Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model

Abstract

Ornithine decarboxylase (ODC) activity is elevated in and necessary for oral carcinogenesis, but the mechanism for its deregulation is unclear. Using subtractive hybridization, a 1029 bp full-length cDNA encoding a 222 amino acid open reading frame has been isolated from normal hamster oral keratinocytes. The hamster cDNA is homologous to the human, mouse and rat ornithine decarboxylase antizyme gene (ODC-Az). The hamster ODC-Az gene demonstrated a restriction fragment length polymorphism (RFLP) upon Southern blot analysis comparing normal and tumor hamster genomic DNA. Northern blot analysis revealed that normal hamster oral keratinocytes express readily detectable level of ODC-Az mRNA. Malignant oral keratinocytes demonstrate reduced expression of the ODC-Az mRNA. In contrast, malignant hamster oral keratinocytes have elevated ODC mRNA levels and lengthened ODC protein halflife when compared to the normal counterparts. This was corroborated by direct measurement of ODC enzymatic activity. These data support the hypothesis that the reduced and/or loss of expression and function of the ODC-Az gene is an important event for the early de-regulation of cellular proliferation during oral tumor development.

Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

“…Elevated ODC levels in dysplastic oral epithelium leads to elevated polyamine levels and has been proposed as a negative prognostic indicator (Shin et al, 1990; Williams et al, 1995). In a previous report, we have demonstrated the downregulation of ODC-Az is concurrent with ODC overactivity in malignant hamster oral keratinocytes (Tsuji et al, 1998). We now present data that ectopic expression of ODC-Az in malignant hamster oral keratinocytes induces terminal dierentiation and DNA hypomethylation.…”

“…ODC activity assay ODC activity assay was performed as described by Wetters with minor modi®cation (Tsuji et al, 1998;Wetters et al, 1989). Brie¯y, the ODC activity was quantitated the release of [ 14 C]CO 2 during ODC-catalyzed conversion of ornithine to putrescine and CO 2 .…”

Regulation of cell proliferation by the antizyme inhibitor: evidence for an antizyme-independent mechanism

“…ODC has been established as an oncogene, capable of increasing both proliferation and transformation (Auvinen et al, 1992;Moshier et al, 1993). Consistent with this hypothesis, antizyme is downregulated in certain carcinomas (Koike et al, 1999;Tsuji et al, 1998), and its upregulation has been associated with cell-cycle arrest and with differentiation of carcinoma cells (Koike et al, 1999;Tsuji et al, 2001). Recent evidence, however, suggests that the antizyme-mediated degradation pathway may have additional targets (Lin et al, 2002;Newman et al, 2004).…”

“…Antizyme upregulation or overexpression correlates with growth suppression in several model systems including H-Ras transformed NIH-3T3 cells (Iwata et al, 1999), malignant hamster keratinocytes (Tsuji et al, 1998) and polyamine-treated prostate carcinoma cells (Koike et al, 1999). Antizyme overexpression also induces terminal differentiation in hamster keratinocytes (Tsuji et al, 2001).…”

Association of OAZ1 Gene Polymorphisms With Subclinical and Clinical Vascular Events

“…Consistently, the reduction or the lack of expression of the OAZ1 gene was observed in certain late stage cancers, both in animals and humans. 14,15 Other data suggest that antizyme 1 may also influence the cell proliferation through a direct interaction with cell cycle regulators. For example, functional OAZ1 can act as a tumor suppressor by targeting the cyclin D1 for degradation, this cyclin also participating in the progression through the G1 phase of the VSMC cycle.…”