GALT

Gene Summary

Gene:GALT; galactose-1-phosphate uridylyltransferase
Location:9p13.3
Summary:Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:galactose-1-phosphate uridylyltransferase
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (9)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplastic Cell Transformation
  • Tumor Burden
  • Gene Expression
  • UTP-Hexose-1-Phosphate Uridylyltransferase
  • src-Family Kinases
  • Pedigree
  • Genotype
  • Ovarian Cancer
  • Galactosyltransferases
  • Case-Control Studies
  • Lactose
  • Computer Simulation
  • Transcription
  • Risk Factors
  • Phenotype
  • Biological Models
  • Base Sequence
  • Phosphorylation
  • California
  • Mutation
  • Cancer Gene Expression Regulation
  • Odds Ratio
  • Enzymologic Gene Expression Regulation
  • Cell Cycle
  • Genetic Predisposition
  • Chromosome 9
  • Galactose
  • Transcriptional Activation
  • Sp1 Transcription Factor
  • Messenger RNA
  • Endometriosis
  • Glycosylation
  • Molecular Sequence Data
  • Genetic Linkage
  • Breast Cancer
  • Cell Movement
  • Oligonucleotide Array Sequence Analysis
  • Sequence Homology
  • Polymorphism
  • Dairy Products
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GALT (cancer-related)

Rothschild DE, Zhang Y, Diao N, et al.
Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M.
EBioMedicine. 2017; 15:36-47 [PubMed] Free Access to Full Article Related Publications
Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m(-/-) mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m(-/-) animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m(-/-) mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m(-/-) mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

Tang M, Etokidem E, Lai K
The Leloir Pathway of Galactose Metabolism - A Novel Therapeutic Target for Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(12):6265-6271 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most lethal types of cancer worldwide, with poor prognosis and limited treatments. In order to identify novel therapeutic targets that will lead to development of effective therapies with manageable side effects, we tested the hypothesis that knocking-down galactokinase (GALK1) or galactose-1 phosphate uridylyltransferase (GALT) gene expression would control the growth of cultured hepatoma cells. Our results showed small interfering RNA (siRNA) against GALK1 or GALT inhibited the growth of HepG2 cells in culture. Western blot analysis revealed simultaneous down-regulation of multiple players of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) growth signaling pathway, as well as heat-shock protein 90 (HSP90) and poly ADP ribose polymerase (PARP). Reverse transcription-polymerase chain reaction (RT-PCR) data, however, showed no significant mRNA reduction of the encoded genes. Our study thus not only supports GALK1 and GALT as being possible novel targets for treating HCC, but also uncovers new post-transcriptional regulatory mechanisms that link the galactose metabolic pathway to protein expression of the PI3K/AKT pathway in hepatoma.

Gatto F, Miess H, Schulze A, Nielsen J
Flux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism.
Sci Rep. 2015; 5:10738 [PubMed] Free Access to Full Article Related Publications
Flux balance analysis is the only modelling approach that is capable of producing genome-wide predictions of gene essentiality that may aid to unveil metabolic liabilities in cancer. Nevertheless, a systemic validation of gene essentiality predictions by flux balance analysis is currently missing. Here, we critically evaluated the accuracy of flux balance analysis in two cancer types, clear cell renal cell carcinoma (ccRCC) and prostate adenocarcinoma, by comparison with large-scale experiments of gene essentiality in vitro. We found that in ccRCC, but not in prostate adenocarcinoma, flux balance analysis could predict essential metabolic genes beyond random expectation. Five of the identified metabolic genes, AGPAT6, GALT, GCLC, GSS, and RRM2B, were predicted to be dispensable in normal cell metabolism. Hence, targeting these genes may selectively prevent ccRCC growth. Based on our analysis, we discuss the benefits and limitations of flux balance analysis for gene essentiality predictions in cancer metabolism, and its use for exposing metabolic liabilities in ccRCC, whose emergent metabolic network enforces outstanding anabolic requirements for cellular proliferation.

Gao F, Zhao ZL, Zhao WT, et al.
miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells.
Biochem Biophys Res Commun. 2013; 431(3):610-6 [PubMed] Related Publications
The functions of miR-9 in some cancers are recently implicated in regulating proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis, apoptosis, and tumor angiogenesis, etc. miR-9 is commonly down-regulated in nasopharyngeal carcinoma (NPC), but the exact roles of miR-9 dysregulation in the pathogenesis of NPC remains unclear. Therefore, we firstly used miR-9-expressing CNE2 cells to determine the effects of miR-9 overexpression on global gene expression profile by microarray analysis. Microarray-based gene expression data unexpectedly demonstrated a significant number of up- or down-regulated immune- and inflammation-related genes, including many well-known interferon (IFN)-induced genes (e.g., IFI44L, PSMB8, IRF5, PSMB10, IFI27, PSB9_HUMAN, IFIT2, TRAIL, IFIT1, PSB8_HUMAN, IRF1, B2M and GBP1), major histocompatibility complex (MHC) class I molecules (e.g., HLA-B, HLA-C, HLA-F and HLA-H) and interleukin (IL)-related genes (e.g., IL20RB, GALT, IL7, IL1B, IL11, IL1F8, IL1A, IL6 and IL7R), which was confirmed by qRT-PCR. Moreover, the overexpression of miR-9 with the miRNA mimics significantly up- or down-regulated the expression of above-mentioned IFN-inducible genes, MHC class I molecules and IL-related genes; on the contrary, miR-9 inhibition by anti-miR-9 inhibitor in CNE2 and 5-8F cells correspondingly decreased or increased the aforementioned immune- and inflammation-related genes. Taken together, these findings demonstrate, for the first time, that miR-9 can modulate the expression of IFN-induced genes and MHC class I molecules in human cancer cells, suggesting a novel role of miR-9 in linking inflammation and cancer, which remains to be fully characterized.

Sato T, Furukawa K
[Regulation of human β-1,4-galactosyltransferase V gene expression in cancer cells].
Yakugaku Zasshi. 2012; 132(6):691-7 [PubMed] Related Publications
β-1,4-Galactosyltransferase (β-1,4-GalT) V - whose human and mouse genes were cloned by us - has been suggested to be involved in the biosyntheses of N-glycans, O-glycans, and lactosylceramide by in vitro studies. Our recent study showed that β-1,4-GalT V-knockout mice are embryonic lethal, suggesting the importance of the glycans synthesized by β-1,4-GalT V for embryonic development. A subsequent study showed that murine β-1,4-GalT V is involved in the biosynthesis of lactosylceramide. It is well known that the glycosylation of cell surface glycoproteins and glycolipids changes dramatically upon the malignant transformation of cells. We found that among six β-1,4-GalTs the gene expression of only β-1,4-GalT V increases upon malignant transformation. The expression of the β-1,4-GalT V gene has been shown to be regulated by transcription factors Sp1 and Ets-1 in cancer cells. Both transcription factors regulate the gene expression levels of not only glycosyltransferases, but also key molecules involved in tumor growth, invasion and metastasis. Therefore, the abnormal glycosylation and malignant phenotypes of cancer cells are considered to be suppressed by regulating the expression levels of the transcription factor genes. This review gives a summary account of the gene discovery, in vivo function, and transcriptional mechanism of β-1,4-GalT V. Also, a perspective on applications of the manipulation of transcription factor genes to cancer therapy will be discussed.

Villegas-Comonfort S, Serna-Marquez N, Galindo-Hernandez O, et al.
Arachidonic acid induces an increase of β-1,4-galactosyltransferase I expression in MDA-MB-231 breast cancer cells.
J Cell Biochem. 2012; 113(11):3330-41 [PubMed] Related Publications
Arachidonic acid (AA) is a common dietary n-6 cis polyunsaturated fatty acid that under physiological conditions is present in an esterified form in cell membrane phospholipids, and it might be present in the extracellular microenvironment. AA and its metabolites are implicated in FAK activation and cell migration in MDA-MB-231 breast cancer cells, and an epithelial-to-mesenchymal-like transition process in mammary non-tumorigenic epithelial cells MCF10A. During malignant transformation is present an altered expression of glycosiltransferases, which promote changes on the glycosilation of cell-surface proteins. The β-1,4-galactosyltransferase I (GalT I) is an enzyme that participates in a variety of biological functions including cell growth, migration, and spreading. However, the participation of AA in the regulation of GalT I expression and the role of this enzyme in the cell adhesion process in breast cancer cells remains to be investigated. In the present study, we demonstrate that AA induces an increase of GalT I expression through a PLA2α, Src, ERK1/2, and LOXs activities-dependent pathway in MDA-MB-231 breast cancer cells. Moreover, MDA-MB-231 cells adhere to laminin via GalT I expression and pretreatment of cells with AA induces an increase of cell adhesion to laminin. In conclusion, our findings demonstrate, for the first time, that AA promotes an increase of GalT I expression through an AA metabolism, Src and ERK1/2 activities-dependent pathway, and that GalT I plays a pivotal role in cell adhesion to laminin in MDA-MB-231 breast cancer cells.

Fisicaro N, Londrigan SL, Brady JL, et al.
Versatile co-expression of graft-protective proteins using 2A-linked cassettes.
Xenotransplantation. 2011 Mar-Apr; 18(2):121-30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Expression of multiple graft-protective proteins targeted to different locations (i.e., intracellular, cell surface, and secreted) has become an increasingly important goal in xenotransplantation. The 2A "ribosome skip" signal is used as a linker to enable transgene co-expression, but some studies have shown that post-translational modification and trafficking of 2A-linked proteins may be adversely affected depending on their position relative to 2A. We tested whether several relevant proteins, subject to a range of processing and localization mechanisms, could be efficiently co-expressed using the 2A system.
METHODS: Six expression cassettes were constructed, each containing up to four 2A-linked open reading frames, encoding combinations of human CD55, thrombomodulin (TBM), CD39, CTLA4-Ig and hygromycin resistance. Each linker incorporated a furin cleavage site to remove the carboxy-terminal extension that remains on upstream proteins after 2A processing. The cassettes were used to produce vectors for transfection, adenoviral transduction and transgenesis. Expression was detected by flow cytometry and/or Western blotting.
RESULTS: All proteins were expressed in the appropriate location following transient transfection of COS-7 cells, irrespective of the number of linked genes. The percentage of stable transfectants expressing a linked gene was increased 10-fold (from 4-5% to 58-67%) by incorporating the hygromycin resistance gene into the cassette. Stable transfection of transgenic GalT KO pig fibroblasts with a hygromycin- TBM-CD39 construct resulted in surface expression of both TBM and CD39 by the majority of hygromycin-resistant cells. Expression was maintained after flow cytometric sorting and expansion. Adenoviral transduction of NIT-1 mouse insulinoma cells with a TBM-CD39 construct resulted in strong expression of both genes on the cell surface. Mice transgenic for 3-gene (CD55- TBM-CD39) or 4-gene (CD55- TBM-CTLA4Ig-CD39) constructs expressed all genes except CD55.
CONCLUSIONS: These results confirm the versatility of the 2A system, and demonstrate that careful construct design can minimize potential problems with post-translational modification and trafficking. In addition, incorporation of a selection marker into the 2A-linked chain can dramatically increase the proportion of stable transfectants expressing proteins of interest. This provides a powerful method for the rapid modification of existing genetically modified pigs.

Martin J, St-Pierre MV, Dufour JF
Hit proteins, mitochondria and cancer.
Biochim Biophys Acta. 2011; 1807(6):626-32 [PubMed] Related Publications
The histidine triad (HIT) superfamily comprises proteins that share the histidine triad motif, His-ϕ-His-ϕ-His-ϕ-ϕ, where ϕ is a hydrophobic amino acid. HIT proteins are ubiquitous in prokaryotes and eukaryotes. HIT proteins bind nucleotides and exert dinucleotidyl hydrolase, nucleotidylyl transferase or phosphoramidate hydrolase enzymatic activity. In humans, 5 families of HIT proteins are recognized. The accumulated epidemiological and experimental evidence indicates that two branches of the superfamily, the HINT (Histidine Triad Nucleotide Binding) members and FHIT (Fragile Histidine Triad), have tumor suppressor properties but a conclusive physiological role can still not be assigned to these proteins. Aprataxin forms another discrete branch of the HIT superfamily, is implicated in DNA repair mechanisms and unlike the HINT and FHIT members, a defective protein can be conclusively linked to a disease, ataxia with oculomotor apraxia type 1. The scavenger mRNA decapping enzyme, DcpS, forms a fourth branch of the HIT superfamily. Finally, the GalT enzymes, which exert specific nucleoside monophosphate transferase activity, form a fifth branch that is not implicated in tumorigenesis. The molecular mechanisms by which the HINT and FHIT proteins participate in bioenergetics of cancer are just beginning to be unraveled. Their purported actions as tumor suppressors are highlighted in this review.

Gauthier S, Tremblay MJ
Interleukin-4 inhibits an early phase in the HIV-1 life cycle in the human colorectal cell line HT-29.
Clin Immunol. 2010; 135(1):146-55 [PubMed] Related Publications
Intestinal epithelial cells are continuously in contact with the gut-associated lymphoid tissues (GALT). Gastrointestinal infection by viruses, bacteria and parasites or the presence of an inflammatory bowel disease may influence the GALT cytokine network. However, the effect of the different cytokines on susceptibility of human intestinal epithelial cells to HIV-1 infection remains undefined. We demonstrate here that IL-4 inhibits infection with reporter HIV-1 viruses pseudotyped with NDK-Env without affecting integrated proviral DNA. Furthermore, IL-4 also inhibits, in a dose-dependent manner, infection of HT-29 cells with HIV-1-based AMLV, HTLV-I and VSV-G pseudotypes. A fusion assay showed that this event is not affected by IL-4, thus suggesting that a post-fusion step is affected. A reduction in the completion of DNA retrotranscription indicates that IL-4 may affect this step, or any prior event. Altogether our data indicate that IL-4 is negatively affecting an early post-fusion step in the HIV-1 replication cycle in HT-29 cells.

Wei Y, Liu D, Zhou F, et al.
Identification of beta-1,4-galactosyltransferase I as a target gene of HBx-induced cell cycle progression of hepatoma cell.
J Hepatol. 2008; 49(6):1029-37 [PubMed] Related Publications
BACKGROUND/AIMS: The hepatitis B virus-encoded HBx protein contributes to hepatocarcinogenesis with largely unknown mechanisms. It is widely known that N-linked oligosaccharides on glycoproteins are structurally altered during malignant transformation and these alterations are often associated with malignant transformation of cells. beta-1,4-galactosyltransferase I (GalT I) contributes to the biosynthesis of Galbeta-->4GlcNAc structure in the outer chain moieties of N-glycans.
METHODS: The difference of GalT I expression between normal liver and hepatoma tissues were investigated; the effect of HBx on GalT I expression was investigated; the role of GalT I in hepatoma cell growth and HBx-induced hepatoma cell growth were investigated.
RESULTS: GalT I was highly expressed in hepatocellular carcinoma and transcriptionally up-regulated by HBx, and functioned as a positive growth regulator in hepatoma cells. Furthermore, decreasing the expression of GalT I in hepatoma cells reduced the ability of tumor formation in vivo and inhibited HBx-induced cell cycle progression.
CONCLUSIONS: HBx-induced GalT I expression might contribute to HBx-mediated HCC development and progression.

Jiang J, Wei Y, Shen J, et al.
Functional interaction of E1AF and Sp1 in glioma invasion.
Mol Cell Biol. 2007; 27(24):8770-82 [PubMed] Free Access to Full Article Related Publications
Transcription factor E1AF is widely known to play critical roles in tumor metastasis via directly binding to the promoters of genes involved in tumor migration and invasion. Here, we report for the first time E1AF as a novel binding partner for ubiquitously expressed Sp1 transcription factor. E1AF forms a complex with Sp1, contributes to Sp1 phosphorylation and transcriptional activity, and functions as a mediator between epidermal growth factor and Sp1 phosphorylation and activity. Sp1 functions as a carrier bringing E1AF to the promoter region, thus activating transcription of glioma-related gene for beta1,4-galactosyltransferase V (GalT V; EC 2.4.1.38). Biologically, E1AF functions as a positive invasion regulator in glioma in cooperation with Sp1 partly via up-regulation of GalT V. This report describes a new mechanism of glioma invasion involving a cooperative effort between E1AF and Sp1 transcription factors.

Crowell CK, Qin Q, Grampp GE, et al.
Sodium butyrate alters erythropoietin glycosylation via multiple mechanisms.
Biotechnol Bioeng. 2008; 99(1):201-13 [PubMed] Related Publications
Recombinant human erythropoietin (rHuEPO) produced in a human kidney fibrosarcoma cell line, HT1080, was used as a model to study the effects of sodium butyrate (SB) on protein glycosylation. Treatment with 2 mM SB resulted in complex changes with respect to sugar nucleotide pools including an increase in UDP-Gal and a decrease in UDP-GlcNac. In addition, polylactosamine structures present on rHuEPO increased after SB treatment. To determine if these phenotypic changes correlated with changes in mRNA abundance, we profiled mRNA levels over a 24-h period in the presence or absence of SB using oligonucleotide microarrays. By filtering our data through a functional glycomics gene list associated with the processes of glycan degradation, glycan synthesis, and sugar nucleotide synthesis and transport we identified 26 genes with significantly altered mRNA levels. We were able to correlate the changes in message in six of these genes with measurable phenotypic changes within our system including: neu1, b3gnt6, siat4b, b3gnt1, slc17a5, and galt. Interestingly, for the two genes: cmas and gale, our measurable phenotypic changes did not correlate with changes in mRNA expression. These data demonstrate both the utility and pit falls of coupling biochemical analysis with high throughput oligonucleotide microarrays to predict how changes in cell culture environments will impact glycoprotein oligosaccharide content.

