Publications (59)586.91 Total impact
-
Article: Adrenomedullin Haploinsufficiency Predisposes to Secondary Lymphedema
Journal of Investigative Dermatology 01/2013; · 6.31 Impact Factor -
Article: Adrenomedullin Haploinsufficiency Predisposes to Secondary Lymphedema.
[show abstract] [hide abstract]
ABSTRACT: Secondary lymphedema is a debilitating condition and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is a peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene. AM and its putative receptor CLR are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (Adm(AM+/Δ) animals). After hind limb skin incision, Adm mRNA expression was up-regulated in wounded tissue of both Adm(AM+/+) and Adm(AM+/Δ) mice. However, only Adm(AM+/Δ) animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in Adm(AM+/Δ) mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics and blood vessels. Our study identified previously unrecognized role for endogenous AM as a key player in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder.Journal of Investigative Dermatology accepted article preview online, 30 January 2013;. doi:10.1038/jid.2013.47.Journal of Investigative Dermatology 01/2013; · 6.31 Impact Factor -
Article: The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis.
[show abstract] [hide abstract]
ABSTRACT: Delta-like 4 (DLL4), a membrane-bound ligand belonging to the Notch signaling family, plays a fundamental role in vascular development and angiogenesis. We identified a conserved microRNA family, miR-30, which targets DLL4. Overexpression of miR-30b in endothelial cells led to increased vessel number and length in an in vitro model of sprouting angiogenesis. Microinjection of miR-30 mimics into zebrafish embryos resulted in suppression of dll4 and subsequent excessive sprouting of intersegmental vessels and reduction in dorsal aorta diameter. Use of a target protector against the miR-30 site within the dll4 3'UTR upregulated dll4 and synergized with Vegfa signaling knockdown to inhibit angiogenesis. Furthermore, restoration of miR-30b or -30c expression during Kaposi's sarcoma herpesvirus (KSHV) infection attenuated viral induction of DLL4. Together these results demonstrate that the highly conserved molecular targeting of DLL4 by the miR-30 family regulates angiogenesis.Blood 10/2012; · 9.90 Impact Factor -
Article: Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA.
[show abstract] [hide abstract]
ABSTRACT: The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki-Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2-(dimethylamino)ethyl ether-modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide-transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis indicated that the small molecule carrier guanidines are stabilized by π-cation interactions with the biphenyl system, thus not only increasing the basicity or pKa but also shielding the charge. The binding affinities of various small molecule carriers for siRNA were investigated using isothermal calorimetry and gel shift assays. Small molecule carrier-mediated siRNA delivery to cultured fibroblasts is demonstrated, showing that small molecule carriers possess the ability to transport functional siRNA into cells. Knockdown of Cdc7 kinase, a target for cancer, is achieved.Chemical Biology & Drug Design 01/2012; 79(1):9-21. · 2.28 Impact Factor -
Article: KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition.
[show abstract] [hide abstract]
ABSTRACT: Kaposi sarcoma (KS), an angioproliferative disease associated with Kaposi sarcoma herpesvirus (KSHV) infection, harbors a diversity of cell types ranging from endothelial to mesenchymal cells of unclear origin. We developed a three-dimensional cell model for KSHV infection and used it to demonstrate that KSHV induces transcriptional reprogramming of lymphatic endothelial cells to mesenchymal cells via endothelial-to-mesenchymal transition (EndMT). KSHV-induced EndMT was initiated by the viral proteins vFLIP and vGPCR through Notch pathway activation, leading to gain of membrane-type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive properties and concomitant changes in viral gene expression. Mesenchymal markers and MT1-MMP were found codistributed with a KSHV marker in the same cells from primary KS biopsies. Our data explain the heterogeneity of cell types within KS lesions and suggest that KSHV-induced EndMT may contribute to KS development by giving rise to infected, invasive cells while providing the virus a permissive cellular microenvironment for efficient spread.Cell host & microbe 12/2011; 10(6):577-90. · 13.02 Impact Factor -
Article: Genomic and epigenomic integration identifies a prognostic signature in colon cancer.
[show abstract] [hide abstract]
ABSTRACT: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis. Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model. We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37-4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07-5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16-34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04-4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00-5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05-1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03-16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109). CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer.Clinical Cancer Research 01/2011; 17(6):1535-45. · 7.74 Impact Factor -
Article: Kaposi's sarcoma and its associated herpesvirus.
[show abstract] [hide abstract]
ABSTRACT: Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.Nature Reviews Cancer 10/2010; 10(10):707-19. · 29.54 Impact Factor -
Article: In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation.
