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

Molecular and Cellular Endocrinology
Mickey M MartinT S Elton

Abstract

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/m...Continue Reading

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Citations

Jul 3, 2007·American Journal of Physiology. Lung Cellular and Molecular Physiology·Mickey M MartinTerry S Elton
Dec 19, 2009·BMC Cancer·Roger BesançonAlain Puisieux
Oct 12, 2012·Journal of Cell Communication and Signaling·Michael JewerLynne-Marie Postovit
Jul 25, 2009·Cellular and Molecular Life Sciences : CMLS·Danijela Markovic, R A John Challiss
May 6, 2006·The Journal of Biological Chemistry·Mickey M MartinTerry S Elton
Jun 26, 2007·The Journal of Biological Chemistry·Mickey M MartinTerry S Elton

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