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41.
42.
DNA replication in eukaryotes is considered to proceed according to a precise program in which each chromosomal region is
duplicated in a defined temporal order. However, recent studies reveal an intrinsic temporal disorder in the replication of
yeast chromosome VI. Here we provide a model of the chromosomal duplication to study the temporal sequence of origin activation
in budding yeast. The model comprises four parameters that influence the DNA replication system: the lengths of the chromosomes,
the explicit chromosomal positions for all replication origins as well as their distinct initiation times and the replication
fork migration rate. The designed model is able to reproduce the available experimental data in form of replication profiles.
The dynamics of DNA replication was monitored during simulations of wild type and randomly perturbed replication conditions.
Severe loss of origin function showed only little influence on the replication dynamics, so systematic deletions of origins
(or loss of efficiency) were simulated to provide predictions to be tested experimentally. The simulations provide new insights
into the complex system of DNA replication, showing that the system is robust to perturbation, and giving hints about the
influence of a possible disordered firing.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
43.
Hibert M Hoflack J Trumpp-Kallmeyer S Mouillac B Chini B Mahé E Cotte N Jard S Manning M Barberis C 《Journal of receptor and signal transduction research》1999,19(1-4):589-596
Three-dimensional models of G protein-coupled receptors (GPCR) have been defined using most experimental data available and protein modeling techniques. The endogenous ligand binding sites have been qualitatively described and putative receptor activation mechanisms have been proposed. The model has been recently refined to take into account recent crystallographic data. Most experimental results published are in excellent qualitative agreement with the initial model. We have undertaken to study more systematically by site directed mutagenesis the vasopressin/oxytocin receptor binding domain as a prototype of neuropeptide receptors. The experimental results are in very good agreement with the models. The residues responsible for the neuropeptide binding have been identified and confirm the predicted localization of the neuromediator in the transmembrane domain of the receptors. The side chain of the 8th residue of vasopressin interacts with a non-conserved receptor residue located in the first extracellular loop. As predicted from the model, this interaction is completely responsible for the selectivity of the ligand-receptor interaction. Finally, aromatic residues which allow the modulation of the efficacy of agonists have been identified. 相似文献
44.
PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects 总被引:11,自引:0,他引:11
Patrucco E Notte A Barberis L Selvetella G Maffei A Brancaccio M Marengo S Russo G Azzolino O Rybalkin SD Silengo L Altruda F Wetzker R Wymann MP Lembo G Hirsch E 《Cell》2004,118(3):375-387
The G protein-coupled, receptor-activated phosphoinositide 3-kinase gamma (PI3Kgamma) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration. Here, we report that mice carrying a targeted mutation in the PI3Kgamma gene causing loss of kinase activity (PI3KgammaKD/KD) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3KgammaKD/KD hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3KgammaKD/KD mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC). Finally, our data indicate that PI3Kgamma is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction. Thus, cardiac PI3Kgamma participates in two distinct signaling pathways: a kinase-dependent activity that controls PKB/Akt as well as MAPK phosphorylation and contributes to TAC-induced cardiac remodeling, and a kinase-independent activity that relies on protein interactions to regulate PDE3B activity and negatively modulates cardiac contractility. 相似文献
45.
46.
Petrini EM Zacchi P Barberis A Mozrzymas JW Cherubini E 《The Journal of biological chemistry》2003,278(18):16271-16279
Speed and reliability of synaptic transmission are essential for information coding in neuronal networks and require the presence of clustered neurotransmitter receptors at the plasma membrane in precise apposition to presynaptic terminals. Receptor clusterization is the result of highly regulated processes involving functional and structural proteins. Among the structural elements, microtubules are known to play a crucial role in anchoring of gamma-aminobutyric acid, type A (GABA(A)) receptors. Here we show that microtubule depolymerization with nocodazole induces the declusterization of GABA(A) receptors and modifies the kinetic properties of GABAergic currents in cultured hippocampal neurons. In particular, this drug, applied either in the bath or via the patch pipette, induced the acceleration of the onset kinetics of miniature inhibitory postsynaptic currents (mIPSCs) without significantly affecting their frequency, thus suggesting a main postsynaptic site of action. After nocodazole treatment, current responses to ultrafast applications of GABA exhibited a faster rise time and an accelerated onset of desensitization. A quantitative analysis of GABA-evoked currents and model simulations suggest that declusterization affects the gating properties of GABA(A) receptors. In particular, a faster entry into the desensitized state of declustered GABA(A) receptors may account for the changes in the kinetic properties of mIPSCs after nocodazole treatment. Hence it appears that the clustered condition of GABA(A) receptors contributes in shaping GABAergic currents. 相似文献
47.
