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Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.

ABSTRACT: Upper aerodigestive tract (UADT) cancers of the oral cavity and esophagus are a significant global health burden, and there is an urgent need to develop relevant animal models to identify chemopreventive and therapeutic strategies to combat these diseases. Antizyme (AZ) is a multifunctional negative regulator of cellular polyamine levels, and here, we evaluate the susceptibility of keratin 5 (K5)-AZ transgenic mice to tumor models that combine chemical carcinogenesis with dietary and genetic risk factors known to influence human susceptibility to UADT cancer and promote UADT carcinogenesis in mice. First, p53(+/-) and K5-AZ/p53(+/-) (AZ/p53(+/-)) mice were placed on a zinc-deficient (ZD) or zinc-sufficient (ZS) diet and chronically exposed to 4-nitroquinoline 1-oxide. Tongue tumor incidence, multiplicity and size were substantially reduced in both ZD and ZS AZ/p53(+/-) mice compared with p53(+/-). AZ expression also reduced progression to carcinoma in situ or invasive carcinoma and decreased expression of the squamous cell carcinoma biomarkers K14, cyclooxygenase-2 and metallothionein. Next, AZ-expressing p53(+/-) and p53 null mice were placed on the ZD diet and treated with a single dose of N-nitrosomethylbenzylamine. Regardless of p53 status, forestomach (FST) tumor incidence, multiplicity and size were greatly reduced with AZ expression, which was also associated with a significant decrease in FST epithelial thickness along with reduced proliferation marker K6 and increased differentiation marker loricrin. These studies demonstrate the powerful tumor suppressive effects of targeted AZ expression in two distinct and unique mouse models and validate the polyamine metabolic pathway as a target for chemoprevention of UADT cancers.

SUBMITTER: Feith DJ

PROVIDER: S-EPMC3581602 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.

Feith David J DJ Pegg Anthony E AE Fong Louise Y Y LY

Carcinogenesis 20121207 3

Upper aerodigestive tract (UADT) cancers of the oral cavity and esophagus are a significant global health burden, and there is an urgent need to develop relevant animal models to identify chemopreventive and therapeutic strategies to combat these diseases. Antizyme (AZ) is a multifunctional negative regulator of cellular polyamine levels, and here, we evaluate the susceptibility of keratin 5 (K5)-AZ transgenic mice to tumor models that combine chemical carcinogenesis with dietary and genetic ris ...[more]

PMID: 23222816

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Project description:BACKGROUND: Ornithine decarboxylase antizymes are proteins which negatively regulate cellular polyamine levels via their affects on polyamine synthesis and cellular uptake. In virtually all organisms from yeast to mammals, antizymes are encoded by two partially overlapping open reading frames (ORFs). A +1 frameshift between frames is required for the synthesis of antizyme. Ribosomes change translation phase at the end of the first ORF in response to stimulatory signals embedded in mRNA. Since standard sequence analysis pipelines are currently unable to recognise sites of programmed ribosomal frameshifting, proper detection of full length antizyme coding sequences (CDS) requires conscientious manual evaluation by a human expert. The rapid growth of sequence information demands less laborious and more cost efficient solutions for this problem. This manuscript describes a rapid and accurate computer tool for antizyme CDS detection that requires minimal human involvement. RESULTS: We have developed a computer tool, OAF (ODC antizyme finder) for identifying antizyme encoding sequences in spliced or intronless nucleic acid sequenes. OAF utilizes a combination of profile hidden Markov models (HMM) built separately for the products of each open reading frame constituting the entire antizyme coding sequence. Profile HMMs are based on a set of 218 manually assembled antizyme sequences. To distinguish between antizyme paralogs and orthologs from major phyla, antizyme sequences were clustered into twelve groups and specific combinations of profile HMMs were designed for each group. OAF has been tested on the current version of dbEST, where it identified over six thousand Expressed Sequence Tags (EST) sequences encoding antizyme proteins (over two thousand antizyme CDS in these ESTs are non redundant). CONCLUSION: OAF performs well on raw EST sequences and mRNA sequences derived from genomic annotations. OAF will be used for the future updates of the RECODE database. OAF can also be useful for identifying novel antizyme sequences when run with relaxed parameters. It is anticipated that OAF will be used for EST and genome annotation purposes. OAF outputs sequence annotations in fasta, genbank flat file or XML format. The OAF web interface and the source code are freely available at http://recode.ucc.ie/oaf/ and at a mirror site http://recode.genetics.utah.edu/oaf/.

Dataset Information

Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.

Publications

Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.

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