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 used a panel of compounds, including mimosine, to probe the relationship between the exit from the G1 phase of the cell cycle, i.e., the onset of DNA replication, and the formation of hypusine by the enzyme deoxyhypusyl hydroxylase (DOHH). These two parameters displayed the same dose dependency and structure-activity relationship. Only compounds that inhibited DOHH also suppressed proliferation. This effect was observed: (i) in spontaneously proliferating, virally transformed, and mitogen-stimulated cells; (ii) for both anchorage-dependent and anchorage-independent proliferation; and (iii) with normal and malignant cell lines. DOHH reactivation occurred rapidly after inhibitor withdrawal and correlated with synchronized entry into S. The changes in the expression of specific genes during the G1-to-S transition mimicked the physiological pattern. These findings suggest that hypusine formation in eIF-5A which occurs in a specific, invariant sequence motif acquired early in evolution, may be involved in the G1-to-S transition in the eukaryotic cells tested.
Hanauske-Abel
H M
HM
Department of Pediatrics, New York Hospital-Cornell University Medical College, NY 10021.
Park
M H
MH
Hanauske
A R
AR
Popowicz
A M
AM
Lalande
M
M
Folk
J E
JE
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis / Q000096:biosynthesis; D008898:Mimosine / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010448:Peptide Initiation Factors / Q000737:chemistry; D011753:Pyrones / Q000494:pharmacology; D016601:RNA-Binding Proteins; D016196:S Phase / Q000187:drug effects*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D000097574:Eukaryotic Translation Initiation Factor 5A
D000409:Alanine; D004791:Enzyme Inhibitors; D008239:Lysine; D008898:Mimosine; D006899:Mixed Function Oxygenases; D010448:Peptide Initiation Factors; D011753:Pyrones; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C011890:kojic acid; C012787:3-pyridylalanine; C047991:deoxyhypusine hydroxylase