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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-06-1796.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4164-4171
RED CELLS
Alternative 5' exons and differential splicing regulate
expression of protein 4.1R isoforms with distinct N-termini
Marilyn K. Parra,
Sherry L. Gee,
Mark J. Koury,
Narla Mohandas, and
John G. Conboy
From the Lawrence Berkeley National Laboratory,
Life Sciences Division, Berkeley, CA; the Department of Medicine,
Vanderbilt University, Veterans Affairs Medical Centers, Nashville, TN;
and the New York Blood Center, New York, NY.
Among the alternative pre-mRNA splicing events that characterize
protein 4.1R gene expression, one involving exon 2' plays a critical
role in regulating translation initiation and N-terminal protein
structure. Exon 2' encompasses translation initiation site AUG1
and is located between alternative splice acceptor sites at the 5' end
of exon 2; its inclusion or exclusion from mature 4.1R mRNA regulates
expression of longer or shorter isoforms of 4.1R protein, respectively.
The current study reports unexpected complexity in the 5' region of the
4.1R gene that directly affects alternative splicing of exon 2'.
Identified far upstream of exon 2 in both mouse and human
genomes were 3 mutually exclusive alternative 5' exons, designated 1A,
1B, and 1C; all 3 are associated with strong transcriptional promoters
in the flanking genomic sequence. Importantly, exons 1A and 1B splice
differentially with respect to exon 2', generating transcripts with
different 5' ends and distinct N-terminal protein coding capacity. Exon
1A-type transcripts splice so as to exclude exon 2' and therefore
utilize the downstream AUG2 for translation of 80-kDa 4.1R
protein, whereas exon 1B transcripts include exon 2' and initiate at
AUG1 to synthesize 135-kDa isoforms. RNA blot analyses revealed that 1A
transcripts increase in abundance in late erythroblasts, consistent
with the previously demonstrated up-regulation of 80-kDa 4.1R during
terminal erythroid differentiation. Together, these results suggest
that synthesis of structurally distinct 4.1R protein isoforms in
various cell types is regulated by a novel mechanism requiring
coordination between upstream transcription initiation events and
downstream alternative splicing events.
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