IKKα Regulates Mitogenic Signaling through Transcriptional Induction of Cyclin D1 via Tcf

The Wnt/β-catenin/Tcf and IκB/NF-κB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/β-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear β-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IκB kinase complex (IKK) that phosphorylates IκB contains IKKα, IKKβ, and IKKγ. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/β-catenin and IκB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(−/−) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IκB/IKKα or β-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKα. In IKKα(−/−) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKα restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKα(−/−) cells, β-catenin phosphorylation was decreased and purified IKKα was sufficient for phosphorylation of β-catenin through its N-terminus in vitro. Because IKKα but not IKKβ induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKα and IKKβ may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms

IκBα and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFκB Pathways

Notch and NFκB pathways are key regulators of numerous cellular events such as proliferation, differentiation, or apoptosis. In both pathways, association of effector proteins with nuclear corepressors is responsible for their negative regulation. We have previously described that expression of a p65-NFκB mutant that lacks the transactivation domain (p65ΔTA) induces cytoplasmic translocation of N-CoR leading to a positive regulation of different promoters. Now, we show that cytoplasmic sequestration of p65 by IκBα is sufficient to both translocate nuclear corepressors SMRT/N-CoR to the cytoplasm and upregulate transcription of Notch-dependent genes. Moreover, p65 and IκBα are able to directly bind SMRT, and this interaction can be inhibited in a dose-dependent manner by the CREB binding protein (CBP) coactivator and after TNF-α treatment, suggesting that p65 acetylation is modulating this interaction. In agreement with this, TNF-α treatment results in downregulation of the Hes1 gene. Finally, we present evidence on how this mechanism may influence cell differentiation in the 32D myeloid progenitor system

Quercetin: a flavonoid with the potential to treat asthma

Allergic asthma is a complex inflammatory disorder characterized by airway hyperresponsiveness, eosinophilic inflammation and hypersecretion of mucus. Current therapies include β2-agonists, cysteinyl leukotriene receptor 1 antagonists and corticosteroids. Although these drugs demonstrate beneficial effects, their adverse side effects limit their long-term use. Thus, the development of new compounds with similar therapeutic activities and reduced side effects is both desirable and necessary. Natural compounds are used in some current therapies, as plant-derived metabolites can relieve disease symptoms in the same manner as allopathic medicines. Quercetin is a flavonoid that is naturally found in many fruits and vegetables and has been shown to exert multiple biological effects in experimental models, including the reduction of major symptoms of asthma: bronchial hyperactivity, mucus production and airway inflammation. In this review, we discuss results from the literature that illustrate the potential of quercetin to treat asthma and its exacerbations.A asma alérgica é uma doença inflamatória complexa caracterizada por hiperresponsividade das vias aéreas, inflamação eosinofílica e hipersecreção de muco. As terapias atuais incluem β2-agonistas, antagonistas do receptor 1 de cisteinil leucotrienos e corticosteróides. Embora estes fármacos demonstrem efeitos benéficos, seus efeitos adversos limitam seus usos a longo prazo. Assim, o desenvolvimento de novos compostos com atividades terapêuticas similares e reduzido efeitos adversos é tanto desejável quanto necessário. Compostos naturais podem ser utilizados nas terapias atuais, uma vez que metabólitos derivados de plantas são capazes de aliviar os sintomas de forma comparável aos medicamentos alopáticos. A quercetina é um flavonóide que ocorre naturalmente em muitas frutas e vegetais e tem mostrado vários efeitos biológicos, principalmente em modelos experimentais, incluindo a redução dos principais fenótipos da asma: hiperreatividade brônquica, produção de muco e inflamação das vias aéreas. Nesta revisão, nós discutimos os resultados da literatura que revelam o potencial da quercetina para tratar a asma e suas exacerbações

Invariant-mass spectroscopy of "1"0Li and "1"1Li

Break-up of secondary "1"1Li ion beams (280 MeV/nucleon) on C and Pb targets into "9Li and neutrons is studied experimentally. Cross sections and neutron multiplicity distributions are obtained, characterizing different reaction mechanisms. Invariant-mass spectroscopy for "1"1Li and "1"0Li is performed. The E1 strength distribution, deduced from electromagnetic excitation of "1"1Li up to an excitation energy of 4 MeV comprises #approx#8% of the Thomas-Reiche-Kuhn energy-weighted sum-rule strength. Two low-lying resonance-like structures are observed for "1"0Li at decay energies of 0.21(5) and 0.62(10) MeV, the former one carrying 26(10)% of the strength and likely to be associated with an s-wave neutron decay. A strong di-neutron correlation in "1"1Li can be discarded. Calculations in a quasi-particle RPA approach are compared with the experimental results for "1"0Li and "1"1Li. (orig.)SIGLEAvailable from TIB Hannover: RO 801(97-14) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

"6He and neutron momentum distributions from "8He in nuclear break-up reactions at 240 MeV/u

Neutron and "6He momentum distributions from "8He break-up reactions in a C-target have been measured at 240 MeV/u. The two-neutron removal cross section was found to be #sigma#_-_2_n=0.27#+-#0.03 b. The nature of the momentum distributions is interpreted in some simple reaction scenarios. (orig.)32 refs.SIGLEAvailable from TIB Hannover: RO 801(96-04) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Neutron momentum distribution from ''core break-up'' reactions of halo nuclei

Neutron angular distributions from violent break-up reactions of "1"1Li and "1"1Be have been measured at 28 MeV/u and 280 MeV/u and at 41 MeV/u and 460 MeV/u, respectively. The derived neutron momentum distributions show a narrow component in transverse momentum that is within uncertainties independent of beam energy and target charge. This component is suggested to be simply related to the momentum distribution of the loosely bound halo neutron(s) in the projectiles. (orig.)SIGLEAvailable from TIB Hannover: RO 801(95-02) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Invariant mass spectrum and #alpha# - n correlation function studied in the fragmentation of "6He on a carbon target

Momentum distributions and invariant mass spectra from the breakup of "6He ions with an energy of 250 MeV/u interacting with a carbon target have been studied. The data were used to extract information about the reaction mechanism which is influenced by the structure of "6He. It is found that the dominant reaction mechanism is a two-step process: knock out of one neutron followed by the decay of the "5He resonance. The shape of the (#alpha#+n) two-body invariant mass spectrum is interpreted as mainly reflecting the "5He ground state which is a J "#pi# =3/2"- resonance. However, no evidence for correlations between #alpha# particles and neutrons is observed in the momentum widths of the distributions. It is demonstrated that a combined analysis of the two-body invariant mass spectrum and an appropriate correlation function may be used to determine the properties of the intermediate resonance. (orig.)Available from TIB Hannover: RO 801(97-61) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman