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Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes

G J Ortiz1,2, Y Li3, S M Post4

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Oncogene
|September 20, 2017
PubMed

Insights

The MDM2 SNP309G polymorphism influences cancer risk differently across tissues. It exacerbates tumor development with radiation but protects against skin cancer, regulated by E2F6 in a tissue-specific manner.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • MDM2 is an E3 ubiquitin ligase inhibiting the p53 tumor suppressor, frequently elevated in human cancers.
  • The MDM2 SNP309G polymorphism increases MDM2 levels, reducing p53 activity and impacting tumor development.
  • Mdm2SNP309G/G mice show increased spontaneous tumor formation compared to Mdm2SNP309T/T mice.

Purpose of the Study:

  • To investigate the tissue-specific effects of the MDM2 SNP309G polymorphism on tumor susceptibility.
  • To determine how environmental factors interact with MDM2 SNP309G in cancer development.
  • To elucidate the molecular mechanisms underlying the tissue-specific regulation of MDM2 by SNP309G.

Main Methods:

  • Comparative analysis of tumor development in Mdm2SNP309G/G and Mdm2SNP309T/T mice under various conditions (spontaneous, ionizing radiation, UVB, Benzo(a)pyrene).
  • Assessment of MDM2 expression levels across different tissues in both mouse genotypes.
  • Utilizing the ENCODE ChIP-seq database to identify potential transcriptional regulators of MDM2, followed by experimental validation.

Main Results:

  • MDM2 SNP309G exacerbates tumor development with ionizing radiation but protects against skin squamous cell carcinoma induced by UVB or Benzo(a)pyrene.
  • Basal MDM2 levels are higher in most tissues of Mdm2SNP309G/G mice, but paradoxically lower in keratinocytes.
  • The transcriptional repressor E2F6 was identified and shown to suppress MDM2 expression specifically in cells with the SNP309G allele.

Conclusions:

  • MDM2 SNP309G exhibits significant tissue-specific regulation of MDM2 expression and differential impact on cancer risk.
  • The interaction between E2F6 and the MDM2 promoter in the context of SNP309G explains the contrasting susceptibility observed in different tissues.
  • Understanding these tissue-specific mechanisms is crucial for targeted cancer prevention and treatment strategies.

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