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J. Biol. Chem., Vol. 282, Issue 48, 34700-34706, November 30, 2007

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Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis^*

Mervi T. Hyvönen¹, Tuomo A. Keinänen¹, Marc Cerrada-Gimenez, Riitta Sinervirta, Nikolay Grigorenko², Alex R. Khomutov, Jouko Vepsäläinen^¶, Leena Alhonen, and Juhani Jänne³

From the A. I. Virtanen Institute for Molecular Sciences and the ^¶Department of Chemistry, University of Kuopio, P. O. Box 1627, FI-70211 Kuopio, Finland and the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 117984, Russia

We have earlier shown that -methylated spermidine and spermine analogues rescue cells from polyamine depletion-induced growth inhibition and maintain pancreatic integrity under severe polyamine deprivation. However, because -methylspermidine can serve as a precursor of hypusine, an integral part of functional eukaryotic translation initiation factor 5A required for cell proliferation, and because , -bismethylspermine can be converted to methylspermidine, it is not entirely clear whether the restoration of cell growth is actually attributable to hypusine formed from these polyamine analogues. Here, we have used optically active isomers of methylated spermidine and spermine and show that polyamine depletion-induced acute cytostasis in cultured cells could be reversed by all the isomers of the methylpolyamines irrespective of whether they served or not as precursors of hypusine. In transgenic rats with activated polyamine catabolism, all the isomers similarly restored liver regeneration and reduced plasma -amylase activity associated with induced pancreatitis. Under the above experimental conditions, the (S, S)- but not the (R, R)-isomer of bismethylspermine was converted to methylspermidine apparently through the action of spermine oxidase strongly preferring the (S, S)-isomer. Of the analogues, however, only (S)-methylspermidine sustained cell growth during prolonged (more than 1 week) inhibition of polyamine biosynthesis. It was also the only isomer efficiently converted to hypusine, indicating that deoxyhypusine synthase likewise possesses hidden stereospecificity. Taken together, the results show that growth inhibition in response to polyamine depletion involves two phases, an acute and a late hypusine-dependent phase.

Received for publication, May 24, 2007 , and in revised form, September 27, 2007.

^* This work was supported in part by grants from the Academy of Finland and from the Finnish Cancer Organizations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² Present address: Dept. of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.

³ To whom correspondence should be addressed. Tel.: 358-17-163049; Fax: 358-17-163025; E-mail: Juhani.Janne{at}uku.fi.

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