Novel initiation genes in squamous cell carcinomagenesis: A role for substrate-specific ubiquitylation in the control of cell survival

Amador Albor, Molly Kulesz-Martin

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The study of experimental epidermal carcinogenesis offers several advantages over other epithelial carcinogenesis models, including easy accessibility and a database of research findings spanning over a century. Our studies make use of a clonal in vitro/in vivo keratinocyte carcinogenesis model with low frequency of ras mutation and derivative clonal-initiated lineages with distinct tumor fate. Analysis of this model has yielded candidate genes involved in the stages of initiation and tumorigenic progression, and has revealed novel roles for ubiquitylation in transcriptional control of survival and apoptotic pathways during the early stages of carcinogenesis. The expression of a recently described E3-ubiquitin ligase, Trim32, is elevated during initiation, and ectopic expression of Trim32 confers extended survival in response to terminal differentiation and ultraviolet light (UV) B/TNF-α death signals. Trim32 binds and ubiquitylates Piasy, controlling its stability and accumulation. Piasy is a SUMOylation factor involved in the control of apoptosis, senescence, and NF-κB activation. NF-κB is a survival factor for keratinocytes in response to UV irradiation, the main carcinogenic stimulus for the epidermis. Piasy inhibits NF-κB activity, and promotes keratinocyte apoptosis in response to UV and TNF-α. In human skin squamous cell carcinoma (SCC) samples, we found an inverse correlation between Trim32 and Piasy expression supporting a role for Trim32-Piasy interaction in human epidermal carcinogenesis. Our hypothesis is that increased expression of Trim32 may enhance epidermal carcinogenesis, by increasing the threshold of NF-κB activity through Piasy downmodulation.

Original languageEnglish (US)
Pages (from-to)585-590
Number of pages6
JournalMolecular Carcinogenesis
Volume46
Issue number8
DOIs
StatePublished - Aug 1 2007

Keywords

  • Carcinogenesis
  • E3-ubiquitin ligase
  • Piasy
  • Protein degradation
  • Trim family scaffold proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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