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Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, Thomas JW, Hiebert S, Haase VH, Boothby MR
(2016) Nature 537: 234-238
MeSH Terms: Animals, Antibodies, B-Lymphocytes, Cell Hypoxia, Cell Proliferation, Cell Survival, Cytosine Deaminase, Germinal Center, Hypoxia, Immunoglobulin Class Switching, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Multiprotein Complexes, TOR Serine-Threonine Kinases
Show Abstract · Added August 9, 2016
Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.
1 Communities
4 Members
0 Resources
15 MeSH Terms
Genetic analysis of the localization of APOBEC3F to human immunodeficiency virus type 1 virion cores.
Donahue JP, Levinson RT, Sheehan JH, Sutton L, Taylor HE, Meiler J, D'Aquila RT, Song C
(2015) J Virol 89: 2415-24
MeSH Terms: Cell Line, Cytosine Deaminase, DNA Mutational Analysis, Genes, Reporter, HIV-1, Humans, Luciferases, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Missense, Staining and Labeling, Virus Assembly, beta-Galactosidase
Show Abstract · Added January 24, 2015
UNLABELLED - Members of the APOBEC3 family of cytidine deaminases vary in their proportions of a virion-incorporated enzyme that is localized to mature retrovirus cores. We reported previously that APOBEC3F (A3F) was highly localized into mature human immunodeficiency virus type 1 (HIV-1) cores and identified that L306 in the C-terminal cytidine deaminase (CD) domain contributed to its core localization (C. Song, L. Sutton, M. Johnson, R. D'Aquila, J. Donahue, J Biol Chem 287:16965-16974, 2012, http://dx.doi.org/10.1074/jbc.M111.310839). We have now determined an additional genetic determinant(s) for A3F localization to HIV-1 cores. We found that one pair of leucines in each of A3F's C-terminal and N-terminal CD domains jointly determined the degree of localization of A3F into HIV-1 virion cores. These are A3F L306/L368 (C-terminal domain) and A3F L122/L184 (N-terminal domain). Alterations to one of these specific leucine residues in either of the two A3F CD domains (A3F L368A, L122A, and L184A) decreased core localization and diminished HIV restriction without changing virion packaging. Furthermore, double mutants in these leucine residues in each of A3F's two CD domains (A3F L368A plus L184A or A3F L368A plus L122A) still were packaged into virions but completely lost core localization and anti-HIV activity. HIV virion core localization of A3F is genetically separable from its virion packaging, and anti-HIV activity requires some core localization.
IMPORTANCE - Specific leucine-leucine interactions are identified as necessary for A3F's core localization and anti-HIV activity but not for its packaging into virions. Understanding these signals may lead to novel strategies to enhance core localization that may augment effects of A3F against HIV and perhaps of other A3s against retroviruses, parvoviruses, and hepatitis B virus.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1 Communities
3 Members
0 Resources
13 MeSH Terms
APOBEC3 deletion polymorphism is associated with breast cancer risk among women of European ancestry.
Xuan D, Li G, Cai Q, Deming-Halverson S, Shrubsole MJ, Shu XO, Kelley MC, Zheng W, Long J
(2013) Carcinogenesis 34: 2240-3
MeSH Terms: Adult, Aged, Breast Neoplasms, Case-Control Studies, Cytosine Deaminase, European Continental Ancestry Group, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Middle Aged, Odds Ratio, Polymorphism, Genetic, Risk Factors, Tennessee
Show Abstract · Added December 10, 2013
Copy number variations occur frequently in the genome and are a significant source of human genetic variation accounting for disease. Recently, we discovered a common deletion located in the APOBEC3A and APOBEC3B genes significantly associated with breast cancer in Chinese women. Investigating this locus in other populations would be an expedient way to evaluate the generalizability of the novel finding. We analyzed the APOBEC3 deletion in a large study of 3273 European-ancestry women (including 1671 breast cancer cases and 1602 controls) from the population-based Nashville Breast Health Study. All participants were genotyped using real-time qualitative PCR. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between the deletion polymorphism and breast cancer risk. The APOBEC3 deletion was observed in 12.4% of cases and 10.4% of controls. The deletion was significantly associated with breast cancer risk, with ORs and 95% CIs of 1.21 (1.02-1.43) associated with one-copy deletion and 2.29 (1.04-5.06) associated with two-copy deletion compared with women with no deletion (P for trend = 0.005). The positive association of the APOBEC3 deletion with breast cancer risk was similar for estrogen receptor-positive and estrogen receptor-negative breast cancer and was not modified by known breast cancer risk factors. Results from this study confirmed the association of the APOBEC3 deletion with breast cancer risk among women of European ancestry.
0 Communities
6 Members
0 Resources
15 MeSH Terms
A common deletion in the APOBEC3 genes and breast cancer risk.
Long J, Delahanty RJ, Li G, Gao YT, Lu W, Cai Q, Xiang YB, Li C, Ji BT, Zheng Y, Ali S, Shu XO, Zheng W
(2013) J Natl Cancer Inst 105: 573-9
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Breast Neoplasms, China, Cytosine Deaminase, DNA Copy Number Variations, Female, Gene Deletion, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Odds Ratio, Real-Time Polymerase Chain Reaction, Risk Assessment, Risk Factors
Show Abstract · Added December 10, 2013
BACKGROUND - Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.
METHODS - We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.
RESULTS - Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10(-4)) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10(-22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10(-24)).
