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See detailHuman/bovine chimeric MxA-like GTPases reveal a contribution of N-terminal domains to the magnitude of anti-influenza A activity
Garigliany, Mutien-Marie ULg; Cornet, Anne ULg; Desmecht, Daniel ULg

in Journal of Interferon & Cytokine Research (2012), 32(7), 326-331

Type I interferons (IFN-) provide powerful and universal innate intracellular defence mechanisms against viruses. Among the antiviral effectors induced by IFN-, Mx proteins of some species appear as ... [more ▼]

Type I interferons (IFN-) provide powerful and universal innate intracellular defence mechanisms against viruses. Among the antiviral effectors induced by IFN-, Mx proteins of some species appear as key components of defence against influenza A viruses. The body of work published to date suggests that to exert anti-influenza activity, an Mx protein must possess a GTP-binding site, structural bases allowing multimerisation, and a specific C-terminal GTPase effector domain (GED). The human MxA and bovine Mx1 proteins both meet these minimal requirements, but the bovine protein is more active against influenza viruses. Here we measured the anti-influenza activity exerted by two human/bovine chimeric Mx proteins. We show that substituting the bovine GED for the human one in human MxA does not affect the magnitude of anti-influenza activity. Strikingly, however, substituting the human GED for the bovine one in bovine Mx1 yields a chimeric protein with much higher anti-influenza activity than the human protein. We conclude, in contradiction to the hypothesis currently in vogue in the literature, that the GED is not the sole determinant controlling the magnitude of the anti-influenza activity exercised by an Mx protein that can bind GTP and multimerise. Our results suggest that one or several motifs that remain to be discovered, located N-terminally with respect to the GED, may interact with a viral component or a cellular factor so as to alter the viral cycle. Identifying, in the N-terminal portion of bovine Mx1, the motif(s) responsible for its higher anti-influenza activity could contribute to the development of new anti-influenza molecules. [less ▲]

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See detailInfluenza A strain-dependent pathogenesis in fatal H1N1 and H5N1 infections of mice
Garigliany, Mutien-Marie ULg; Habyarimana, Jean ULg; Lambrecht, Bénédicte et al

in Emerging Infectious Diseases (2010), 16(4), 595-603

Two different influenza A viruses showing no pathogenicity towards the laboratory mouse were forced to evolve by serial passaging. Although both adapted viruses evoked diffuse alveolar damage and showed a ... [more ▼]

Two different influenza A viruses showing no pathogenicity towards the laboratory mouse were forced to evolve by serial passaging. Although both adapted viruses evoked diffuse alveolar damage and showed a similar 50% mouse lethal dose and the same peak lung concentration, they elicited dramatically different pathological signatures and ARDS courses. In the absence of any virus labeling, a histologist unaware of which infection he was looking at could readily distinguish infections caused by these two viruses. This suggests that fatal infections caused by different highly virulent influenza A viruses do not necessarily share the same pathogenesis. The different histological pictures shown here refute the hypothesis of a single, universal “cytokine storm” underlying all fatal influenzal diseases. Research is thus crucially needed to identify underlying sets of virulence markers and to examine whether it might be advantageous to tailor treatment to the influenza virus pathotype. [less ▲]

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See detailSprouty1, a new target of the angiostatic agent 16K prolactin, negatively regulates angiogenesis
Sabatel, Céline ULg; Cornet, Anne ULg; Tabruyn, Sébastien ULg et al

in Molecular Cancer (2010), 9(1), 231

BACKGROUND:Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future ... [more ▼]

BACKGROUND:Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future anti-cancer therapies. Sprouty1 (SPRY1), an inhibitor of the MAPK pathway, might be one of these new genes. We identified SPRY1 by comparing the transcriptomes of untreated endothelial cells with those of endothelial cells treated by the angiostatic agent 16K prolactin (16K hPRL). In the present study, we aimed to explore the potential function of SPRY1 in angiogenesis.RESULTS:We confirmed 16K hPRL induced up-regulation of SPRY1 in primary endothelial cells. In addition, we demonstrated the positive SPRY1 regulation in a chimeric mouse model of human colon carcinoma in which 16K hPRL treatment was shown to delay tumor growth. Expression profiling by qRT-PCR with species-specific primers revealed that induction of SPRY1 expression by 16K hPRL occurs only in the (murine) endothelial compartment and not in the (human) tumor compartment. The regulation of SPRY1 expression was NF-kappaB dependent. Partial SPRY1 knockdown by RNA interference protected endothelial cells from apoptosis as well as increased endothelial cell proliferation, migration, capillary network formation, and adhesion to extracellular matrix proteins. SPRY1 knockdown was also shown to affect the expression of cyclinD1 and p21 both involved in cell-cycle regulation. These findings are discussed in relation to the role of SPRY1 as an inhibitor of ERK/MAPK signaling and to a possible explanation of its effect on cell proliferation.CONCLUSIONS:Taken together, these results suggest that SPRY1 is an endogenous angiogenesis inhibitor. [less ▲]

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See detailSurra-induced lymphopenia is directly triggered by a membrane-associated parasite protein
Antoine-Moussiaux, Nicolas ULg; Cornet, Anne ULg; Cornet, François et al

Conference (2009, May 24)

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See detailA non-cytosolic protein of Trypanosoma evansi induces CD45-dependent lymphocyte death.
Antoine-Moussiaux, Nicolas ULg; Cornet, Anne ULg; Cornet, François ULg et al

in PLoS ONE (2009), 4(5), 5728

In a recent study dealing with a mouse model of Trypanosoma evansi-associated disease, a remarkable synchrony between the parasitaemia peak and the white-blood-cell count nadir was noticed. The present ... [more ▼]

In a recent study dealing with a mouse model of Trypanosoma evansi-associated disease, a remarkable synchrony between the parasitaemia peak and the white-blood-cell count nadir was noticed. The present study was designed to establish whether there is a direct causal link between the parasite load during its exponential phase of growth and the disappearance of peripheral blood leukocytes. In vitro experiments performed with trypanosomes and purified peripheral blood mononucleated cells revealed the existence of a lymphotoxin embedded in the T. evansi membrane: a protein sensitive to serine proteases, with a molecular mass of less than 30 kDa. Lymphocytes death induced by this protein was found to depend on the intervention of a lymphocytic protein tyrosine phosphatase. When lymphocytes were exposed to increasing quantities of a monoclonal antibody raised against the extracellular portion of CD45, a transmembrane protein tyrosine phosphatase covering over 10% of the lymphocyte surface, T. evansi membrane extracts showed a dose-dependent decrease in cytotoxicity. As the regulatory functions of CD45 concern not only the fate of lymphocytes but also the activation threshold of the TCR-dependent signal and the amplitude and nature of cytokinic effects, this demonstration of its involvement in T. evansi-dependent lymphotoxicity suggests that T. evansi might manipulate, via CD45, the host's cytokinic and adaptive responses. [less ▲]

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See detailInvestigations on Surra-induced lymphopoenia in a murine model
Antoine-Moussiaux, Nicolas ULg; Cornet, Anne ULg; Cornet, et al

Conference (2009, March)

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See detailInhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL
Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg; Blacher, Silvia ULg et al

in Molecular Therapy : The Journal of the American Society of Gene Therapy (2007), 15(12), 2094-2100

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic ... [more ▼]

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic therapy, therefore, holds potential as an attractive strategy for inhibiting metastasis development. Human 16K PRL (16K hPRL), a potent inhibitor of angiogenesis, has been demonstrated to prevent tumor growth in two xenograft mouse models, but whether it also affects tumor metastasis is unknown. In this study we will investigate the ability of 16K hPRL to prevent the establishment of metastasis. We demonstrate that 16K hPRL administered via adenovirus-mediated gene transfer, inhibits tumor growth by 86% in a subcutaneous (SC) B16-F10 mouse melanoma model. Computer-assisted image analysis shows that 16K hPRL treatment results in a reduction of tumor-vessel length and width, leading to a 57% reduction of average vessel size. In a pre-established tumor model, moreover, 16K hPRL can significantly delay tumor development. Finally, for the first time, we provide evidence that 16K hPRL considerably reduces the establishment of B16-F10 metastasis in an experimental lung metastasis model. Both the number and size of metastases are reduced by 50% in 16K hPRL-treated mice. These results highlight a potential role for 16K hPRL in anticancer therapy for both primary tumors and metastases. [less ▲]

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See detailEvaluation of the antitumor activity of 16K prolactin
Kinet, Virginie; Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg et al

Poster (2007)

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See detailL’interférence de l’ARN (ARNi): un mécanisme fondamental longtemps ignoré
Cornet, Anne ULg

Conference (2006, December 05)

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See detailMolecular profiling of 16K PRL treated tumours by an antibody-array approach
Cornet, Anne ULg; Nguyen, Ngoc-Quynh-Nhu ULg; Lion, Michelle ULg et al

Poster (2006, May)

Tumour development is often accompanied by the formation of new blood vessels from existing vasculature. This new intratumoral blood network is driven by the process of angiogenesis, providing the ... [more ▼]

