Disease relevance of TFRC

• PIK3CA and TFRC located in 3q are new prognostic factors in esophageal squamous cell carcinoma [1].
• TFRC mRNA expression correlated with distant metastasis (P = .04) [1].
• The cell lines of pancreatic cancer were characterised by a low expression of TFRC in vitro [2].
• Three neuroendocrine carcinomas showed positive expression of TFRC by malignant tumour cells [2].
• In patients with secondary iron overload, a down-regulation of duodenal TfR gene expression and a concomitant increase in ferritin mRNA content were documented [3].

Psychiatry related information on TFRC

• Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome [4].
• These results suggest that transferrin receptor density was decreased in some cortical areas including the hippocampus in Alzheimer's disease but relatively unchanged in cerebral microvessels [5].
• It is suggested that the elevation of plasma TfR levels might be a trait phenomenon in bipolar disorder [6].
• Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls [7].
• We describe the analysis of a thyroid hormone receptor (TR) beta causing resistance to thyroid hormone, the patient exhibiting hypothyroid symptoms (severe mental retardation, hypoactivity, obesity) and hyperthyroid symptoms (tachycardia, low serum cholesterol) and, additionally, relative early puberty, advanced bone age, and short stature [8].

High impact information on TFRC

• TTP specifically regulates the internalization of the transferrin receptor [9].
• Structure of the human transferrin receptor-transferrin complex [10].
• How does the iron (Fe) binding protein, transferrin (Tf), bind to the transferrin receptor 1 (TfR1) to donate Fe to cells [11]?
• Diferric Trf interacts with cell-surface Trf receptor (Trfr) to undergo receptor-mediated endocytosis into specialized endosomes [12].
• Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor [13].

Chemical compound and disease context of TFRC

• Experiments, using human hepatoma cells (HuH7) transfected with TR antisense (sense for control) RNA expression vectors to suppress TR expression, were performed to examine the effect of unlabeled NTB-Fe as iron citrate on the uptake of 59Fe-125I-transferrin [14].
• Suramin, a compound that has been used to treat metastatic prostate cancer, has been demonstrated to antagonize the binding of transferrin to the transferrin receptor and to suppress uptake of iron by hematopoietic cells [15].
• During erythrocytic differentiation of murine erythroleukemia (MEL) cells induced by dimethylsulfoxide, expression of TfR1 increased, whereas TfR2 decreased [16].
• Single-chain immunotoxins directed at the human transferrin receptor containing Pseudomonas exotoxin A or diphtheria toxin: anti-TFR(Fv)-PE40 and DT388-anti-TFR(Fv) [17].
• In this study, exogenous NO produced by adding the NO-generator S-nitroso-N-acetyl penicillamine gave a dose-dependent upregulation of transferrin receptor expression by K562 erythroleukemia cells and increased levels of transferrin receptor mRNA [18].

Biological context of TFRC

• Iron regulatory proteins (IRPs) 1 and 2 post-transcriptionally control mammalian iron homeostasis by binding to iron-responsive elements (IREs), conserved RNA stem-loop structures located in the 5'- or 3'-untranslated regions of genes involved in iron metabolism (e.g. FTH1, FTL, and TFRC) [19].
• This study analyzed the clinical effect of messenger RNA (mRNA) expression for PIK3CA (the gene that encodes phosphatidylinositol-3 kinase catalytic alpha-polypeptide) and TFRC (the gene that encodes the transferrin receptor), which map within chromosome 3q in ESCC [1].
• Stratification of HFE genotype by TFRC genotype did not change the results [20].
• NotI linking/jumping clones of human chromosome 3: mapping of the TFRC, RAB7 and HAUSP genes to regions rearranged in leukemia and deleted in solid tumors [21].
• We investigated whether the cytoplasmic domain of 65 N-terminal amino acids or phosphorylated sites within this domain constitute a structure that is required for TR endocytosis [22].

Anatomical context of TFRC

• It was strongly expressed by malignant epithelial cells; normal stromal and endothelial cells were not stained by anti-TFRC antibodies [2].
• The expression of TFRC was negative in benign neuroendocrine tumours of the pancreas [2].
• The TFRC gene was mapped to 3q29, close to the telomeric marker D3S2344, by linkage analysis, a panel of hybrid cell lines, GeneBridge 4 panel and FISH [21].
• On a cell membrane containing both proteins, HFE would 'lie down' parallel to the membrane, such that the HFE helices that delineate the counterpart of the MHC peptide-binding groove make extensive contacts with helices in the TfR dimerization domain [23].
• Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy [24].

