INHIBITION OF THE G1-S TRANSITION OF THE CELL-CYCLE BY INHIBITORS OF DEOXYHYPUSINE HYDROXYLATION

The formation of the unusual amino-acid hypusine in eIF-5A (eukaryotic initiation factor 5A) is associated with cellular proliferation. We u sed a panel of compounds, including mimosine, to probe the relationshi p between the exit from the GI phase of the cell cycle, i.e., the onse t of DNA replication, and the formation of hypusine by the enzyme deox yhypusyl hydroxylase (DOHH). These two parameters displayed the same d ose dependency and structure-activity relationship. Only compounds tha t inhibited DOHH also suppressed proliferation. This effect was observ ed: (i) in spontaneously proliferating, virally transformed, and mitog en-stimulated cells; (ii) for both anchorage-dependent and anchorage-i ndependent proliferation; and (iii) with normal and malignant cell lin es. DOHH reactivation occurred rapidly after inhibitor withdrawal and correlated with synchronized entry into S. The changes in the expressi on of specific genes during the G1-to-S transition mimicked the physio logical pattern. These findings suggest that hypusine formation in eIF -5A which occurs in a specific, invariant sequence motif acquired earl y in evolution, may be involved in the G1-to-S transition in the eukar yotic cells tested.