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

Abstract

region (UTR); heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1); pteroylglutamate (PteGlu); Dulbecco's PBS (D-PBS); chloramphenicol acetyltransferase (CAT); with a cis-element (+cis); lacking a cis-element (-cis).

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

“…The short-term negative impact of this procedure upon total Folr1 expression supports the finding of Saitsu et al (2003) and Sato et al (2008), where the site of neural tube closure/neural crest formation also is a principal site of Folr1 expression in the early (2-10 somite) embryo. The apparent rebound effect of the Folr1 expression that occurred between 48 and 96 hr subsequent its initial knockdown is consistent with the magnitude of Folr1 up-regulation that can occur within 8 hr of the onset of a folate deficiency in several cell lines or in kidney cells (Hsueh and Dolnick, 1993;Said et al, 2000;Zhu et al, 2001;Sadasivan et al, 2002;Antony et al, 2004). Additionally, the expression of the folate receptor can be induced during folate insufficiency in some tissues where it is not normally expressed (Xiao et al, 2005).…”

Influence of Physiologic Folate Deficiency on Human Papillomavirus Type 16 (HPV16)-harboring Human Keratinocytes in Vitro and in Vivo

“…NIH 3T3 cells were likewise adapted to modified F-HF or F-LF medium for over 10 weeks to ensure stable intracellular folate levels (10). Before being placed on the raft, (HPV16)BC-1-Ep/SL-HF and (HPV16)BC-1-Ep/ SL-LF cells were cultured on mitomycin C-treated F-HF or F-LF NIH3T3 feeder layers, respectively.…”

“…4D, the measured mRNA levels of pCAT control were not signifi- . pSV-␤-gal was used as an internal control, and the chemiluminescent assay for quantitative determination of ␤-galactosidase activity in transfected cells was employed to monitor transfection efficiency (10). All data were normalized by internal standard and protein content of each treatment.…”

“…Because this RNA-protein interaction was stimulated by homocysteine, which accumulates intracellularly during folate deficiency, this work established a link between perturbed folate metabolism and coordinated translational regulation of folate receptors (10). Using purified components, we recently determined that the molecular mechanism of this posttranscriptional up-regulation of folate receptors during folate deficiency involves a concentration-dependent homocysteinylation of various cysteine residues within the (mRNA-binding) K-homology domains of hnRNP-E1, which probably leads to the sequential disruption of critical cysteine-S-S-cysteine bonds by the formation of multiple homocysteine-S-S-cysteine mixed disulfide bonds in hnRNP-E1 (11).…”

“…Because this research had uncovered unexpected connections between folate deficiency, homocysteine, hnRNP-E1, and HPV16 (7,10,11), we determined the functional physiological consequence of folate deficiency to HPV16 viral capsid protein expression using a model of HPV16-harboring human keratinocytes ((HPV16)BC-1-Ep/SL cells) that expressed the full complement of HPV16 RNA when propagated as monolayers. Further extension of these studies to HPV16-organotypic rafts and additional animal studies suggests that folate deficiency is a likely (reversible) co-factor in HPV16-induced malignancies.…”