multiple mechanisms inactivate this pathway including mutations of the p53 gene itself and overexpression of the MDM2 and MDM4 genes which encode inhibitors of p53. Using mouse models, we have shown the functional importance of Mdm2 and Mdm4, an Mdm2-related protein, as inhibitors of p53 activity. Deletion of Mdm2 or Mdm4 in mice causes an embryo lethal phenotype that is completely rescued by concomitant deletion of p53. Additionally, mice heterozygous for Mdm2 or Mdm4 show increased p53 activity in response to ionizing radiation suggesting that even two fold differences in p53 inhibitors may affect tumor onset. Such two fold changes in MDM2 or MDM4 levels may affect tumor incidence in humans as an MDM2 polymorphism that increases MDM2 levels is associated with earlier age of onset of cancer. In response to DNA damage, the Mdm2 gene is also alternatively spliced to generate small Mdm2 isoforms that inhibit Mdm2 and thus activate p53. The role of these isoforms in tumorigenesis is controversial. We will test the hypothesis that alterations in the levels of the p53 inhibitors Mdm2 and Mdm4 affect the timing of tumor onset and the kinds of tumors that develop. First, we plan to examine the effects of Mdm2 or Mdm4 haploinsufficiency in tumor prone mice with p53 or K-ras mutations. We will generate a mouse model that cannot make the Mdm2 isoforms to examine effects on tumorigenesis. We will also characterize transgenic mice that overexpress Mdm4 to examine its role in tumorigenesis. Lastly, we will examine the relationship of Mdm2 and Mdm4 in inhibition of p53 by replacing the Mdm2 gene with the Mdm4 gene.
Funding Period: ----------------1988 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Mdm2 and Mdm4 loss regulates distinct p53 activities
    Juan A Barboza
    Department of Cancer Genetics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 4095, USA
    Mol Cancer Res 6:947-54. 2008
  2. pmc The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival
    Y A Valentin-Vega
    Department of Genetics, Program in Genes and Development, The Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Cell Death Differ 15:1772-81. 2008
  3. pmc Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4
    Shunbin Xiong
    Departments of Genetics and Veterinary Medicine and Surgery, The University of Texas M D Anderson Cancer Center Houston, TX 77030, USA
    Cancer Res 70:7148-54. 2010
  4. pmc Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy
    Qin Li
    Department of Genetics, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Clin Cancer Res 19:34-41. 2013
  5. pmc The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity
    Vinod Pant
    Department of Genetics
    Genes Dev 27:1857-67. 2013
  6. pmc Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors
    Qin Li
    Authors Affiliations Department of Genetics, Program in Genes and Development, Graduate School of Biomedical Sciences, and
    Mol Cancer Res 12:901-11. 2014
  7. pmc A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development
    Sean M Post
    Department of Genetics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Cell 18:220-30. 2010

Detail Information

Publications7

  1. pmc Mdm2 and Mdm4 loss regulates distinct p53 activities
    Juan A Barboza
    Department of Cancer Genetics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 4095, USA
    Mol Cancer Res 6:947-54. 2008
    ..Additionally, stabilization of p53 in cells lacking Mdm4 with the Mdm2 antagonist nutlin-3 was sufficient to induce a cell death response. These data further differentiate the roles of Mdm2 and Mdm4 in the regulation of p53 activities...
  2. pmc The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival
    Y A Valentin-Vega
    Department of Genetics, Program in Genes and Development, The Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Cell Death Differ 15:1772-81. 2008
    ..While Mdm2 is a critical inhibitor of p53 in the intestinal epithelium, the tissue employs a series of processes that compensate for cell death...
  3. pmc Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4
    Shunbin Xiong
    Departments of Genetics and Veterinary Medicine and Surgery, The University of Texas M D Anderson Cancer Center Houston, TX 77030, USA
    Cancer Res 70:7148-54. 2010
    ..Mdm4 is thus a bona fide oncogene in vivo and cooperates with p53 heterozygosity to drive tumorigenesis. These Mdm4 mice will be invaluable for in vivo drug studies of Mdm4 inhibitors...
  4. pmc Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy
    Qin Li
    Department of Genetics, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Clin Cancer Res 19:34-41. 2013
    ..Antitumor activities of these molecules have already been confirmed in preclinical studies and early-phase clinical trials. These research endeavors and clinical advances constitute the main focus of this review...
  5. pmc The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity
    Vinod Pant
    Department of Genetics
    Genes Dev 27:1857-67. 2013
    ..Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies...
  6. pmc Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors
    Qin Li
    Authors Affiliations Department of Genetics, Program in Genes and Development, Graduate School of Biomedical Sciences, and
    Mol Cancer Res 12:901-11. 2014
    ..Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the Mdm2-overexpressing angiosarcomas...
  7. pmc A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development
    Sean M Post
    Department of Genetics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Cell 18:220-30. 2010
    ..These data provide causal evidence for increased cancer risk in carriers of the Mdm2(SNP309G) allele...