Defective dendrite elongation but normal fertility in mice lacking the Rho-like GTPase activator Dbl
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Hirsch E Pozzato M Vercelli A Barberis L Azzolino O Russo C Vanni C Silengo L Eva A Altruda F 《Molecular and cellular biology》2002,22(9):3140-3148
Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho and Cdc42 and to induce a transformed phenotype. Dbl is specifically expressed in brain and gonads, but its in vivo functions are largely unknown. To assess its role in neurogenesis and gametogenesis, targeted deletion of the murine Dbl gene was accomplished in embryonic stem cells. Dbl-null mice are viable and did not show either decreased reproductive performances or obvious neurological defects. Histological analysis of mutant testis showed normal morphology and unaltered proliferation and survival of spermatogonia. Dbl-null brains indicated a correct disposition of the major neural structures. Analysis of cortical stratification indicated that Dbl is not crucial for neuronal migration. However, in distinct populations of Dbl-null cortical pyramidal neurons, the length of dendrites was significantly reduced, suggesting a role for Dbl in dendrite elongation. 相似文献
48.
Defective Rac-mediated proliferation and survival after targeted mutation of the beta1 integrin cytodomain
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Hirsch E Barberis L Brancaccio M Azzolino O Xu D Kyriakis JM Silengo L Giancotti FG Tarone G Fässler R Altruda F 《The Journal of cell biology》2002,157(3):481-492
Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta1 integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the beta1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control. 相似文献
49.
Giordano S Corso S Conrotto P Artigiani S Gilestro G Barberis D Tamagnone L Comoglio PM 《Nature cell biology》2002,4(9):720-724
Semaphorins are cell surface and soluble signals that control axonal guidance. Recently, semaphorin receptors (plexins) have been discovered and shown to be widely expressed. Their biological activities outside the nervous system and the signal transduction mechanism(s) they utilize are largely unknown. Here, we show that in epithelial cells, Semaphorin 4D (Sema 4D) triggers invasive growth, a complex programme that includes cell#150;cell dissociation, anchorage-independent growth and branching morphogenesis. Interestingly, the same response is also controlled by scatter factors through their tyrosine kinase receptors, which share striking structural homology with plexins in their extracellular domain. We found that in cells expressing the endogenous proteins, Plexin B1 (the Sema 4D Receptor) and Met (the Scatter Factor 1/ Hepatocyte Growth Factor Receptor) associate in a complex. In addition, binding of Sema 4D to Plexin B1 stimulates the tyrosine kinase activity of Met, resulting in tyrosine phosphorylation of both receptors. Finally, cells lacking Met expression do not respond to Sema 4D unless exogenous Met is expressed. This work identifies a novel biological function of semaphorins and suggests the involvement of an unexpected signalling mechanism, namely, the coupling of a plexin to a tyrosine kinase receptor. 相似文献
50.
C. Barberis 《FEBS letters》1983,162(2):400-405
Characterization of specific vasopressin binding sites to rat hippocampal membranes has been assayed using tritiated lysine-vasopressin labelled on the tyrosyl residue. At 30°C specific [3H]vasopressin binding was saturable. The estimated equilibrium dissociation constant was 7.1 nM, the mean maximal binding capacity was 78 fmol/mg protein. Arginine-vasopressin has a high affinity (Kd = 2.8 nM) and dDAVP has a low affinity (Kd = 249 nM) for hippocampal synaptic membranes. (OH)AVP and Phe2Orn8VT are at least as active as AVP in inhibiting [3H]vasopressin binding. Adenylate cyclase was activated by VIP and inhibited by PIA, but not affected by lysine-vasopressin. 相似文献