[show abstract] [hide abstract]
ABSTRACT: Genome-wide DNA hypomethylation was one of the first epigenetic alterations described in cancer cells. However, the cause of this hypomethylation is still poorly understood. We have previously developed a line of primary mesenchymal stem cells (MSC, the putative origin of various types of sarcoma) in which five oncogenic steps toward a fully transformed state are sequentially introduced including: human telomerase, inactivation of p53 and pRb tumor suppressor genes and activation of the oncogenes c-Myc and H-Ras. We hypothesized that DNA hypomethyation would occur during stepwise transformation of MSC and could be a model to investigate the mechanism of global hypomethylation in cancer. Here we show, firstly, that satellite-2 and long interspersed nuclear element 1 repetitive elements became hypomethylated (54 and 30% reduction, respectively) on the introduction of oncogenic H-Ras after the final step of transformation. Secondly, we observed hypomethylation only after 4 weeks in culture following the introduction of H-Ras, suggesting a gradual loss of methylation. Finally, using an inducible estrogen receptor-Ras fusion construct, we were able to transform MSC's in the absence of detectable hypomethylation, suggesting that it was not a requirement for transformation. These studies show that DNA hypomethylation can occur late during stepwise transformation, although in vitro transformation could also take place in the absence of hypomethylation. These data support the hypothesis that DNA hypomethylation occurs via a gradual mechanism and is not a requirement for transformation.Carcinogenesis 05/2010; 31(10):1854-62. · 5.70 Impact Factor -
Article: miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator.
[show abstract] [hide abstract]
ABSTRACT: MicroRNAs are small, non-coding RNAs that negatively regulate gene expression. It has been proposed that microRNAs could function in the regulation of innate immunity, but this has not been demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.Nature Cell Biology 04/2010; 12(5):513-9. · 19.49 Impact Factor -
Article: DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status.
[show abstract] [hide abstract]
ABSTRACT: It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA-methylation profiling on familial breast cancers (n = 33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2, and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified, and normal-like). We used methylated DNA immunoprecipitation (MeDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2), and 36% (BRCAx) but did not accurately predict the intrinsic subtypes defined by gene expression. Furthermore, using unsupervised hierarchical clustering, we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We validated these findings in the 33 tumors in the test set, as well as in an independent validation set of 47 formalin-fixed, paraffin-embedded familial breast tumors, by pyrosequencing and Epityper. Finally, gene-expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene-expression, and copy-number data sets, revealing frequent hypermethylation of genes that also displayed loss of heterozygosity, as well as of genes that show copy-number gains, providing a potential mechanism for expression dosage compensation. Together, these data show that methylation profiles for familial breast cancers are defined by the mutation status and are distinct from the intrinsic subtypes.The American Journal of Human Genetics 03/2010; 86(3):420-33. · 10.60 Impact Factor -
Article: KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming.
[show abstract] [hide abstract]
ABSTRACT: Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs but not in BECs. We identify a novel role for MAF as a transcriptional repressor, preventing expression of BEC-specific genes, thereby maintaining the differentiation status of LECs. These findings demonstrate that viral miRNAs could influence the differentiation status of infected cells, and thereby contribute to KSHV-induced oncogenesis.Genes & development 01/2010; 24(2):195-205. · 12.08 Impact Factor -
Article: KSHV manipulates Notch signaling by DLL4 and JAG1 to alter cell cycle genes in lymphatic endothelia.
[show abstract] [hide abstract]
ABSTRACT: Increased expression of Notch signaling pathway components is observed in Kaposi sarcoma (KS) but the mechanism underlying the manipulation of the canonical Notch pathway by the causative agent of KS, Kaposi sarcoma herpesvirus (KSHV), has not been fully elucidated. Here, we describe the mechanism through which KSHV directly modulates the expression of the Notch ligands JAG1 and DLL4 in lymphatic endothelial cells. Expression of KSHV-encoded vFLIP induces JAG1 through an NFkappaB-dependent mechanism, while vGPCR upregulates DLL4 through a mechanism dependent on ERK. Both vFLIP and vGPCR instigate functional Notch signalling through NOTCH4. Gene expression profiling showed that JAG1- or DLL4-stimulated signaling results in the suppression of genes associated with the cell cycle in adjacent lymphatic endothelial cells, indicating a role for Notch signaling in inducing cellular quiescence in these cells. Upregulation of JAG1 and DLL4 by KSHV could therefore alter the expression of cell cycle components in neighbouring uninfected cells during latent and lytic phases of viral infection, influencing cellular quiescence and plasticity. In addition, differences in signaling potency between these ligands suggest a possible complementary role for JAG1 and DLL4 in the context of KS.PLoS Pathogens 10/2009; 5(10):e1000616. · 9.13 Impact Factor -
Chapter: Kaposi’s Sarcoma and the Lymphatics
[show abstract] [hide abstract]
ABSTRACT: Kaposi’s sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). KS presents as multifocal, angiogenic lesions involving an inflammatory infiltrate and KSHV-infected spindle cells display characteristic markers of lymphatic endothelia. The precise origin of the spindle cell component of KS lesions is uncertain and may derive from the reprogramming of the transcriptome of endothelial cells or their precursors to adopt a lymphatic-like gene expression profile. The lymphotrophic nature of KSHV corresponds to its pathological association with two further AIDS-related malignancies: primary effusion lymphomas (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KSHV infection of B-cells in lymph node follicles creates a reservoir for the persistence of KSHV infection that may influence the characteristics of the associated lymphomas. Here we discuss the mechanisms of KSHV infection in the context of KS and KSHV-associated lymphomas and examine the potential for KSHV to determine the fate of cells associated with the lymphatic system.09/2009: pages 211-229; -
Article: The CD8 and CD4 T-cell response against Kaposi's sarcoma-associated herpesvirus is skewed towards early and late lytic antigens.