Chen X, Jiang J, Yang J, et al.
Down-regulation of the expression of beta1,4-galactosyltransferase V promotes integrin beta1 maturation.
Biochem Biophys Res Commun. 2006; 343(3):910-6 [PubMed] Related Publications
In previous study, we have shown that beta1,4-galactosyltransferase V (GalT V) functions as a positive growth regulator in glioma. Here, we reported that down-regulation of the expression of GalT V in SHG44 cells by transfection with antisense cDNA specifically up-regulated the expression of cell surface integrin beta1 without the change of its mRNA, and with integrin beta1 125 kDa mature form increased and 105 kDa precursor form decreased. It is well known that the N-glycans of integrins modulate the location and functions of integrins. The SHG44 cells transfected with antisense cDNA of GalT V demonstrated decreased Golgi localization of integrin beta1, strengthened the interaction between integrin alpha5 and beta1 subunit, and enhanced the adhesion ability to fibronectin and the level of focal adhesion kinase phosphorylation. Our results suggested that the down-regulation of the expression of GalT V could promote the expression of cell surface integrin beta1 and subsequently inhibit glioma malignant phenotype.

Jiang J, Chen X, Shen J, et al.
Beta1,4-galactosyltransferase V functions as a positive growth regulator in glioma.
J Biol Chem. 2006; 281(14):9482-9 [PubMed] Related Publications
beta1,4-galactosyltransferase V (GalT V; EC 2.4.1.38) can effectively galactosylate the GlcNAcbeta1-->6Man arm of the highly branched N-glycans that are characteristic of glioma. Previously, we have reported that the expression of GalT V is increased in the process of glioma. However, currently little is known about the role of GalT V in this process. In this study, the ectopic expression of GalT V could promote the invasion and survival of glioma cells and transformed astrocytes. Furthermore, decreasing the expression of GalT V in glioma cells promoted apoptosis, inhibited the invasion and migration and the ability of tumor formation in vivo, and reduced the activation of AKT. In addition, the activity of GalT V promoter could be induced by epidermal growth factor, dominant active Ras, ERK1, JNK1, and constitutively active AKT. Taken together, our results suggest that GalT V functioned as a novel glioma growth activator and might represent a novel target in glioma therapy.

Zhu X, Jiang J, Shen H, et al.
Elevated beta1,4-galactosyltransferase I in highly metastatic human lung cancer cells. Identification of E1AF as important transcription activator.
J Biol Chem. 2005; 280(13):12503-16 [PubMed] Related Publications
The elevated levels of beta1,4-galactosyltransferase I (GalT I; EC 2.4.1.38) are detected in highly metastatic lung cancer PGBE1 cells compared with its less metastatic partner PGLH7 cells. Decreasing the GalT I surface expression by small interfering RNA or interfering with the surface of GalT I function by mutation inhibited cell adhesion on laminin, the invasive potential in vitro, and tyrosine phosphorylation of focal adhesion kinase. The mechanism by which GalT I activity is up-regulated in highly metastatic cells remains unclear. To investigate the regulation of GalT I expression, we cloned the 5'-region flanking the transcription start point of the GalT I gene (-1653 to +52). Cotransfection of the GalT I promoter/luciferase reporter and the Ets family protein E1AF expression plasmid increased the luciferase reporter activity in a dose-dependent manner. By deletion and mutation analyses, we identified an Ets-binding site between nucleotides -205 and -200 in the GalT I promoter that was critical for responsiveness to E1AF. It was identified that E1AF could bind to and activate the GalT I promoter by electrophoretic mobility shift assay in PGLH7 cells and COS1 cells. A stronger affinity of E1AF for DNA has contributed to the elevated expression of GalT I in PGBE1 cells. Stable transfection of the E1AF expression plasmid resulted in increased GalT I expression in PGLH7 cells, and stable transfectants migrated faster than control cells. Meanwhile, the content of the beta1,4-Gal branch on the cell surface was increased in stably transfected PGLH7 cells. GalT I expression can also be induced by epidermal growth factor and dominant active Ras, JNK1, and ERK1. These data suggest an essential role for E1AF in the activation of the human GalT I gene in highly metastatic lung cancer cells.

Sato T, Furukawa K
Transcriptional regulation of the human beta-1,4-galactosyltransferase V gene in cancer cells: essential role of transcription factor Sp1.
J Biol Chem. 2004; 279(38):39574-83 [PubMed] Related Publications
Beta-1,4-galactosyltransferase (beta-1,4-GalT) V is a constitutively expressed enzyme that can effectively galactosylate the GlcNAcbeta1-->6Man group of the highly branched N-glycans that are characteristic of tumor cells. Upon malignant transformation of cells, the expression of the beta-1,4-GalT V gene increases in accordance with the increase in the amounts of highly branched N-glycans. Lectin blot analysis showed that the galactosylation of highly branched N-glycans is inhibited significantly in SH-SY5Y human neuroblastoma cells by the transfection of the antisense beta-1,4-GalT V cDNA, indicating the biological importance of the beta-1,4-GalT V for the functions of highly branched N-glycans. We cloned the 2.3-kb 5'-flanking region of the human beta-1,4-GalT V gene, and we identified the region -116/-18 relative to the transcription start site as that having promoter activity. The region was found to contain several putative binding sites for transcription factors, including AP2, AP4, N-Myc, Sp1, and upstream stimulatory factor. Electrophoretic mobility shift assay showed that Sp1 binds to nucleotide positions -81/-69 of the promoter region. Mutations induced in the Sp1-binding site showed that the promoter activity of the beta-1,4-GalT V gene is impaired completely in cancer cells. In contrast, the promoter activity increased significantly by the transfection of the Sp1 cDNA into A549 human lung carcinoma cells. Mithramycin A, which inhibits the binding of Sp1 to its binding site, reduced the promoter activation and expression of the beta-1,4-GalT V gene in A549 cells. These results indicate that Sp1 plays an essential role in the transcriptional activity of the beta-1,4-GalT V gene in cancer cells.

