Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions

Asok Antony, Ying Sheng Tang, Rehana A. Khan, Mangatt P. Biju, Xiangli Xiao, Qing Jun Li, Xin Lai Sun, Hiremagalur N. Jayaram, Sally P. Stabler

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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 transfactor (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.

Original languageEnglish
Pages (from-to)285-301
Number of pages17
JournalJournal of Clinical Investigation
Volume113
Issue number2
DOIs
StatePublished - Jan 2004

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Heterogeneous-Nuclear Ribonucleoproteins
Homocysteine
Folic Acid
Up-Regulation
RNA
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions. / Antony, Asok; Tang, Ying Sheng; Khan, Rehana A.; Biju, Mangatt P.; Xiao, Xiangli; Li, Qing Jun; Sun, Xin Lai; Jayaram, Hiremagalur N.; Stabler, Sally P.

In: Journal of Clinical Investigation, Vol. 113, No. 2, 01.2004, p. 285-301.

Research output: Contribution to journalArticle

Antony, Asok ; Tang, Ying Sheng ; Khan, Rehana A. ; Biju, Mangatt P. ; Xiao, Xiangli ; Li, Qing Jun ; Sun, Xin Lai ; Jayaram, Hiremagalur N. ; Stabler, Sally P. / Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 2. pp. 285-301.
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abstract = "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 transfactor (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.",
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