[show abstract] [hide abstract]
ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi's sarcoma (KS), the most common malignancy in untreated individuals with HIV/AIDS. The adaptive T-cell immune response against KSHV has not been fully characterized. To achieve a better understanding of the antigenic repertoire of the CD8 and CD4 T-cell responses against KSHV, we constructed a library of lentiviral expression vectors each coding for one of 31 individual KSHV open reading frames (ORFs). We used these to transduce monocyte-derived dendritic cells (moDCs) isolated from 14 KSHV-seropositive (12 HIV-positive) and 7 KSHV-seronegative (4 HIV-positive) individuals. moDCs were transduced with up to 3 KSHV ORFs simultaneously (ORFs grouped according to their expression during the viral life cycle). Transduced moDCs naturally process the KSHV genes and present the resulting antigens in the context of MHC class I and II. Transduced moDCs were cultured with purified autologous T cells and the CD8 and CD4 T-cell proliferative responses to each KSHV ORF (or group) was assessed using a CFSE dye-based assay. Two pools of early lytic KSHV genes ([ORF8/ORF49/ORF61] and [ORF59/ORF65/K4.1]) were frequently-recognized targets of both CD8 and CD4 T cells from KSHV seropositive individuals. One pool of late lytic KSHV genes ([ORF28/ORF36/ORF37]) was a frequently-recognized CD8 target and another pool of late genes ([ORF33/K1/K8.1]) was a frequently-recognized CD4 target. We report that both the CD8 and CD4 T-cell responses against KSHV are skewed towards genes expressed in the early and late phases of the viral lytic cycle, and identify some previously unknown targets of these responses. This knowledge will be important to future immunological investigations into KSHV and may eventually lead to the development of better immunotherapies for KSHV-related diseases.PLoS ONE 02/2009; 4(6):e5890. · 4.09 Impact Factor -
Article: Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients.
[show abstract] [hide abstract]
ABSTRACT: Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78-5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age-phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. ACCESSION NUMBERS: The microarray data and associated .BED and .WIG files can be accessed through Gene Expression Omnibus accession number: GSE14603.Human Molecular Genetics 02/2009; 18(7):1332-42. · 7.64 Impact Factor -
Article: Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets.
[show abstract] [hide abstract]
ABSTRACT: Since the sequencing of the human genome, recent efforts in cancer drug target discovery have focused more on the identification of novel functions of known genes and the development of more appropriate tumor models. In the present study, we investigated in vitro transformed human adult mesenchymal stem cells (MSC) to identify novel candidate cancer drug targets by analyzing the transcriptional profile of known enzymes compared with non-transformed MSC. The identified enzymes were compared with published cancer gene expression data sets. Surprisingly, the majority of up-regulated enzymes are already known cancer drug targets or act within known druggable pathways. Only three enzymes (RNASEH2A, ADARB1, and PPAP2C) are potentially novel targets that are up-regulated in transformed MSC and expressed in numerous carcinomas and sarcomas. We confirmed the overexpression of RNASEH2A, PPAP2C, and ADARB1 in transformed MSC, transformed fibroblasts, and cancer cell lines MCF7, SK-LMS1, MG63, and U2OS. In functional assays, we show that small interfering RNA knockdown of RNASEH2A inhibits anchorage-independent growth but does not alter in vitro proliferation of cancer cell lines, normal MSC, or normal fibroblasts. Knockdown of PPAP2C impaired anchorage-dependent in vitro growth of cancer cell lines and impaired the in vitro growth of primary MSC but not differentiated human fibroblasts. We show that the knockdown of PPAP2C decreases cell proliferation by delaying entry into S phase of the cell cycle and is transcriptionally regulated by p53. These in vitro data validate PPAP2C and RNASEH2A as putative cancer targets and endorse this in silico approach for identifying novel candidates.Molecular Cancer Therapeutics 02/2009; 8(1):249-60. · 5.23 Impact Factor -
Article: Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus.