Kawado T, Hayashi O, Sato T, et al.
Rapid cell senescence-associated changes in galactosylation of N-linked oligosaccharides in human lung adenocarcinoma A549 cells.
Arch Biochem Biophys. 2004; 426(2):306-13 [PubMed] Related Publications
Rapid senescence was induced into human lung adenocarcinoma A549 cells by transforming growth factor-beta1. Lectin blot analysis of membrane glycoprotein samples showed that the binding of Ricinus communis agglutinin-I to protein bands increased markedly while those of other lectins together with protein components did not change significantly with senescence. This indicates that the beta-1,4-galactosylation of N-linked oligosaccharides is stimulated by rapid senescence. Analysis of the enzymatic background of senescence showed 1.5 times higher beta-1,4-galactosyltransferase (beta-1,4-GalT) activity and 2-5 times higher expression levels of beta-1,4-GalT II, III, V, and VI genes are associated with rapid senescence. Incubation of the cells on RCA-I-coated plates in the absence of fetal calf serum showed that the viability of the senescent cells is half that of the control cells. Therefore, it is hypothesized that galactose residues expressed by rapid senescent can induce a lethal signal in cells if they interact with appropriate receptors.

Basu S, Ma R, Mikulla B, et al.
Apoptosis of human carcinoma cells in the presence of inhibitors of glycosphingolipid biosynthesis: I. Treatment of Colo-205 and SKBR3 cells with isomers of PDMP and PPMP.
Glycoconj J. 2004; 20(3):157-68 [PubMed] Related Publications
Apoptosis, or programmed cell death, plays an important role in many physiological and diseased conditions. Induction of apoptosis in cancer cells by anti-cancer drugs and biosynthetic inhibitors of cells surface glycolipids in the human colon carcinoma cells (Colo-205) are of interest in recent years. In our present studies, we have employed different stereoisomers of PPMP and PDMP (inhibit GlcT-glycosyltransferase (GlcT-GLT)) to initiate apoptosis in Colo-205 cells grown in culture in the presence of (3)H-TdR and (3)H/or (14)C-L-Serine. Our analysis showed that the above reagents (between 1 to 20 microM) initiated apoptosis with induction of Caspase-3 activities and phenotypic morphological changes in a dose-dependent manner. We have observed an increase of radioactive ceramide formation in the presence of a low concentration (1-4 microM) of these reagents in these cell lines. However, high concentrations (4-20 microM) inhibited incorporation of radioactive serine in the higher glycolipids. Colo-205 cells were treated with L-threo-PPMP (0-20 microM) and activities of different GSL: GLTs were estimated in total Golgi-pellets. The cells contained high activity of GalT-4 (UDP-Gal: LcOse3Cer beta 1-4galactosyltransferase), whereas negligible activity of GalT-3 (UDP-Gal: GM2 beta 1-3galactosyltransferase) or GM2-synthase activity of the ganglioside pathway was detected. Previously, GLTs involved in the biosynthetic pathway of SA-Le(x) formation had been detected in these colon carcinoma (or Colo-205) cells (Basu M et al. Glycobiology 1, 527-35 (1991)). However, during progression of apoptosis in Colo-205 cells with increasing concentrations of L-PPMP, the GalT-4 activity was decreased significantly. These changes in the specific activity of GalT-4 in the total Golgi-membranes could be the resultant of decreased gene expression of the enzyme.

Fung WL, Risch H, McLaughlin J, et al.
The N314D polymorphism of galactose-1-phosphate uridyl transferase does not modify the risk of ovarian cancer.
Cancer Epidemiol Biomarkers Prev. 2003; 12(7):678-80 [PubMed] Related Publications
It has been proposed that high levels of galactose consumption increase the risk of ovarian cancer. Galactose levels are determined, in part, by the galactose-1-phosphate uridyl transferase gene (GALT). The N314D allele of the GALT gene has been associated with low GALT activity and with an increased risk of ovarian cancer. We screened for the presence of the N314D GALT allele in 891 incident cases of epithelial ovarian cancer and in 364 unaffected female controls. No significant difference in the prevalence of the N314D allele was observed between the cases (18.1%) and the controls (18.7%). The odds ratio associated with the presence of one N314D allele was 0.94 (95% confidence interval (CI), 0.68-1.3; P = 0.70), and the odds ratio associated with two N314D alleles was 1.62 (95% CI, 0.34-7.7; P = 0.54). Subanalyses of the cases by histological type, by age, by ethnic group, by family history, and by BRCA1/2 mutation status did not reveal any significant associations. We conclude that the GALT N314D allele does not predispose to epithelial ovarian cancer.

Lai K, Langley SD, Khwaja FW, et al.
GALT deficiency causes UDP-hexose deficit in human galactosemic cells.
Glycobiology. 2003; 13(4):285-94 [PubMed] Related Publications
Previously we reported that stable transfection of human UDP-glucose pyrophosphorylase (hUGP2) rescued galactose-1-phosphate uridyltransferase (GALT)-deficient yeast from "galactose toxicity." Here we test in human cell lines the hypothesis that galactose toxicity was caused by excess accumulation of galactose-1-phosphate (Gal-1-P), inhibition of hUGP2, and UDP-hexose deficiency. We found that SV40-transformed fibroblasts derived from a galactosemic patient accumulated Gal-1-P from 1.2+/-0.4 to 5.2+/-0.5 mM and stopped growing when transferred from 0.1% glucose to 0.1% galactose. Control fibroblasts accumulated little Gal-1-P and continued to grow. The GALT-deficient cells had 157+/-10 micromoles UDP-glucose/100 g protein and 25+/-5 micromoles UDP-galactose/100 g protein when grown in 0.1% glucose. The control cells had 236+/-25 micromoles UDP- glucose/100 g protein and 82+/-10 micromoles UDP-galactose/100 g protein when grown in identical medium. When we transfected the GALT-deficient cells with either the hUGP2 or GALT gene, their UDP-glucose content increased to 305+/-28 micromoles/100 g protein (hUGP2-transfected) and 210+/-13 micromoles/100 g protein (GALT-transfected), respectively. Similarly, UDP-galactose content increased to 75+/-12 micromoles/100 g protein (hUGP2-transfected) and 55+/-9 micromoles/100 g protein (GALT-transfected), respectively. Though the GALT-transfected cells grew in 0.1% galactose with little accumulation of Gal-1-P (0.2+/-0.02 mM), the hUGP2-transfected cells grew but accumulated some Gal-1-P (3.1+/-0.4 mM). We found that 2.5 mM Gal-1-P increased the apparent KM of purified hUGP2 for glucose-1-phosphate from 19.7 microM to 169 microM, without changes in apparent Vmax. The Ki of the reaction was 0.47 mM. Gal-1-P also inhibited UDP-N-acetylglucosamine pyrophosphorylase, which catalyzes the formation of UDP-N-acetylglucosamine. We conclude that intracellular concentrations of Gal-1-P found in classic galactosemia inhibit UDP-hexose pyrophosphorylases and reduce the intracellular concentrations of UDP-hexoses. Reduced Sambucus nigra agglutinin binding to glycoproteins isolated from cells with increased Gal-1-P is consistent with the resultant inhibition of glycoprotein glycosylation.

