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T-cell tropism of simian T-cell leukaemia virus type 1 and cytokine profiles in relation to proviral load and immunological changes during chronic infection of naturally infected mandrills (Mandrillus sphinx)

Author(s) : Souqui?re S, Mouinga-Ondeme A, Makuwa M, Beggio P, Radaelli A, De Giuli Morghen C, Mortreux F, Kazanji M,
Journal : J Med Primatol

TGF-beta induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation.

Author(s) : Terme J, Lhermitte L, Asnafi V, Jalinot P,
Journal : Blood
T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelialcells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration ofTAL1 is regulated by transforming growth factor beta (TGF-beta), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-beta and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.

The evolutionary context of robust and redundant cell biological mechanisms.

Author(s) : Delattre M, Felix M,
Journal : Bioessays
The robustness of biological processes to perturbations has so far been mainly explored in unicellular organisms; multicellular organisms have been studied fordevelopmental processes or in the special case of redundancy between gene duplicates. Here we explore the robustness of cell biological mechanisms of multicellular organisms in an evolutionary context. We propose that the reuse ofsimilar cell biological mechanisms in different cell types of the same organism has evolutionary implications: (1) the maintenance of apparently redundant mechanisms over evolutionary time may in part be explained by their differentialrequirement in various cell types; (2) the relative requirement for two alternative mechanisms may evolve among homologous cells in different organisms.We present examples of cell biological processes, such as centrosome separation in prophase, spindle formation or cleavage furrow positioning, that support the first proposition. We propose experimental tests of these hypotheses.

The germ cell nuclear proteins hnRNP G-T and RBMY activate a testis-specific exon

Author(s) : Liu Y, Bourgeois C, Pang S, Kudla M, Dreumont N, Kister L, Sun Y, Stevenin J, Elliott D,
Journal : PLoS Genet

The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts.

Author(s) : Spichty M, Taly A, Hagn F, Kessler H, Barluenga S, Winssinger N, Karplus M,
Journal : Biophys Chem
We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We samplethe macrocyclic scaffold of the unbound ligand by parallel tempering simulationsand dock the most populated conformations to yeast HSP90. Docking poses are thenevaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of backbone (15)N provides an additional evaluation criteria. As a final test we check the binding modes against available structure-activity-relationships. We find that the most likelybinding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex.

The leukemogenic activity of TaxHTLV-1 during human alphabeta T cell development.

Author(s) : Wencker M, Gazzolo L, Duc Dodon M,
Journal : Front Biosci (Schol Ed)
The regulatory Tax protein of HTLV-1 (Human T-cell Leukaemia Virus type 1) is critically involved in the initiation of ATL (adult T-cell leukaemia). Indeed, Tax provides infected T-cells with a growth advantage and with the potential to get transformed through the deregulation of cell-cycle progression and the acquisition of genetic alterations. Considering that leukemias are induced by disturbances in hematopoietic cells development, we hypothesize that the expression of Tax in human immature thymocytes is a prerequisite to the emergence of ATL cells. Studies of alph abeta T-cell development in the thymus have shown that beta-selection, an early important checkpoint, is regulated by transcription factors that are decisive in the control of cell proliferation, differentiation and survival. Interestingly, Tax is endowed with the ability to interfere with the activity of these transcription factors. We therefore propose that the HTLV-1 infection of these specific target thymocytes leads to a transcriptional deregulation of early alphabeta T cell development, thus inducing a pre-leukemogenic event that favours the subsequent proliferation of ATL cells.

The phytoestrogen genistein affects zebrafish development through two different pathways.