CONCLUSIONS - We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
0 Communities
4 Members
0 Resources
17 MeSH Terms
Transcriptional control of activation-induced cytidine deaminase and error-prone DNA polymerases is functionally mature in the B cells of infants at birth.
Bowen AL, Tian C, LaFleur BJ, Crowe JE
(2006) Hum Immunol 67: 43-6
MeSH Terms: Adult, B-Lymphocytes, Cytidine Deaminase, Cytosine Deaminase, DNA-Directed DNA Polymerase, Gene Expression Regulation, Enzymologic, Humans, Infant, Newborn, Somatic Hypermutation, Immunoglobulin, Transcription, Genetic, Up-Regulation
Show Abstract · Added August 6, 2012
Somatic hypermutation (SHM) of immunoglobulin genes requires activation-induced cytidine deaminase (AID). The error-prone DNA polymerases, such as Pol eta, Pol zeta, and Pol iota, also have been implicated in the process. Human adult antibodies directed to microbial pathogens are increased in affinity and function compared with those of infants. Adult antibodies achieve this increased affinity through somatic mutations, which are lacking in the B cells of infants. It is unknown if infant B cells are capable of upregulating the cell machinery needed to introduce mutations after stimulation through the antigen receptor. We show here that infant B cells exhibit similar kinetics and magnitude of transcription of AID and pol eta genes and only marginally lower levels of pol iota and pol zeta genes after stimulation through the B cell receptor. These data suggest that the ability to upregulate gene transcription of enzymes mediating SHM is not a limiting determinant of the functional quality of infant antibody responses.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery.
Wei J, Blum S, Unger M, Jarmy G, Lamparter M, Geishauser A, Vlastos GA, Chan G, Fischer KD, Rattat D, Debatin KM, Hatzopoulos AK, Beltinger C
(2004) Cancer Cell 5: 477-88
MeSH Terms: Animals, Bone Neoplasms, Bystander Effect, Carcinoma, Lewis Lung, Cell Hypoxia, Cytosine Deaminase, Embryonic and Fetal Development, Endothelium, Vascular, Fluorouracil, Gene Targeting, Genes, Transgenic, Suicide, Genetic Therapy, Genetic Vectors, Injections, Intravenous, Killer Cells, Natural, Lung Neoplasms, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Neovascularization, Pathologic, Osteosarcoma, Pentosyltransferases, Prodrugs, Recombinant Fusion Proteins, Stem Cells, Survival Rate, Uracil, Vascular Endothelial Growth Factor A
Show Abstract · Added November 18, 2010
We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.
1 Communities
1 Members
0 Resources
29 MeSH Terms
The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines.
Ge Y, Jensen TL, Stout ML, Flatley RM, Grohar PJ, Ravindranath Y, Matherly LH, Taub JW
(2004) Cancer Res 64: 728-35
MeSH Terms: Base Sequence, Cell Death, Cell Line, Tumor, Cells, Cultured, Cytarabine, Cytosine Deaminase, DNA Primers, DNA-Binding Proteins, Down Syndrome, Erythroid-Specific DNA-Binding Factors, Exons, GATA1 Transcription Factor, Humans, Introns, Leukemia, Molecular Sequence Data, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Transcription, Genetic
Show Abstract · Added March 5, 2014
Myeloblasts from Down syndrome (DS) children with acute myeloid leukemia (AML) are significantly more sensitive in vitro to 1-beta-D-arabinofuranosylcytosine (ara-C) and generate higher 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) than non-DS AML myeloblasts. Semiquantitative reverse transcription-PCR analyses demonstrated that transcripts for cytidine deaminase (CDA) were 2.7-fold lower in DS than for non-DS myeloblasts. In contrast, transcripts of cystathionine-beta-synthase and deoxycytidine kinase were a median 12.5- and 2.6-fold higher in DS compared with non-DS myeloblasts. The ratio of deoxycytidine kinase/CDA transcripts significantly correlated with ara-C sensitivities and ara-CTP generation. In clinically relevant AML cell line models, high cystathionine-beta-synthase transcripts in DS CMK cells were accompanied by 10-fold greater ara-C sensitivity and 2.4-fold higher levels of ara-CTP compared with non-DS CMS cells. Overexpression of CDA in non-DS THP-1 cells was associated with a 100-fold decreased ara-C sensitivity and 40-fold decreased ara-CTP generation. THP-1 cells secreted CDA into the incubation media and converted extracellular ara-C completely to 1-beta-D-arabinofuranosyluracil within 30 min. Rapid amplification of 5'-cDNA ends (5'-RACE) and reverse transcription-PCR assays identified short- (sf) and long-form (lf) CDA transcripts in THP-1 cells with different 5' untranslated regions and translational start sites; however, only the latter resulted in the active CDA. Although 5' flanking sequences for both CDA transcripts exhibited promoter activity in reporter gene assays, activity for the CDAlf was low. The presence of several GATA1 binding sites in the CDAsf promoter and the uniform detection of GATA1 mutations in DS megakaryocytic leukemia suggested the potential role of GATA1 in regulating CDA transcription and the CDAsf promoter acting as an enhancer. Transfection of GATA1 into Drosophila Mel-2 cells stimulated the CDAlf promoter in a dose-dependent fashion. Additional identification of the mechanisms of differential expression of genes encoding enzymes involved in ara-C metabolism between DS and non-DS myeloblasts may lead to improvements in AML therapy.
0 Communities
1 Members
0 Resources
19 MeSH Terms