Simpson JL
Molecular approach to common causes of female infertility.
Best Pract Res Clin Obstet Gynaecol. 2002; 16(5):685-702 [PubMed] Related Publications
Pivotal genetic information has been derived for a host of rare genetic disorders, but progress has been much slower in relation to the common causes of female infertility. In this chapter, we shall illustrate the approaches being applied in elucidating conditions causing infertility that are inherited in a polygenic/multifactorial fashion. The task is to determine the number of genes responsible and their chromosomal location(s). The first approach is to use genome-wide quantitative linkage analysis, searching throughout the genome with no prior expectation that a given gene or chromosomal region is casually involved. A second approach is to search across the genome for altered gene expression, for example comparing endometriosis and normal (non-endometriosis)cells. The third approach is less indiscriminate and more focused, depending upon identifying specific candidate genes. Aromatase, calhedrin, oestrogen receptor, galactose-1-phosphate uridyl transferase (GALT) and tumour suppressor genes such as p53 are attractive candidate genes for endometriosis. Endometriosis, which has long been suspected to possess a familial tendency, has been subjected to genome-wide linkage analysis in Oxford, UK, where sib-pair analysis uses polymorphic DNA markers and fluorescence-based automated analysis. Several regions of exclusion have been found, but no linkages have so far been reported. A candidate gene approach focuses on the presence of chromosomal aberrations, the assumption being that endometriosis parallels neoplasia. At Baylor College of Medicine, we thus began by showing chromosome alterations involving trisomy 11, monosomy 16 and monosomy 17 in late-stage endometriosis. A loss of only the p53 tumour suppressor gene, rather than a loss (monosomy) of chromosome 17 per se, however, seems to be the pivotal event. A second representative polygenic/multifactorial disorder causing female infertility is polycystic ovarian syndrome. Both quantitative linkage analysis and candidate gene approaches are being pursued. In the far more commonly observed 'idiopathic' variety (non-adrenal polycystic ovarian syndrome and hirsutism), consensus has long existed that one or more dominant genes causes the condition. Although the mode of inheritance in 'essential' polycystic ovarian syndrome remains uncertain, dominant tendencies are clearly more pertinent than recessive ones. Genes for adrenal biosynthetic enzymes, insulin receptors, leptin and leptin receptors, follistatin, activin and inhibins are attractive candidates for polycystic ovarian disease. A linkage to 37 candidate genes was sought using affected sib-pair analysis and transmission/disequilibrium methods.

Xu S, Zhang S, Chen C, et al.
Over-expression of beta-1,4-galactosyltransferase V increases the growth of astrocytoma cell line.
J Exp Clin Cancer Res. 2002; 21(3):409-14 [PubMed] Related Publications
Our previous study showed that the gene expression of beta-1,4-galactosyltransferase V (beta-1,4-GalT V), preferentially galactosylating GlcNAc1-->6Man of oligosaccharides, increased in the process of astrocytoma progress, with the highest level in grade IV astrocytoma. To investigate the function of this beta-1,4-GalT in cell proliferation, the sense and antisense cDNA of beta-1,4-GalT V was constructed as pcDNA3-HA-GalT V and pcDNA3-anti-GalT V respectively and transfected into SHG cell, a kind of human astrocytoma cell line. The transfection was confirmed with Northern and Western blot assay. It was found that the growth of SHG/HA-GalT V in serum-containing medium was faster than that of mock-transfectant with the vector pcDNA3, whereas the growth of SHG/GalTV-AS was slower than that of mock-transfectant. GalTV-HA/SHG showed a stronger capability for colony formation than that of GalTV-AS/SHG as evaluated by anchorage-independent growth in soft agar assay. This result was consistent with that of the growth curve. By RCA-1 lectin assay, the galactosylation on the surface of GalTV-HA/SHG and SHG/GalTV-AS was stained stronger (P<0.001) and weaker (P<0.05) respectively compared with the mock transfectant. This indicates that beta-1,4-GalT V was involved in the malignant phenotype of astrocytoma cells, possibly causing the high galactosylation on the cell surface.

Goodman MT, Wu AH, Tung KH, et al.
Association of galactose-1-phosphate uridyltransferase activity and N314D genotype with the risk of ovarian cancer.
Am J Epidemiol. 2002; 156(8):693-701 [PubMed] Related Publications
Deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme results in accumulation of galactose and its metabolites in the ovary (Am J Epidemiol 1989;130:904-10). Galactose may raise gonadotropin levels, resulting in proliferation of ovarian epithelium. In 1993-1999, the authors conducted a population-based case-control study of ovarian cancer in Hawaii and Los Angeles, California, to examine the hypothesis that reduced GALT activity is associated with an increased risk of ovarian cancer. A total of 239 ovarian cancer cases and 244 population controls were interviewed. A blood sample was collected to measure levels of GALT and to assay for the N314D (A940G) polymorphism of the GALT gene. Covariate-adjusted mean GALT activity was similar between cases (23.8 micro mol per hour/g hemoglobin (Hb)) and controls (23.7 micro mol per hour/g Hb) (p = 0.83). No evidence was found for a dose-response relation between the odds ratios for ovarian cancer and GALT activity or the ratio of lactose intake to GALT activity. The risk associated with the presence of at least one variant Asp314 allele was 0.77 (95% confidence interval: 0.42, 1.41). This study did not support the hypothesis that reduced galactose metabolism is a risk factor for ovarian cancer, although increased GALT activity attenuated the inverse association of oral contraceptive pill use with risk.

