TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2

At least four alternatively spliced mRNAs can be synthesized from the human AT(1)R (hAT(1)R) gene that differ only in the inclusion or exclusion of exon 2 and/or 3. RT-PCR experiments demonstrate that splice variants harboring exon 2 accounts for at least 30% of all the hAT(1)R mRNA transcripts expr...

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Veröffentlicht in:Molecular and cellular endocrinology 2006-04, Vol.249 (1-2), p.21-31
Hauptverfasser: Martin, Mickey M, Buckenberger, Jessica A, Knoell, Daren L, Strauch, Arthur R, Elton, Terry S
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container_issue 1-2
container_start_page 21
container_title Molecular and cellular endocrinology
container_volume 249
creator Martin, Mickey M
Buckenberger, Jessica A
Knoell, Daren L
Strauch, Arthur R
Elton, Terry S
description At least four alternatively spliced mRNAs can be synthesized from the human AT(1)R (hAT(1)R) gene that differ only in the inclusion or exclusion of exon 2 and/or 3. RT-PCR experiments demonstrate that splice variants harboring exon 2 accounts for at least 30% of all the hAT(1)R mRNA transcripts expressed in the human tissues investigated. Since exon 2 contains two upstream AUGs or open reading frames (uORFs), we hypothesized that these AUGs would inhibit the translation of the downstream hAT(1)R protein ORF harbored in exon 4. This study demonstrates that the inclusion of exon 2 in hAT(1)R mRNA transcripts dramatically reduces hAT(1)R protein levels (nine-fold) and significantly attenuates Ang II responsiveness ( approximately four-fold). Interestingly, only when both AUGs were mutated in combination were the hAT(1)R density and Ang II signaling levels comparable with those values obtained using mRNA splice variants that did not include exon 2. This observation is consistent with a model where the majority of the ribosomes likely translate uORF#1 and are then unable to reinitiate at the downstream hAT(1)R ORF, in part due to the presence of AUG#2 and to the short intercistronic spacing. Importantly, TGF-beta(1) treatment (4ng/ml for 4h) of fibroblasts up-regulated hAT(1)R mRNA splice variants, which harbored exon 2, six-fold. Since AT(1)R activation is closely associated with cardiovascular disease, the inclusion of exon 2 by alternative splicing represents a novel mechanism to reduce the overall production of the hAT(1)R protein and possibly limit the potential pathological effects of AT(1)R activation.
doi_str_mv 10.1016/j.mce.2006.01.009
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subjects Alternative Splicing
Base Sequence
Codon, Initiator - physiology
Exons
Humans
Molecular Sequence Data
Receptor, Angiotensin, Type 1 - biosynthesis
Receptor, Angiotensin, Type 1 - genetics
RNA, Messenger - metabolism
Sequence Alignment
Transforming Growth Factor beta - pharmacology
Transforming Growth Factor beta - physiology
Up-Regulation
title TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2
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