eIF5A‐controlled gene expression: A molecular concept for the anti‐cancer and anti‐HIV activity of hypusine disruptors.

Mature eIF5A contains a functionally decisive hypusine residue, formed by the sequential action of deoxyhypusine synthase (DOHS) and deoxyhypusine hydroxylase (DOHH). The hypusine dependency of G1 exit was first noted in 1987 [ Eur J Cell Biol 43 , Suppl 17, 60 ], the oncologic promise of hypusine disruptors in 1989/90 [ Blut 59 , 286; Proc Amer Assoc Cancer Res 31 ; 417 ], and their antiretroviral activity in 1998 [ Biochem Pharmacol 55 , 1807 ]. The targets for hypusine disruptors, human DOHS and DOHH, are now well known [ Umland et al., J Biol Chem 279 , 28697 (2004); Park et al., PNAS, in print ] and clinical anti‐cancer/HIV trials of hypusine disruptors are commencing. However, the eIF5A mode‐of‐action is unclear. eIF5A stability and preponderance appear incompatible with the model that a few mature eIF5A molecules suffice to effect cell cycle phase‐specific control of translational expression of a subset of mRNAs [ FEBS Lett. 366 , 92(1995 )]. We propose that only de novo hypusinated eIF5A mediates translational control of gene expression, and that its reutilization for that purpose is precluded, likely by further modification of hypusine, e.g. at its OH moiety. This single‐use concept is based on flow cytometric analysis of hypusine disruption: i ) DOHH inhibitor exposure blocks cell exit from G1, inhibitor removal synchronously releases cells into S phase; ii ) inhibitor re‐addition after >30 min. fails to reestablish the block, yet becomes effective once more after the released cells complete passage through S‐G2‐M and re‐enter G1. Supported in part by NIH BIRCWH Grant HD‐1457 and New Jersey State Grant 05‐2405‐CCR‐EO