Swiersz LM
Role of endometriosis in cancer and tumor development.
Ann N Y Acad Sci. 2002; 955:281-92; discussion 293-5, 396-406 [PubMed] Related Publications
Endometriosis, like cancer, is characterized by cell invasion and unrestrained growth. Furthermore, endometriosis and cancer are similar in other aspects, such as the development of new blood vessels and a decrease in the number of cells undergoing apoptosis. In spite of these similarities, endometriosis is not considered a malignant disorder. The possibility that endometriosis could, however, transform and become cancer has been debated in the literature since 1925. Mutations in the genes that encode for metabolic and detoxification enzymes, such as GALT and GSTM, have been implicated in the pathogenesis of endometriosis and in the progression to carcinoma of the ovary. PTEN, a tumor suppressor commonly mutated (50%) in endometrial carcinoma, is found mutated in endometrioid carcinoma of the ovary, but not in other forms of ovarian cancer. A recent study has shown that somatic mutations in the PTEN gene were identified in 20% of endometrioid carcinomas and 20.6% of solitary endometrial cysts, suggesting that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma. In addition to cancerous transformation at the site of endometriosis, there is recent evidence to indicate that having endometriosis itself may increase a woman's risk of developing non-Hodgkin's lymphoma, malignant melanoma, and breast cancer.

Guo S, Sato T, Shirane K, Furukawa K
Galactosylation of N-linked oligosaccharides by human beta-1,4-galactosyltransferases I, II, III, IV, V, and VI expressed in Sf-9 cells.
Glycobiology. 2001; 11(10):813-20 [PubMed] Related Publications
Several studies showed that Sf-9 cells can synthesize the galactosylated N-linked oligosaccharides if beta-1,4-galactosyltransferase (beta-1,4-GalT) is supplied. The full-length human beta-1,4-GalT I, II, III, IV, V, and VI cDNAs were independently transfected into Sf-9 cells, and the galactosylation of endogenous membrane glycoproteins was examined by lectin blot analysis using Ricinus communis agglutinin-I (RCA-I), which preferentially interacts with oligosaccharides terminated with Galbeta1-->4GlcNAc group. Several RCA-I-reactive bands appeared in all of the gene-transfected cells, and disappeared on treatment of blots with beta-1,4-galactosidase or N-glycanase prior to incubation with lectin. Introduction of the antisense beta-1,4-GalT II and V cDNAs separately into human colorectal adenocarcinoma SW480 cells, in which beta-1,4-GalT I, II, and V genes were expressed, resulted in the reduction of RCA-I binding toward N-linked oligosaccharides of the membrane glycoproteins. Differences were found in their K(m) values toward UDP-Gal and GlcNAcbeta-S-pNP and in their acceptor specificities toward oligosaccharides with the GlcNAcbeta1-->4(GlcNAcbeta1-->2)Man branch and with the GlcNAcbeta1-->6(GlcNAcbeta1-->2)Man branch. These results indicate that beta-1,4-GalTs II, III, IV, V, and VI are involved in the N-linked oligosaccharide biosynthesis cooperatively but not in a redundant manner with beta-1,4-GalT I within cells.

Xu S, Zhu X, Zhang S, et al.
Over-expression of beta-1,4-galactosyltransferase I, II, and V in human astrocytoma.
J Cancer Res Clin Oncol. 2001; 127(8):502-6 [PubMed] Related Publications
PURPOSE: beta-1,4-Galactosyltransferase (beta-1,4-GalT) I, II, and V are the enzymes responsible for the biosynthesis of N-acetyllactosamine on N-glycans by transferring UDP-galactose to the terminal N-acetylglucosamine (N-GlcNAc) residues with the formation of a beta-1,4-linkage. Neoplasms undergo various changes in the carbohydrate of their glycoconjugates, indicating the possible changes in glycosyltransferases themselves.
METHOD: Therefore, we compared the expression of beta-1,4-GalTs between astrocytoma and normal brain tissues.
RESULTS: Our reverse-transcription polymerase chain reaction (RT-PCR) results showed that beta-1,4-GalT I transcript was absent in normal adult brain but detectable in grade II, III, and IV astrocytomas; the level of beta-1,4-GalT II transcript was increased in grade II, III, and IV astrocytomas while only a trace amount was found in normal brain; beta-1,4-GalT V transcript existed in normal brain and increased in the process of astrocytoma progress, with the highest level in grade IV astrocytoma. By Ricinus communis agglutinin-1 (RCA-1) lectin blot assay, we also found the more extensive galactosylated bands in astrocytomas compared with normal brain. A major 61kD protein was galactosylated in astrocytoma but not in normal brain tissues.
CONCLUSION: These results indicate that the increase of galactosylation in astrocytomas may be caused by the alterations of gene expression of beta-1,4-GalT I, II, and V and that the malignant degree of astrocytoma is correlated with the expression of beta-1,4-GalT V.

Sato T, Shirane K, Kido M, Furukawa K
Correlated gene expression between beta-1,4-galactosyltransferase V and N-acetylglucosaminyltransferase V in human cancer cell lines.
Biochem Biophys Res Commun. 2000; 276(3):1019-23 [PubMed] Related Publications
Since our previous study showed that the gene expression level of beta-1,4-galactosyltransferase (beta-1,4-GalT) V is only increased in mouse NIH3T3 transformant and that beta-1,4-GalT V preferentially galactosylates the GlcNAcbeta1 --> 6Man branch of oligosaccharides [Shirane et al. (1999) Biochem. Biophys. Res. Commun. 265, 434-438], whether its gene expression is correlated with malignant transformation was investigated. Northern blot analysis of beta-1, 4-GalTs I, II, III, IV, V, and VI and N-acetylglucosaminyltransferase (GlcNAcT)V in human cancer cell lines showed that the gene expression levels of beta-1,4-GalT V but not other beta-1,4-GalTs are strongly correlated with those of GlcNAcT V whose activity was shown to increase by malignant transformation. These results indicate that beta-1,4-GalT V is involved in the galactosylation of highly branched oligosaccharides characteristic of malignantly transformed cells.

