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J. Biol. Chem., Vol. 277, Issue 34, 30699-30706, August 23, 2002
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From the Department of Cellular and Molecular Medicine,
Glycobiology Training and Research Center, University of California
at San Diego, La Jolla, California 92093-0687
We report the full-length 5'-untranslated
region (5'-UTR) sequences of the four vertebrate heparan
sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferases (NDSTs) and
their role in translational regulation in vivo and in
vitro. All four NDST 5'-UTR sequences are unusually long, have a
high degree of predicted secondary structure, and contain multiple
upstream AUG codons, which together impose a major barrier to
conventional, cap-dependent ribosomal scanning. At least
two alternatively spliced forms of NDST2 differing in their 5'-UTRs
exist, and two forms of NDST4 arise from alternative transcriptional
start sites. The 5'-UTRs do not show any significant sequence
similarity between isozymes, but possess highly conserved regions
between mouse and human orthologs, pointing toward evolutionarily conserved functions. Expression of bicistronic vector constructs showed
that the 5'-UTRs of NDST1-4 are capable of regulating translation differentially in vivo dependent on cell type and culture
conditions. In vitro translation of a reporter gene located
downstream of the UTRs demonstrated the presence of internal ribosome
entry sites, providing an additional, cap-independent step in
fine-tuning NDST expression. Comparative studies of NDST1-3 mRNAs
and protein expression in brain and embryonic extracts revealed
striking differences in translational efficiency. Other genes necessary
for glycosaminoglycan synthesis in addition to the NDST isozymes have
long, structured 5'-UTRs. Because several growth factors and morphogens
that bind heparan sulfate also contain structured 5'-UTRs,
translational regulation may coordinate the action of these factors and
their heparan sulfate co-receptors.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF520867, AF520868, AF520869, and AF520870.
Regulated Translation of Heparan Sulfate
N-Acetylglucosamine
N-Deacetylase/N-Sulfotransferase Isozymes by
Structured 5'-Untranslated Regions and Internal Ribosome Entry
Sites*
*
This work was supported by Grants R37GM33063 and P01HL57345
from the National Institutes of Health (to J. D. E.) and Deutsche Forschungsgemeinschaft Grant GR-1748 (to K.G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Cellular and
Molecular Medicine, University of California at San Diego, 9500 Gilman
Dr., CMM-East 1055, La Jolla, CA 92093-0687. Tel.: 858-822-1100; Fax:
858-534-5611; E-mail: jesko@ucsd.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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