Based on our previous studies (6,15,20,32-34) and others (2,23,24,35,36), we propose a model delineating the regulation of expression of the p53 gene by cellular polyamines and the involvement of p53 in the process of growth inhibition of normal small intestinal mucosa after polyamine depletion (Fig. 4). In this model, polyamines negatively regulate posttranscriptional regulation of the p53 gene, and the activation of p53 expression plays a critical role in the negative control of the small intestinal mucosal growth. Depletion of cellular polyamines, either by inhibition of their synthesis, stimulation of catabolism, or suppression of polyamine uptake, enhances expression of the p53 gene via both the stabilization of p53 mRNA and the decrease in p53 protein degradation. Although the exact mechanism by which polyamine depletion stabilizes p53 mRNA remains unclear, our previous studies have demonstrated that induced NPM interacts with and stabilizes p53 protein in polyamine-deficient cells. The resultant accumulation of p53 after polyamine depletion activates the transcription of cell-cycle arrest genes such as p21, which then blocks the Gj-S phase transition, decreases proliferation, and inhibits mucosal growth of the small inte stine.
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