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J. Biol. Chem., Vol. 278, Issue 20, 18037-18044, May 16, 2003
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From the The mammalian
gonadotropin-releasing hormone (GnRH) gene consists of four short exons
(denoted as 1, 2, 3, and 4) and three intervening introns (A, B, and
C). Recently, we demonstrated that excision of the first intron (intron
A) from the GnRH transcript is regulated in a tissue- and developmental
stage-specific fashion and is severely attenuated in hypogonadal (hpg)
mouse because of its lack of exonic splicing enhancers (ESE) 3 and 4. In the present study, we examined the influence of intron A on
translational efficiency, thereby establishing a post-transcriptional
control over GnRH biosynthesis. First, we verified that an intron
A-retained GnRH transcript is a splicing variant but not a splicing
intermediate. Intron A-retained transcripts can be transported to the
cytoplasm in contrast to intron B-containing transcripts, which are
restricted to the nucleus. This result implicates the intron A-retained
GnRH transcript as a splicing variant; it has a long 5'-untranslated region, as the GnRH prohormone open reading frame (ORF) begins on exon
2. We investigated whether an intron A-retained GnRH transcript can
properly initiate translation at the appropriate start codon and found
that intron A completely blocks the translation initiation of its
downstream reporter ORF both in vivo and in
vitro. The inhibition of translation initiation appears to be due
to the presence of a tandem repeat of ATG sequences within intron A. Constructs bearing mutations of ATGs to AAGs restored translation initiation at the downstream start codon; the extent of this
restoration correlated with the number of mutated ATGs. Besides the
failure in the translation initiation of GnRH-coding region in the
intron A-containing variant, the present study also suggests that the interference between mature GnRH mRNA and intron A-retained
splicing variant could occur to lower the efficiency of GnRH
biosynthesis in the GT1-1-immortalized GnRH-producing cell line.
Therefore, our results indicate that the precise and efficient
excision of intron A and the joining of adjacent exons may be a
critical regulatory step for the post-transcriptional regulation of
GnRH biosynthesis.
Excision of the First Intron from the Gonadotropin-releasing
Hormone (GnRH) Transcript Serves as a Key Regulatory Step for GnRH
Biosynthesis*
§,§,,, and
School of Biological Sciences, Seoul
National University, Seoul 151-742, Korea and the ¶ Hormone
Research Center, Chonnam National University,
Kwangju 500-757, Korea
*
This work was supported by the Korea Ministry of Science and
Technology through Korean Brain Science and National Research Laboratory Grant 2000-N-NL-01-C-149 and a grant from Basic Research Program of the Korea Science and Engineering Foundation.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. Tel.:
82-2-880-6694; Fax: 82-2-884-6560; E-mail: kyungjin@snu.ac.kr.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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