Author(s) : Sassi-Messai S, Gibert Y, Bernard L, Nishio S, Ferri Lagneau K, Molina J, Andersson-Lendahl M, Benoit G, Balaguer P, Laudet V,
Journal : PLoS One
BACKGROUND: Endocrine disrupting chemicals are widely distributed in the environment and derive from many different human activities or can also be natural products synthesized by plants or microorganisms. The phytoestrogen, genistein (4', 5, 7-trihydroxy-isoflavone), is a naturally occurring compound found in soy products. Genistein has been the subject of numerous studies because of its known estrogenic activity. METHODOLOGY/PRINCIPAL FINDINGS: We report thatgenistein exposure of zebrafish embryos induces apoptosis, mainly in the hindbrain and the anterior spinal cord. Timing experiments demonstrate that apoptosis is induced during a precise developmental window. Since adding ICI 182,780, an ER antagonist, does not rescue the genistein-induced apoptosis and since there is no synergistic effect between genistein and estradiol, we conclude that this apoptotic effect elicited by genistein is estrogen-receptors independent. However, we show in vitro, that genistein binds and activates the three zebrafish estrogen receptors ERalpha, ERbeta-A and ERbeta-B. Furthermore using transgenic ERE-Luciferase fish we show that genistein is able to activate the estrogen pathway in vivo during larval stages. Finally we show that genistein is able to induce ectopic expression of the aromatase-B gene in an ER-dependent manner in the anterior brain in pattern highly similar to the one resulting fromestrogen treatment at low concentration. CONCLUSION/SIGNIFICANCE: TAKEN TOGETHERTHESE RESULTS INDICATE THAT GENISTEIN ACTS THROUGH AT LEAST TWO DIFFERENT PATHWAYS IN ZEBRAFISH EMBRYOS: (i) it induces apoptosis in an ER-independent manner and (ii) it regulates aromatase-B expression in the brain in an ER-dependent manner. Our results thus highlight the multiplicity of possible actions of phytoestrogens, such as genistein. This suggests that the use of standardized endpoints to study the effect of a given compound, even when this compound has well known targets, may carry the risk of overlooking interesting effects of this compound.

The yeast Pif1 helicase prevents genomic instability caused by G-quadruplex-forming CEB1 sequences in vivo

Author(s) : Ribeyre C, Lopes J, Boulé J, Piazza A, Guédin A, Zakian V, Mergny J, Nicolas A,
Journal : PLoS genetics
In budding yeast, the Pif1 DNA helicase is involved in the maintenance of both nuclear and mitochondrial genomes, but its role in these processes is still poorly understood. Here, we provide evidence for a new Pif1 function by demonstrating that its absence promotes genetic instability of alleles of the G-rich human minisatellite CEB1 inserted in the Saccharomyces cerevisiae genome, but not of other tandem repeats. Inactivation of other DNA helicases, including Sgs1, had no effect on CEB1 stability. In vitro, we show that CEB1 repeats formed stable G-quadruplex (G4) secondary structures and the Pif1 protein unwinds these structures more efficiently than regular B-DNA. Finally, synthetic CEB1 arrays in which we mutated the potential G4-forming sequences were no longer destabilized in pif1Δ cells. Hence, we conclude that CEB1 instability in pif1Δ cells depends on the potential to form G-quadruplex structures, suggesting that Pif1 could play a role in the metabolism of G4-forming sequences

Translation of intronless RNAs is strongly stimulated by the Epstein-Barr virus mRNA export factor EB2.

Author(s) : Ricci E, Mure F, Gruffat H, Decimo D, Medina-Palazon C, Ohlmann T, Manet E,
Journal : Nucleic Acids Res
The Epstein-Barr virus protein (EB2) allows the nuclear export of a particular subset of early and late viral RNAs derived from intronless genes. EB2 is conserved among most herpesvirus members and its presence is essential for the production of infectious particles. Here we show that, besides its role as a nuclear export factor, EB2 strongly stimulates translation of unspliced mRNAs without affecting overall cellular translation. Interestingly, this effect can be reversed by the addition of an intron within the gene. The spliced mRNA is then efficiently exported and translated even in the absence of EB2. Moreover, we show that EB2 associates with translating ribosomes and increases the proportion of its target RNA in the polyribosomal fraction. Finally, testing of EB2 homolog proteins derived from EBV-related herpesviruses, shows that, even if they play similar roles within the replication cycle of their respective virus, their mechanisms of action are different.

Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth

Author(s) : Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, B?n?s V, Roch? H, Dalenc F, Auboeuf D, Millevoi S, Vagner S,
Journal : Cancer Res

Wolbachia interferes with ferritin expression and iron metabolism in insects.

Author(s) : Kremer N, Voronin D, Charif D, Mavingui P, Mollereau B, Vavre F,
Journal : PLoS Pathog
Wolbachia is an intracellular bacterium generally described as being a facultative reproductive parasite. However, Wolbachia is necessary for oogenesiscompletion in the wasp Asobara tabida. This dependence has evolved recently as aresult of interference with apoptosis during oogenesis. Through comparative transcriptomics between symbiotic and aposymbiotic individuals, we observed a differential expression of ferritin, which forms a complex involved in iron storage. Iron is an essential element that is in limited supply in the cell. However, it is also a highly toxic precursor of Reactive Oxygen Species (ROS). Ferritin has also been shown to play a key role in host-pathogen interactions. Measuring ferritin by quantitative RT-PCR, we confirmed that ferritin was upregulated in aposymbiotic compared to symbiotic individuals. Manipulating the iron content in the diet, we showed that iron overload markedly affected wasp development and induced apoptotic processes during oogenesis in A. tabida, suggesting that the regulation of iron homeostasis may also be related to the obligate dependence of the wasp. Finally, we demonstrated that iron metabolism is influenced by the presence of Wolbachia not only in the obligate mutualism with A. tabida, but also in facultative parasitism involving Drosophila simulans and in Aedes aegypti cells. In these latter cases, the expression of Wolbachia bacterioferritin was also increased in the presence of iron, showing that Wolbachia responds to the concentration of iron. Our results indicate that Wolbachia may generally interfere with iron metabolism. The high affinity of Wolbachia for iron might be due to physiological requirement of the bacterium, but it could also be what allows the symbiont to persist in the organism by reducing the labile iron concentration, thus protecting the cell from oxidative stress and apoptosis. These findings also reinforce the idea that pathogenic, parasitic and mutualistic intracellular bacteria all use the same molecular mechanisms to survive and replicate within host cells. By impacting the general physiology of the host, the presence of a symbiont may select for host compensatory mechanisms, which extends the possible consequences of persistent endosymbiont on the evolution of their hosts.

Wolbachia-mediated cytoplasmic incompatibility is associated with impaired histone deposition in the male pronucleus.

Author(s) : Landmann F, Orsi G, Loppin B, Sullivan W,
Journal : PLoS Pathog
Wolbachia is a bacteria endosymbiont that rapidly infects insect populations through a mechanism known as cytoplasmic incompatibility (CI). In CI, crosses between Wolbachia-infected males and uninfected females produce severe cell cycle defects in the male pronucleus resulting in early embryonic lethality. In contrast, viable progeny are produced when both parents are infected (the Rescuecross). An important consequence of CI-Rescue is that infected females have a selective advantage over uninfected females facilitating the rapid spread of Wolbachia through insect populations. CI disrupts a number of prophase and metaphase events in the male pronucleus, including Cdk1 activation, chromosome condensation, and segregation. Here, we demonstrate that CI disrupts earlier interphase cell cycle events. Specifically, CI delays the H3.3 and H4 depositionthat occurs immediately after protamine removal from the male pronucleus. In addition, we find prolonged retention of the replication factor PCNA in the malepronucleus into metaphase, indicating progression into mitosis with incompletelyreplicated DNA. We propose that these CI-induced interphase defects in de novo nucleosome assembly and replication are the cause of the observed mitotic condensation and segregation defects. In addition, these interphase chromosome defects likely activate S-phase checkpoints, accounting for the previously described delays in Cdk1 activation. These results have important implications for the mechanism of Rescue and other Wolbachia-induced phenotypes.