Linked Life Data

20724482

Source:http://linkedlifedata.com/resource/pubmed/id/20724482

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
44
pubmed:dateCreated
2010-10-25
pubmed:abstractText
Folates are essential vitamins that play a key role as one-carbon donors in a spectrum of biosynthetic pathways including RNA and DNA synthesis. The proton-coupled folate transporter (PCFT/SLC46A1) mediates obligatory intestinal folate absorption. Loss-of-function mutations in PCFT result in hereditary folate malabsorption, an autosomal recessive disorder characterized by very low folate levels in the blood and cerebrospinal fluid. Hereditary folate malabsorption manifests within the first months after birth with anemia, immune deficiency, and neurological deficits. Here we studied the role of inducible trans-activators of PCFT gene expression. Bioinformatics identified three putative nuclear respiratory factor 1 (NRF-1) binding sites in the minimal promoter. The following evidence establish that PCFT is an NRF-1-responsive gene; electrophoretic mobility shift assay showed NRF-1 binding to native but not mutant NRF-1 sites, whereas antibody-mediated supershift analysis and chromatin immunoprecipitation revealed NRF-1 binding to its consensus sites within the PCFT promoter. Moreover, mutational inactivation of individual or all NRF-1 binding sites resulted in 40-60% decrease in luciferase reporter activity. Consistently, overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. Conversely, introduction of a dominant-negative NRF-1 construct markedly repressed reporter activity and PCFT mRNA levels; likewise, introduction of NRF-1 siRNA duplexes to cells resulted in decreased PCFT transcript levels. Moreover, NRF-1 silencing down-regulated genes encoding for key folate transporters and enzymes in folate metabolism. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. The implications of this linkage between folate transport and metabolism with mitochondria biogenesis and respiration are discussed.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
29
pubmed:volume
285
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
33602-13
pubmed:dateRevised
2011-10-31
pubmed:meshHeading
pubmed-meshheading:20724482-Amino Acid Sequence, pubmed-meshheading:20724482-Binding Sites, pubmed-meshheading:20724482-Folic Acid, pubmed-meshheading:20724482-Gene Expression Regulation, Neoplastic, pubmed-meshheading:20724482-HeLa Cells, pubmed-meshheading:20724482-Humans, pubmed-meshheading:20724482-Kinetics, pubmed-meshheading:20724482-Membrane Transport Proteins, pubmed-meshheading:20724482-Mitochondria, pubmed-meshheading:20724482-Molecular Sequence Data, pubmed-meshheading:20724482-Mutagenesis, Site-Directed, pubmed-meshheading:20724482-Nuclear Respiratory Factor 1, pubmed-meshheading:20724482-Promoter Regions, Genetic, pubmed-meshheading:20724482-Proton-Coupled Folate Transporter, pubmed-meshheading:20724482-RNA Interference, pubmed-meshheading:20724482-Sequence Homology, Amino Acid
pubmed:year
2010
pubmed:articleTitle
The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1.
pubmed:affiliation
Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
pubmed:publicationType
Journal Article