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Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase

Cheryl A Hobbs1, Gang Wei, Karen DeFeo

  • 1Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.

Cancer Research
|August 17, 2006
PubMed

Insights

Elevated ornithine decarboxylase (ODC) and polyamines drive epithelial tumorigenesis. Increased Tip60 protein, regulated post-transcriptionally by polyamines, contributes to tumor promotion by altering gene expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Elevated ornithine decarboxylase (ODC) and polyamine synthesis are key features of epithelial tumorigenesis.
  • Histone acetyltransferase (HAT) activity is often abnormally high in skin tumors of transgenic mouse models overexpressing ODC.

Purpose of the Study:

  • To investigate the role of Tip60, a candidate enzyme for high HAT activity, in ODC-mediated tumorigenesis.
  • To explore the post-transcriptional regulation of Tip60 by polyamines and its impact on gene expression in epithelial tumors.

Main Methods:

  • Analysis of Tip60 protein and splice variant Tip53 levels in K6/ODC and ODC/Ras transgenic mouse skin and tumors.
  • Assessment of Tip60-interacting proteins, including E2F1, and their binding to target genes.
  • Investigation of mRNA levels for Tip60 and Tip53 in ODC-overexpressing tissues.

Main Results:

  • Tip60 protein and Tip53 levels were significantly elevated in ODC-overexpressing mouse skin and tumors compared to controls.
  • Tumors exhibited unique Tip60 size variants and modified isoforms, with no change in steady-state mRNA levels, suggesting post-transcriptional regulation.
  • Altered association of Tip60 with E2F1 and other transcription factors was observed, with increased E2F1 binding to target genes in ODC-overexpressing skin.

Conclusions:

  • Overabundance of Tip60 protein, likely due to polyamine-mediated post-transcriptional regulation, contributes to epithelial tumorigenesis.
  • Tip60 up-regulation influences the expression of its target genes, playing a role in polyamine-mediated tumor promotion.
  • These findings highlight Tip60 as a potential therapeutic target in polyamine-driven cancers.

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