Translation of the human angiotensin II type 1 receptor mRNA is mediated by a highly efficient internal ribosome entry site.
Activation of the angiotensin II type 1 receptor (AT1R) is closely involved in the pathogenesis of cardiovascular disease. The human AT1R (hAT1R) mRNA splice variants have long 5'-untranslated regions (5'-UTRs) ranging from 272 to 414 bp that have the potential to form stable secondary structures. In this study, we show that the 5'-UTR of hAT(1)R mRNAs contains an internal ribosome entry site (IRES) located within the first 40 bp of the proximal end of exon 1. Experiments utilizing the hAT1R 5'-UTR as a molecular decoy demonstrate a reduction in IRES activity of approximately 50%. This inhibition is most efficient for the hAT1R IRES suggesting that a defined set of trans-factors are required to initiate translation through this cis-element. Translation initiation from the hAT1R IRES appears to be physiologically relevant since IRES activity was maintained during serum starvation, a cellular stress known to inhibit cap-dependent translation. These results suggest that cap-independent translation initiation by internal ribosome entry may represent an important mechanism for the regulation of hAT1R expression.
Martin
Mickey M
MM
Department of Chemistry and Biochemistry, Brigham Young University, C211 BNSN, P.O. Box 25700, Provo, UT 84602-5700, USA.
Garcia
Joseph A
JA
McFarland
Joseph D
JD
Duffy
Aaron A
AA
Gregson
James P
JP
Elton
Terry S
TS
D020121:5' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D009690:Nucleic Acid Conformation; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D012315:RNA Caps; D012333:RNA, Messenger / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012270:Ribosomes / Q000378:metabolism*
D020121:5' Untranslated Regions; D012315:RNA Caps; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins