Posttranslational Regulation

Mammalian ODC has a very fast turnover (9,10). Although the half-life of ODC is usually something between 30 and 60 min, it may be as short as a few minutes. The turnover of mammalian ODC is affected by the cellular polyamine levels (9,10,97). In the presence of polyamine excess, there is a marked increase in the degradation rate of ODC, whereas when cells are depleted of their polyamines, the degradation of ODC is decreased.

As with other cellular proteins with a fast turnover, ODC is degraded by the 26S proteasome (98). However, in contrast to the degradation of most other proteins by the proteasome, the degradation of mammalian ODC is not induced by ubiquitination (98). ODC was the first example of a nonubiquitinated protein being degraded by the 26S pro-teasome. Instead, the degradation of ODC by this proteolytic system is induced by the strong binding of a specific protein, termed antizyme (AZ), to the enzyme (9,10,97). The binding of AZ to ODC inhibits the enzyme activity, most likely because the binding of AZ, which occurs at the monomer level, hampers the formation of the homodimer. Furthermore, the binding of AZ to ODC seems to affect the monomer structure in such a way that the C-terminal part is exposed (9,10). The C-terminal part of ODC has been shown to be essential for the rapid degradation of the enzyme (99). The polyamines induce the degradation of ODC by affecting the synthesis of AZ, which is dependent on a unique mechanism involving ribosomal frameshifting (100,101). The AZ mRNA has two major reading frames, which both have to be translated for the synthesis of the entire protein. Conventional translation of AZ mRNA arrests at a premature stop signal in the first reading frame. However, in the presence of polyamines, there is a +1 frameshift occurring at the premature termination codon, which results in a continued translation of the second reading frame and the production of full-length AZ (Fig. 3). This mechanism is unique and so far no other examples of mammalian ribosomal frameshifting are known. The mechanism is highly dependent on polyamines. In the absence or in the presence of low concentrations of polyamines, the number of ribosomes reading both frames is extremely low (100,101). Thus polyamines control the turnover rate of ODC by affecting the synthesis of AZ. When there is an excess of polyamines in the cell, the synthesis of AZ is increased, resulting in a stimulation of ODC degradation. On the other hand, when cells are depleted of their polyamines, the synthesis of AZ is low resulting in a decreased turnover of ODC. Recently, it was demonstrated that in yeast, polyamines regulate ODC turnover by reducing the degradation of AZ, which occurs by the proteasome in an ubiq-uitin-dependent manner, in addition to inducing its expression (by stimulating frame shifting) (102). However, it is not known yet whether the same mechanism also occurs in mammalian cells. Interestingly, the mammalian genome contains several active AZ genes

Fig. 3. Synthesis of ODC antizyme (AZ). Polyamines stimulate a +1 frameshift, resulting in the synthesis of full-length AZ. In the absence of polyamines translation is terminated at the in-frame stop codon, giving rise to a nonfunctional truncated AZ.

103,104). Whether all these genes are involved in the regulation of ODC degradation or whether they have some other functions is not known yet.

Interestingly, ODC from the trypanosomatid Crithidia fasciculata, a monogenetic parasite that colonize the digestive tract of flies, still turns over rapidly in the parasite as well as when expressed in mammalian cells, even though it lacks the region corresponding to the C-terminal part of mammalian ODC (105,106). C. fasciculata is the first protozoan organism shown to have an ODC with a short half-life. Thus C. fasciculata ODC must contain other signals that target the enzyme for rapid degradation also in mammalian cells. As with the mammalian ODC, C. fasciculata ODC seems to be degraded the 26S proteasome (106). However, in contrast to mammalian ODC, C. fasciculata ODC is not downregulated by polyamines when expressed in mammalian cells, suggesting that the degradation is not dependent on AZ. Instead, the rapid degradation of this ODC may be mediated by ubiquitination. If so, this would be the first demonstration of an ODC being ubiquitinated.

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