Associations of TFRC with chemical compounds

• To test this hypothesis, we modified the cytoplasmic serine residues or introduced a deletion of 36 amino acids by in vitro mutagenesis of a cDNA expression vector for human TR [22].
• Consequently, little if any in TfR expression at the cell surface was measured during Baf treatment [25].
• Transferrin receptor-dependent and -independent iron transport in gallium-resistant human lymphoid leukemic cells [26].
• Thymidine incorporation was maximal early in the second week of culture and coincided with high transferrin receptor expression [27].
• Exposure of cells grown in Fe or treated with DMSO to cycloheximide did not alter Tf receptor mRNA levels, thereby suggesting that receptor expression was not regulated by posttranscriptional processes dependent on protein synthesis [28].

Physical interactions of TFRC

• Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor [23].
• To investigate the underlying mechanism, we generated several TfR mutants with different binding affinities for transferrin [29].
• Multiple, conserved iron-responsive elements in the 3'-untranslated region of transferrin receptor mRNA enhance binding of iron regulatory protein 2 [30].
• Cross-linking of FcalphaRI but not of TfR resulted in up-regulation of major histocompatibility complex (MHC) class II/CD86 expression and secretion of IL-10 and IL-12 by immature Mo-DC [31].
• Co-immunoprecipitation experiments show that hTfR is able to interact with a mu-adaptin subunit from Arabidopsis cytosol, a process that is blocked by tyrphostin A23 [32].

Co-localisations of TFRC

• Interestingly, neither form of DMT1 colocalizes with the transferrin receptor [33].
• In vivo, CLIP-170 colocalizes with a subset of transferrin receptor-positive endocytic structures and, more extensively, with endosomal tubules induced by brefeldin A [34].
• TFPI also colocalized with antibodies to the human transferrin receptor, a marker for early endocytic, recycling compartment [35].
• A zinc finger domain deletion mutant of Hrs was also colocalized with the transferrin receptor, suggesting that the zinc finger domain is not required for its correct localization [36].
• Subcellular fractionation showed that KAP85 co-localizes with a plasma-membrane-enriched fraction that includes the transferrin receptor and KS-1 antigen [37].

Regulatory relationships of TFRC

• Herein we show that TfR is required for and controls the assembly and the intracellular transport and surface expression of HFE [38].
• The uptake of 59Fe-Tf but not 59Fe-PIH could be blocked by an anti-TfR monoclonal antibody [26].
• TfR2-alpha-expressing cells had considerably lower affinity for holotransferrin when compared with TfR1-expressing CHO cells [39].
• The loss of VHL strongly up-regulated transferrin receptor expression in RCC10 cells as a result of hypoxia inducible factor-1 (HIF-1)-mediated transcriptional activation, leading to an increased uptake of transferrin-bound 55Fe [40].
• The acute-phase protein alpha 1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts [41].

Other interactions of TFRC

• We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles [13].
• Metabolic labeling studies indicate that TfR2 protein levels are approximately 20-fold lower than TfR in these cells [42].
• The increase in iron uptake is independent of DMT1 and TfR, suggesting an unknown transporter [43].
• The region of recurrent increase is approximately 30 Mb in extent, ranging from EVI1 to TFRC [44].
• RESULTS: Perl's staining showed increased iron in colorectal cancers, and there was a corresponding overexpression of components of the intracellular iron import machinery (DCYTB, DMT1, and TfR1) [45].

Analytical, diagnostic and therapeutic context of TFRC

• Flow cytometry was used for the investigation of TFRC expression in nine cell lines of ductal pancreatic cancer in vitro [2].
• The expression of TFRC, transferrin and cytokeratin was studied by standard immunohistochemistry [2].
• Case-control studies have reported associations between HFE mutations C282Y/H63D and several cancers, some of which in interaction with the transferrin receptor gene TFRC or dietary iron intake [46].
• Using cryo-electron microscopy, we have produced a density map of the TfR-Tf complex at subnanometer resolution [10].
• Immunofluorescence studies showed that the protein is expressed on the surface of cells, presumably bound to transferrin receptor [47].

References