Transgenic mouse models for studies of the role of polyamines in normal, hypertrophic and neoplastic growth

Abstract

Transgenic mice expressing proteins altering polyamine levels in a tissue-specific manner have considerable promise for evaluation of the roles of polyamines in normal, hypertrophic and neoplastic growth. This short review summarizes the available transgenic models. Mice with large increases in ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase or antizyme, a protein regulating polyamine synthesis by reducing polyamine transport and ODC in the heart, have been produced using constructs in which the protein is expressed from the alpha -myosin heavy-chain promoter. These mice are useful in studies of the role of polyamines in hypertrophic growth. Expression from keratin promoters has been used to target increased synthesis of ODC, spermidine/spermine-N(1)-acetyltransferase (SSAT) and antizyme in the skin. Such expression of ODC leads to an increased sensitivity to chemical and UV carcinogenesis. Expression of antizyme inhibits carcinogenesis in skin and forestomach. Expression of SSAT increases the incidence of skin papillomas and their progression to carcinomas in response to a two-stage carcinogenesis protocol. These results establish the importance of polyamines in carcinogenesis and neoplastic growth and these transgenic mice will be valuable experimental tools to evaluate the importance of polyamines in mediating responses to oncogenes and studies of cancer chemoprevention.

Mouse Ornithine Decarboxylase-like Gene Encodes an Antizyme Inhibitor Devoid of Ornithine and Arginine Decarboxylating Activity

“…Our results also reveal that the overexpression of ODC in HEK 293T cells was associated with a marked increase in putrescine and a moderate elevation of spermidine levels, whereas spermine content was not affected. This situation is similar to that found in transgenic mice where the overproduction of ODC led to an increase of putrescine in some tissues but had less effect on spermidine or spermine (9,71). In any case, the elevation in polyamine levels found in the transfected HEK 293T cells appears to be sufficient to facilitate the frameshifting in the translation of AZ mRNA (22,23).…”

Polyamines and cancer: old molecules, new understanding

“…As discussed earlier, Odc-knockout mice die early during embryogenesis 7 . Increased levels of polyamine have long been associated with proliferation, and recent experiments with genetically altered rodents have confirmed the important roles of these molecules in both normal and neoplastic growth 53 . basis for neoplasia in Burkitt's lymphoma 29 .…”

eIF4E – from translation to transformation

“…Overexpression of ODC transforms NIH 3T3 cells (Moshier et al, 1993;Auvinen et al, 1997). Transgenic expression of polyamine biosynthetic enzymes, such as ODC and S-adenosylmethionine decarboxylase in mice, causes skin cancer (reviewed in Pegg et al, 2003). Also, both intracellular polyamine concentrations and ODC activity are increased in colorectal cancer tissue and in premalignant polyps (reviewed in Wallace and Caslake, 2001).…”