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...
Gespeichert in:
Veröffentlicht in: | Molecular and cellular endocrinology 2006-04, Vol.249 (1-2), p.21-31 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 31 |
---|---|
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 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_67826408</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67826408</sourcerecordid><originalsourceid>FETCH-LOGICAL-p124t-e233a02711b07dbdc4b0683be422a9b0798ead93c4bdbec3f88008f339c186b93</originalsourceid><addsrcrecordid>eNo1kE1OwzAUhL0A0VI4ABvkFbuEZzu1nWVV0YJUFQmVdWQ7L22q_GEnCK7FQTgTQZTVSJ--mcUQcsMgZsDk_TGuHcYcQMbAYoD0jExBgIgUBzUhlyEcAUDNub4gEybnkAg1n5Ltbr2Kvr8Y9bgfKtOXbUPbgh6G2jR0sfvlDru-9bR-2S5o6KrSIX03vjRNH-jBeNv6stlT_Bib_IqcF6YKeH3KGXldPeyWj9Hmef20XGyijvGkj5ALYYArxiyo3OYusSC1sJhwbtKRpRpNnoqR5xadKLQG0IUQqWNa2lTMyN3fbufbtwFDn9VlcFhVpsF2CJlUmssE9CjensTB1phnnS9r4z-z_wfEDzAEW6s</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>67826408</pqid></control><display><type>article</type><title>TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Martin, Mickey M ; Buckenberger, Jessica A ; Knoell, Daren L ; Strauch, Arthur R ; Elton, Terry S</creator><creatorcontrib>Martin, Mickey M ; Buckenberger, Jessica A ; Knoell, Daren L ; Strauch, Arthur R ; Elton, Terry S</creatorcontrib><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.</description><identifier>ISSN: 0303-7207</identifier><identifier>DOI: 10.1016/j.mce.2006.01.009</identifier><identifier>PMID: 16504375</identifier><language>eng</language><publisher>Ireland</publisher><subject>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</subject><ispartof>Molecular and cellular endocrinology, 2006-04, Vol.249 (1-2), p.21-31</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16504375$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martin, Mickey M</creatorcontrib><creatorcontrib>Buckenberger, Jessica A</creatorcontrib><creatorcontrib>Knoell, Daren L</creatorcontrib><creatorcontrib>Strauch, Arthur R</creatorcontrib><creatorcontrib>Elton, Terry S</creatorcontrib><title>TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2</title><title>Molecular and cellular endocrinology</title><addtitle>Mol Cell Endocrinol</addtitle><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.</description><subject>Alternative Splicing</subject><subject>Base Sequence</subject><subject>Codon, Initiator - physiology</subject><subject>Exons</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>Receptor, Angiotensin, Type 1 - biosynthesis</subject><subject>Receptor, Angiotensin, Type 1 - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Sequence Alignment</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming Growth Factor beta - physiology</subject><subject>Up-Regulation</subject><issn>0303-7207</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kE1OwzAUhL0A0VI4ABvkFbuEZzu1nWVV0YJUFQmVdWQ7L22q_GEnCK7FQTgTQZTVSJ--mcUQcsMgZsDk_TGuHcYcQMbAYoD0jExBgIgUBzUhlyEcAUDNub4gEybnkAg1n5Ltbr2Kvr8Y9bgfKtOXbUPbgh6G2jR0sfvlDru-9bR-2S5o6KrSIX03vjRNH-jBeNv6stlT_Bib_IqcF6YKeH3KGXldPeyWj9Hmef20XGyijvGkj5ALYYArxiyo3OYusSC1sJhwbtKRpRpNnoqR5xadKLQG0IUQqWNa2lTMyN3fbufbtwFDn9VlcFhVpsF2CJlUmssE9CjensTB1phnnS9r4z-z_wfEDzAEW6s</recordid><startdate>20060425</startdate><enddate>20060425</enddate><creator>Martin, Mickey M</creator><creator>Buckenberger, Jessica A</creator><creator>Knoell, Daren L</creator><creator>Strauch, Arthur R</creator><creator>Elton, Terry S</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20060425</creationdate><title>TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2</title><author>Martin, Mickey M ; Buckenberger, Jessica A ; Knoell, Daren L ; Strauch, Arthur R ; Elton, Terry S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p124t-e233a02711b07dbdc4b0683be422a9b0798ead93c4bdbec3f88008f339c186b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Alternative Splicing</topic><topic>Base Sequence</topic><topic>Codon, Initiator - physiology</topic><topic>Exons</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>Receptor, Angiotensin, Type 1 - biosynthesis</topic><topic>Receptor, Angiotensin, Type 1 - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Sequence Alignment</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transforming Growth Factor beta - physiology</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martin, Mickey M</creatorcontrib><creatorcontrib>Buckenberger, Jessica A</creatorcontrib><creatorcontrib>Knoell, Daren L</creatorcontrib><creatorcontrib>Strauch, Arthur R</creatorcontrib><creatorcontrib>Elton, Terry S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular and cellular endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martin, Mickey M</au><au>Buckenberger, Jessica A</au><au>Knoell, Daren L</au><au>Strauch, Arthur R</au><au>Elton, Terry S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TGF-β1 regulation of human AT1 receptor mRNA splice variants harboring exon 2</atitle><jtitle>Molecular and cellular endocrinology</jtitle><addtitle>Mol Cell Endocrinol</addtitle><date>2006-04-25</date><risdate>2006</risdate><volume>249</volume><issue>1-2</issue><spage>21</spage><epage>31</epage><pages>21-31</pages><issn>0303-7207</issn><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/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.</abstract><cop>Ireland</cop><pmid>16504375</pmid><doi>10.1016/j.mce.2006.01.009</doi><tpages>11</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0303-7207 |
ispartof | Molecular and cellular endocrinology, 2006-04, Vol.249 (1-2), p.21-31 |
issn | 0303-7207 |
language | eng |
recordid | cdi_proquest_miscellaneous_67826408 |
source | MEDLINE; Elsevier ScienceDirect Journals |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T12%3A51%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TGF-%CE%B21%20regulation%20of%20human%20AT1%20receptor%20mRNA%20splice%20variants%20harboring%20exon%202&rft.jtitle=Molecular%20and%20cellular%20endocrinology&rft.au=Martin,%20Mickey%20M&rft.date=2006-04-25&rft.volume=249&rft.issue=1-2&rft.spage=21&rft.epage=31&rft.pages=21-31&rft.issn=0303-7207&rft_id=info:doi/10.1016/j.mce.2006.01.009&rft_dat=%3Cproquest_pubme%3E67826408%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=67826408&rft_id=info:pmid/16504375&rfr_iscdi=true |