Polyamine Metabolism in Human Epidermal Keratinocytes Transformed with AD12-SV40, HPV16-DNA and K-ras Oncogene

Abstract

The intracellular concentration of the polyamines, spermidine and spermine, and their precursor, putrescine, vary with the growth rate of the cell. Although the specific role of these amines is still not well understood at the molecular level, recent studies have shown that their concentration is highly regulated and that polyamines are necessary for normal cell growth and differentiation (see reviews 1 – 3). The pathway of polyamine biosynthesis from ornithine and methionine in mammalian tissues is well char-acterized (4). Biosynthesis is modulated by rapid induction of both ornithine decarboxylase (ODC) and Sadenosylmethionine decarboxylase (AdoMetDC) both of which are present in very small amounts in quiescent cells and both of which have very short time turnovers (5,6). Exposure of resting cells to growth-promoting stimuli results in a rapid rise in ODC activity which thereafter parallels the proliferation response. In addition to the possibility of rapidly changing their rate of polyamine synthesis, cells are equipped with an effective pathway for degradation of spermidine and spermine. The first, and rate-limiting, step in this degradation is an acetylation of the polyamines, which is catalyzed by the inducible enzyme, spermidine/ spermine N ¹-acetyltransferase (7).This enzyme also has an extremely short half-life (8), is rapidly induced by various polyamines (9) and appears to play a role in cellular protection against the deleterious effects of too high intracellular polyamine concentrations.