Neuronal growth and survival mediated by eIF5A, a polyamine-modified translation initiation factor

*The Solomon H. Snyder Department of Neuroscience,
^‡Department of Pharmacology and Molecular Sciences, and
^§Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; and
^†Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340

Contributed by Solomon H. Snyder, December 27, 2006 (received for review December 7, 2006)

Abstract

Eukaryotic translation initiation factor 5A (eIF5A), the only known protein containing the polyamine-derived amino acid hypusine, modulates protein synthesis. We show that neurotrophic and neuroprotective actions of nerve growth factor (NGF) are mediated by hypusinated eIF5A, which can account for the known roles of polyamines in cell growth and survival. NGF treatment of PC12 cells stimulates eIF5A formation. Moreover, prevention of hypusine formation by a selective inhibitor of deoxyhypusine synthase and by its depletion with RNA interference blocks the NGF-elicited augmentation of neurite outgrowth and cell survival of PC12 cells. In brain cultures, inhibition of hypusine formation also inhibits neuronal process extension.

Footnotes

^¶To whom correspondence should be addressed. E-mail: ssnyder{at}jhmi.edu
Author contributions: Y.H., M.H.P., and S.H.S. designed research; Y.H. and M.H.P. performed research; Y.H., D.S.H., L.H., and M.H.P. contributed new reagents/analytic tools; Y.H. and M.H.P. analyzed data; and Y.H. and S.H.S. wrote the paper.
The authors declare no conflict of interest.
Abbreviations:

eIF5A,

eukaryotic initiation factor 5A;

DHS,

deoxyhypusine synthase;

NGF,

nerve growth factor;

GC-7,

N-guanyl-1,7-diaminoheptane;

BEC,

S-(2-boronoethyl)-l-cysteine;

DMFO,

difluoromethylornithine;

ODC,

ornithine decarboxylase.