Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA.

摘要: Post-transcripti onal regulation oftransferrin receptor mRNA levels byironismediated byaportion ofthe3' untranslated region (UTR)ofthemRNA.We have previously shownthat a678nucleotide fragment ofthe 3'UTRcontains theregulatory element(s). Within this arefive RNAstructures whichresemble theironresponsive element (IRE) inthe5'untranslated oftheferritin whichisregulated translationaily byiron. TheIREsfromtheferritin andtransferrin mRNAs competeinaninvitro assayfor interaction withacytoplasmic protein; theactivity ofthis IRE-binding protein isdependent upontheironstatus ofthecells. Basedonfurther deletion analysis reported here, thesequences required forironregulation transferrin havebeenlimited to250nucleotides which wehaveproduced synthetically andcloned. This sequence, whichcontains threeIREs,iscapable of producing iron-dependent levels. Removal ofthethree IREsfromthe synthetic results inlossofironregulation. Moreover, ofasingle cytosine residue fromeach IREsinthesynthetic regulatory eliminates high-affinity binding totheIRE-binding invitro andresults inlowlevels ofironindependent expression, consistent withproduction ofa constitutively unstable mRNA. Thesedataindicate thattheability ofthemRNA to interact withtheIRE-binding isrequired for Certain other deletions within donotaffect theinvitro between the RNA andtheIREbinding result inrelatively highlevels ofiron-independent with production ofaconstitutively stable mRNA.Collectively, ourdatasupport a modelfortransferrin inwhichtheinteraction theIREbinding andthetransferrin can protect thetranscript fromrapid degradation thatis mediated byarapid turnover determinant region.