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© The Rockefeller University Press, 0021-9525/2000//801 $5.00
The Journal of Cell Biology, Volume 151, Number 4, , 2000 801-810

C-Jun Activation-Dependent Tumorigenic Transformation Induced Paradoxically by Overexpression or Block of S-Adenosylmethionine Decarboxylase

^a Haartman Institute, Department of Pathology, FIN-00014 University of Helsinki, Helsinki, Finland
^b Department of Biochemistry and Biotechnology, 70211 University of Kuopio, FIN-70211 Kuopio, Finland
^c Experimental Cancer Research, Orion-Farmos, Orion Corporation, FIN-20101 Turku, Finland
^d Institute of Biomedicine, Department of Physiology and Department of Clinical Chemistry, FIN-00014 University of Helsinki, Helsinki, Finland
^e National Cancer Institute, Division of Cancer Prevention and Control, Biomarkers and Prevention Research Branch, Rockville, Maryland 20850
Haartman Institute, Department of Pathology, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Helsinki, Finland.358-9-19-12-66-75358-9-19-12-65-16

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 in the biosynthesis of higher polyamines, induces transformation of rodent fibroblasts when expressed in the sense or the antisense orientation. Both transformants were able to induce invasive tumors in nude mice. Neither transformation was associated with activation of the mitogen-activated protein kinases Erk1 and Erk2. Instead, the AdoMet DC sense, but not antisense, transformants displayed constitutive activation of the c-Jun NH₂-terminal kinase (JNK) pathway. However, both transformations converged on persistent phosphorylation of endogenous c-Jun at Ser73. The phenotype of the AdoMetDC sense transformants was reversed by expression of dominant-negative mutants of SEK1 (MKK4), JNK1, and c-Jun (TAM-67), which were also found to impair cytokinesis. Similarly, TAM-67 reverted the morphology of the AdoMetDC-antisense expressors. This report is the first demonstration of a protein whose overexpression or block of synthesis can induce cell transformation. In addition, we show that the polyamine biosynthetic enzymes require c-Jun activation for eliciting their biological effects.

Key Words: cell transformation • c-Jun • JNK • S-adenosylmethionine decarboxylase • polyamines

© 2000 The Rockefeller University Press

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