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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\u00a0nM 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\u00a0nM LCV, and then decreased (~2-fold) with increasing LCV up to 20\u00a0nM. hRFC was localized to the cell surface at low LCV concentrations (0.5\u20131.5\u00a0nM). However, at higher LCV concentrations, significant intracellular hRFC was localized to the ER (endoplasmic reticulum), such that at 20\u00a0nM 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>","DOI":"10.1042\/bsr20140065","type":"journal-article","created":{"date-parts":[[2014,6,23]],"date-time":"2014-06-23T08:38:06Z","timestamp":1403512686000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Post-transcriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency"],"prefix":"10.1042","volume":"34","author":[{"given":"Zhanjun","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Oncology Wayne State University School of Medicine, Detroit, Michigan, U.S.A."},{"name":"Molecular Therapeutics Programme, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Oncology Wayne State University School of Medicine, Detroit, Michigan, U.S.A."},{"name":"Molecular Therapeutics Programme, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry\u00a0H.","family":"Matherly","sequence":"additional","affiliation":[{"name":"Department of Oncology Wayne State University School of Medicine, Detroit, Michigan, U.S.A."},{"name":"Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, U.S.A."},{"name":"Molecular Therapeutics Programme, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2014,8,6]]},"reference":[{"key":"2021111619182935500_B1","first-page":"1","article-title":"Historical perspective on key advances in the biochemistry and physiology of folates","volume-title":"Contemporory Issues in Clinical Nutrition: Folic Acid Metabolism in Health and Diesease","author":"Stokstad","year":"1990"},{"key":"2021111619182935500_B2","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1089\/ars.2012.4554","article-title":"Folate and DNA methylation","volume":"17","author":"Ly","year":"2012","journal-title":"Antioxid. 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