Braakman

Burckhardt

Desmoulin

Flatley

Ifergan

Jansen

Kugel Desmoulin

Laemmli

Larry H. Matherly

Lowry

Lucock

Matherly

Moscow

Payton

Sadasivan

Salazar

Sirotnak

Steve Orr

Stokstad

Stover

Subramanian

Whetstine

Witt

Wong

Zhanjun Hou

Zhao

Bioscience Reports

The RFC (reduced folate carrier) is the principal mechanism by which folates and clinically used antifolates are delivered to mammalian cells. hRFC (human RFC) is subject to complex transcriptional controls and exists as homo-oligomer. To explore the post-transcriptional regulation of hRFC by exogenous folates, hRFC-null HeLa cells were stably transfected with hRFC under control of a constitutive promoter. hRFC transcripts and the total membrane protein increased with increasing LCV [(6R,S)5-formyl tetrahydrofolate (leucovorin)] with a maximum at 20 nM LCV, attributable to reduced turnover of hRFC transcripts. hRFC homo-oligomerization was unaffected by increasing LCV. Cell surface hRFC paralleled [3H]methotrexate transport and increased from 0.5 to 2 nM LCV, and then decreased (~2-fold) with increasing LCV up to 20 nM. hRFC was localized to the cell surface at low LCV concentrations (0.5–1.5 nM). However, at higher LCV concentrations, significant intracellular hRFC was localized to the ER (endoplasmic reticulum), such that at 20 nM LCV, intracellular hRFC was predominated. Our results demonstrate a novel post-transcriptional regulation of hRFC involving: (i) increased hRFC transcripts and proteins, accompanying increased extracellular folates, attributable to differences in hRFC transcript stabilities; and (ii) increased retention of hRFC in the ER under conditions of folate excess, because of impaired intracellular trafficking and plasma membrane targeting.</jats:p

Crossref

Post-transcriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency

http://www.bioscirep.org/content/ppbioscirep/34/4/e00130.full.pdf

Post-transcriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency

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