c-Jun activation-dependent tumorigenic transformation induced paradoxically by overexpression or block of S-adenosylmethionine decarboxylase

All mammalian cells absolutely require polyamines (putrescine, spermidine, and spermine) for growth. Here we show that the overexpression of cDNA for S-adenosylmethionine decarboxylase (AdoMetDC), the main regulatory enzyme i n the biosynthesis of higher polyamines, induces transformation of rodent f ibroblasts when expressed in the sense or the antisense orientation. Both t ransformants were able to induce invasive tumors in nude mice. Neither tran sformation was associated with activation of the mitogen-activated protein kinases Erk1 and Erk2. Instead, the AdoMet DC sense, but not antisense, tra nsformants displayed constitutive activation of the c-Jun NH2-terminal, kin ase (JNK) pathway. However, both transformations converged on persistent ph osphorylation of endogenous c-Jun at Ser73. The phenotype of the AdoMetDC s ense transformants was reversed by expression of dominant-negative mutants of SEK1 (MRK4), JNK1, and c-Jun (TAM-67), which were also found to impair c ytokinesis. Similarly, TAM-67 reverted the morphology of the AdoMetDC-antis ense expressors. This report is the first demonstration of a protein whose overexpression or block of synthesis can induce cell transformation. In add ition, we show that the polyamine biosynthetic enzymes require c-Jun activa tion for eliciting their biological effects.