Cramer DW, Greenberg ER, Titus-Ernstoff L, et al.
A case-control study of galactose consumption and metabolism in relation to ovarian cancer.
Cancer Epidemiol Biomarkers Prev. 2000; 9(1):95-101 [PubMed] Related Publications
Consumption or metabolism of dairy sugar and ovarian cancer have been linked based on evidence that galactose may be toxic to ovarian germ cells and that ovarian cancer is induced in animals by depletion of oocytes. We assessed consumption of dairy products and obtained blood for biochemical and molecular genetic assessment of galactose metabolism in 563 women with newly diagnosed epithelial ovarian cancer and 523 control women selected either by random digit dialing or through lists of residents in eastern Massachusetts and New Hampshire. We observed no significant differences between cases and controls in usual consumption of various types of dairy products or total daily lactose (the principal source of galactose in the diet); nor did we find that RBC activity of either galactose-1-phosphate uridyl transferase (GALT) or galactokinase differed. The mean (and SE) activity of uridine diphospho-galactose 4'-epimerase (in micromoles per hour per gram of hemoglobin) was, however, significantly lower (P < 0.005) in cases compared with controls, 20.32 (0.31) versus 21.64 (0.36). Ovarian cancer cases were also more likely to carry the N314D polymorphism of the GALT gene, generally predisposing to lower GALT activity. The difference was most evident for endometrioid and clear cell types of ovarian cancer, in which 3.9% of cases were found to be homozygous for N314D compared with 0.4% of controls, yielding an odds ratio and 95% confidence interval of 14.17 (2.62-76.60). We conclude that, whereas adult consumption of lactose carries no clear risk for the disease, certain genetic or biochemical features of galactose metabolism may influence disease risk for particular types of ovarian cancer.

Borsig L, Imbach T, Höchli M, Berger EG
alpha1,3Fucosyltransferase VI is expressed in HepG2 cells and codistributed with beta1,4galactosyltransferase I in the golgi apparatus and monensin-induced swollen vesicles.
Glycobiology. 1999; 9(11):1273-80 [PubMed] Related Publications
The major alpha1,3fucosyltransferase activity in plasma, liver, and kidney is related to fucosyltransferase VI which is encoded by the FUT6 gene. Here we demonstrate the presence of alpha1, 3fucosyltransferase VI (alpha3-FucT VI) in the human HepG2 hepatoma cell line by specific activity assays, detection of transcripts, and the use of specific antibodies. First, FucT activity in HepG2 cell lysates was shown to prefer sialyl-N-acetyllactosamine as acceptor substrate indicating expression of alpha3-FucT VI. RT-PCR analysis further confirmed the exclusive presence of the alpha3-FucT VI transcripts among the five human alpha3-FucTs cloned to date. alpha3-FucT VI was colocalized with beta1,4galactosyltransferase I (beta4-GalT I) to the Golgi apparatus by dual confocal immunostaining. Pulse/chase analysis of metabolically labeled alpha3-FucT VI showed maturation of alpha3-FucT VI from the early 43 kDa form to the mature, endoglycosidase H-resistant form of 47 kDa which was detected after 2 h of chase. alpha3-FucT VI was released to the medium and accounted for 50% of overall cell-associated and released enzyme activity. Release occurred by proteolytical cleavage which produced a soluble form of 43 kDa. Monensin treatment segregated alpha3-FucT VI from the Golgi apparatus to swollen peripheral vesicles where it was colocalized with beta4-GalT I while alpha2,6(N)sialyltransferase remained associated with the Golgi apparatus. Both constitutive secretion of alpha3-FucT VI and its monensin-induced relocation to vesicles analogous to beta4-GalT I suggest a similar post-Golgi pathway of both alpha3-FucT VI and beta4-GalT I.

Phillips-Quagliata JM, Faria AM, Han J, et al.
The IgG2a/IgA produced by the murine T560 B lymphoma that arose during a graft-versus-host reaction is polyreactive and somatically mutated.
Autoimmunity. 1999; 29(3):215-33 [PubMed] Related Publications
In mice undergoing a graft-versus-host (GVH) reaction, donor T cells responding to the host's MHC antigens induce polyclonal activation of the host's B cells and secretion of their antibodies and autoantibodies. T560, a CD5- B lymphoma that arose in the gut-associated lymphoid tissue (GALT) of a (B10 x B10.H2aH4(b)pWts) F1 hybrid mouse that had been injected with parental B10.H2aH4b splenocytes, is of particular interest because it produces switched, heavily mutated, but, nevertheless, polyreactive immunoglobulin. T560 bears and contains IgG2a but switches to IgA spontaneously. The T560 Ig variable region is encoded by a V186.2-related VH gene, juxtaposed to DFL 16 and J(H)1, and by a Vkappa gene of the Vkappa 4/5 group juxtaposed to Jkappa1. Both VH and VK are heavily mutated. The IgA binds to polystyrene, to p-azophenyl-phosphorylcholine (PC)-conjugated keyhole limpet hemocyanin (KLH) (PC-KLH), to 2,4,6 trinitrophenylated (TNP)-KLH and to human TNF-beta but not to KLH, human TNF-alpha, or any of several other Ags tested. Hapten inhibition experiments indicate that the polystyrene, PC- and TNP-binding sites do not overlap. The switched isotypes and heavy load of somatic mutations found in the T560 IgG2a/IgA suggest that T cell-dependant somatic selection of the T560 precursor B cell may have been superimposed on polyclonal B cell activation originally associated with the GVH.

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