Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions.
Cellular acquisition of folate is mediated by folate receptors (FRs) in many malignant and normal human cells. Although FRs are upregulated in folate deficiency and downregulated following folate repletion, the mechanistic basis for this relationship is unclear. Previously we demonstrated that interaction of an 18-base cis-element in the 5'-untranslated region of FR mRNA and a cystolic trans-factor (heterogeneous nuclear ribonucleoprotein E1 [hnRNP E1]) is critical for FR synthesis. However, the molecular mechanisms controlling this interaction, especially within the context of FR regulation and folate status, have remained obscure. Human cervical carcinoma cells exhibited progressively increasing upregulation of FRs after shifting of folate-replete cells to low-folate media, without a proportionate rise in FR mRNA or rise in hnRNP E1. Translational FR upregulation was accompanied by a progressive accumulation of the metabolite homocysteine within cultured cells, which stimulated interaction of the FR mRNA cis-element and hnRNP E1 as well as FR biosynthesis in a dose-dependent manner. Abrupt reversal of folate deficiency also led to a rapid parallel reduction in homocysteine and FR biosynthesis to levels observed in folate-replete cells. Collectively, these results suggest that homocysteine is the key modulator of translational upregulation of FRs and establishes the linkage between perturbed folate metabolism and coordinated upregulation of FRs.
Antony
Aśok
A
Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, and Richard L. Roudebush Veteran Affairs Medical Center, Indianapolis, USA. aantony@iupui.edu
Tang
Ying-Sheng
YS
Khan
Rehana A
RA
Biju
Mangatt P
MP
Xiao
Xiangli
X
Li
Qing-Jun
QJ
Sun
Xin-Lai
XL
Jayaram
Hiremagalur N
HN
Stabler
Sally P
SP
D020121:5' Untranslated Regions; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000737:chemistry* / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D020121:5' Untranslated Regions; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058973:Folate Receptors, GPI-Anchored; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C094604:PCBP1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D006710:Homocysteine; D012313:RNA; D005492:Folic Acid