Tumour development is often accompanied by the formation of new blood vessels from existing vasculature. This new intratumoral blood network is driven by the process of angiogenesis, providing the essential nutrients for growth, invasion and metastasis. At the present time, it is well established that inhibitors of angiogenesis prevent the growth and progression of tumours, offering a new therapeutic approach for treatment of cancer. Several studies have already showed that the N-terminal fragment of the human prolactin, 16k-Da PRL, has a potent anti-angiogenic activity. Recently, research groups have demonstrated that the 16k-Da PRL inhibits tumour development in animal models. Despite the fact that several studies leading to improve our knowledge of 16k-Da PRL action were performed, little is known about its role played to prevent tumour growth in vivo. In this study, we first tested the ability of the 16k-Da PRL to inhibit the growth of established HCT116 tumours in nude mice, using an adenovirus approach. As expected, we found that the tumour progression was tightly reduced by the expression of the 16k-Da PRL into the tumours. This antitumour activity was also associated with a slight tumour vascularization. To discover biomarkers that contribute in 16k-Da PRL tumour suppressive effects, we used one of the most powerful multiplexed detection techonologies: the antibody-microarray proposed by Eurogentec. These protein-chips allow to identify multiple proteins from small amounts of samples within a single experiment. Three independent sets of antibody array from samples of 16k-Da PRL treated tumours and controls were analysed. Experimental and analysis optimisations were applied to ensure the correct interpretation of the fluorescent signals from the antibody arrays. In addition, significant results were confirmed by Western blot analysis. Our study allowed to identify several proteins which could be implicated in the tumour dormancy induced by 16k-Da PRL treatment. Additional analysis will provide important biological information for discovering of the new cancer biomarkers and their relationship with the 16k-Da PRL effects on cancer development. [less ▲]

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See detailProlactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis
Nguyen, Ngoc-Quynh-Nhu ULg; Tabruyn, Sébastien ULg; Lins, Laurence ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(39), 14319-14324

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short ... [more ▼]

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis. [less ▲]

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See detailThe antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G(0)-G(1) and the G(2)-M phases
Tabruyn, Sébastien ULg; Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg et al

in Molecular Endocrinology (2005), 19(7), 1932-1942

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate ... [more ▼]

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate that 16K hPRL inhibits serum-induced DNA synthesis in adult bovine aortic endothelial cells. This inhibition is associated with cell cycle arrest at both the G(0)-G(1) and the G(2)-M phase. Western blot analysis revealed that 16K hPRL strongly decreases levels of cyclin D1 and cyclin B1, but not cyclin E. The effect on cyclin D1 is at least partially transcriptional, because treatment with 16K hPRL both reduces the cyclin D1 mRNA level and down-regulates cyclin D1 promoter activity. This regulation may be due to inhibition of the MAPK pathway, but it is independent of the glycogen synthase kinase-3 beta pathway. Lastly, 16K hPRL induces the expression of negative cell cycle regulators, the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1). In summary, 16K hPRL inhibits serum-induced proliferation of endothelial cells through combined effects on positive and negative regulators of cell cycle progression. [less ▲]

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See detailNew features in the treatment of androgen-independent prostate cancer.
Closset, Jean ULg; Ammar, Hayet; Nguyen, Viet-Ha et al

in Current Pharmaceutical Design (2004), 10(5), 513-22

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the ... [more ▼]

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the cancer is diagnosed at a more advanced age. Prostate cancer evolves from an androgen dependant stage to stage where it escapes from all anti-androgenic treatments. The patient usually dies within two years following the diagnosis of advanced cancer. Therefore, it is of great interest to develop new therapies for androgen independent prostate cancer. The androgen independent evolution of prostate cancer is a complex phenomenon at the cellular and molecular levels. It includes an increased sensitivity to growth factors, the control of proliferation pathways, apoptotic and survival pathways as well as the control of angiogenesis. Epidemiological studies have also suggested that certain vitamins or phyto-oestrogens could protect against prostate cancer development. The present review attempts to present an overview of the fundamental research in cellular signalling which could be interesting as target for the treatment of androgen independent prostate cancer. Also the potential interest of non-androgenic steroids was reviewed for the same goal. [less ▲]

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See detailMolecular dissection of a quantitative trait locus: a phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition.
Blott, Sarah; Kim, Jong-Joo; Moisio, Sirja et al

in Genetics (2003), 163(1), 253-66

We herein report on our efforts to improve the mapping resolution of a QTL with major effect on milk yield and composition that was previously mapped to bovine chromosome 20. By using a denser chromosome ... [more ▼]

We herein report on our efforts to improve the mapping resolution of a QTL with major effect on milk yield and composition that was previously mapped to bovine chromosome 20. By using a denser chromosome 20 marker map and by exploiting linkage disequilibrium using two distinct approaches, we provide strong evidence that a chromosome segment including the gene coding for the growth hormone receptor accounts for at least part of the chromosome 20 QTL effect. By sequencing individuals with known QTL genotype, we identify an F to Y substitution in the transmembrane domain of the growth hormone receptor gene that is associated with a strong effect on milk yield and composition in the general population. [less ▲]

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