[show abstract] [hide abstract]
ABSTRACT: The involvement of Toll-like receptor 4 (TLR4) in immunity against human herpesviruses has not been previously demonstrated. We show that infection of endothelial cells with Kaposi sarcoma herpesvirus (KSHV), a human oncogenic virus, leads to rapid suppression of TLR4 expression. This is a mechanism of immune escape as TLR4 mediates innate immunity against KSHV. In vitro, cells lacking TLR4 are more susceptible to KSHV infection, whereas activation of TLR4 protects cells from infection. In vivo, HIV-1-infected individuals carrying a mutant TLR4 allele appear more likely to have multicentric Castleman's disease, a lymphoproliferation associated with enhanced KSHV replication. ERK activation by KSHV structural proteins and the KSHV-encoded vGPCR plays a key role in the TLR4 downregulation, whereas the KSHV vIRF1 also contributes to this effect. Our findings reveal a role for TLR4 in innate immunity against herpesviruses and suggest the potential use of TLR4 agonists for the treatment of KSHV-related neoplasms.Cell host & microbe 12/2008; 4(5):470-83. · 13.02 Impact Factor -
Article: Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome.
[show abstract] [hide abstract]
ABSTRACT: Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappaB (NF-kappaB) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKKgamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappaB pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKKgamma bound to ks-vFLIP at 3.2 A. In addition to identifying and subsequently probing the ks-vFLIP-IKKgamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).Molecular cell 07/2008; 30(5):620-31. · 14.61 Impact Factor -
Article: KSHV LANA inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta type II receptor.
[show abstract] [hide abstract]
ABSTRACT: Signaling through the transforming growth factor-beta (TGF-beta) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)-infected primary effusion lymphoma through down-regulation of the TGF-beta type II receptor (TbetaRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TbetaRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TbetaRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-beta signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-beta signaling by silencing TbetaRII gene expression and immune recognition by suppressing TGF-beta-responsive immune cells through the elevated secretion of TGF-beta1.Blood 06/2008; 111(9):4731-40. · 9.90 Impact Factor -
Article: Associations between Burkitt lymphoma among children in Malawi and infection with HIV, EBV and malaria: results from a case-control study.
[show abstract] [hide abstract]
ABSTRACT: Burkitt lymphoma, a childhood cancer common in parts of sub-Saharan Africa, has been associated with Epstein Barr Virus (EBV) and malaria, but its association with human immunodeficiency virus (HIV) is not clear. We conducted a case-control study of Burkitt lymphoma among children (aged < or = 15 years) admitted to the pediatric oncology unit in Blantyre, Malawi between July 2005 and July 2006. Cases were 148 children diagnosed with Burkitt lymphoma and controls were 104 children admitted with non-malignant conditions or cancers other than hematological malignancies and Kaposi sarcoma. Interviews were conducted and serological samples tested for antibodies against HIV, EBV and malaria. Odds ratios for Burkitt lymphoma were estimated using unconditional logistic regression adjusting for sex, age, and residential district. Cases had a mean age of 7.1 years and 60% were male. Cases were more likely than controls to be HIV positive (Odds ratio (OR)) = 12.4, 95% Confidence Interval (CI) 1.3 to 116.2, p = 0.03). ORs for Burkitt lymphoma increased with increasing antibody titers against EBV (p = 0.001) and malaria (p = 0.01). Among HIV negative participants, cases were thirteen times more likely than controls to have raised levels of both EBV and malaria antibodies (OR = 13.2; 95% CI 3.8 to 46.6; p = 0.001). Reported use of mosquito nets was associated with a lower risk of Burkitt lymphoma (OR = 0.2, 95% CI, 0.03 to 0.9, p = 0.04). Our findings support prior evidence that EBV and malaria act jointly in the pathogenesis of Burkitt lymphoma, suggesting that malaria prevention may decrease the risk of Burkitt lymphoma. HIV may also play a role in the etiology of this childhood tumor.PLoS ONE 01/2008; 3(6):e2505. · 4.09 Impact Factor
Top co-authors
Top Journals
Institutions
-
1999–2013
-
University College London
- Cancer Research UK Health Behaviour Research Centre
London, ENG, United Kingdom -
The University of Edinburgh
Edinburgh, SCT, United Kingdom
-
-
2010
-
University of Miami Miller School of Medicine
- Sylvester Comprehensive Cancer Center
Miami, FL, USA
-
-
2007
-
Cambridge College
Cambridge, MA, USA
-
-
2006
-
Cornell University
- Department of Medicine
Ithaca, NY, USA
-
-
2005
-
National Yang Ming University
- Institute of Microbiology and Immunology
Taipei, Taipei, Taiwan
-
-
2003
-
Cancer Research UK
London, ENG, United Kingdom
-
