A requirement for NF-κB activation in Bcr-Abl-mediated transformation

Bcr-Abl is a chimeric oncoprotein that is strongly implicated in acute lymphoblastic (ALL) and chronic myelogenous leukemias (CML). This deregulated tyrosine kinase selectively causes hematopoietic disorders resembling human leukemias in animal models and transforms fibroblasts and hematopoietic cells in culture. Bcr-Abl also protects cells from death induced on cytokine deprivation or exposure to DNA damaging agents. In addition, the antiapoptotic function of Bcr-Abl is thought to play a necessary role in hematopoietic transformation and potentially in leukemogenesis. The transcription factor NF-κB has been identified recently as an inhibitor of apoptosis and as a potential regulator of cellular transformation. This study shows that expression of Bcr-Abl leads to activation of NF-κB-dependent transcription by causing nuclear translocation of NF-κB as well as by increasing the transactivation function of the Re1A/p65 subunit of NF-κB. Importantly, this activation is dependent on the tyrosine kinase activity of Bcr-Abl and partially requires Ras. The ability of Bcr-Abl to protect cytokine-dependent 32D myeloid cells from death induced by cytokine deprivation or DNA damage does not, however, require functional NF-κB. However, using a super-repressor form of IκBα, we show that NF-κB is required for Bcr-Abl-mediated tumorigenicity in nude mice and for transformation of primary bone marrow cells. This study implicates NF-κB as an important component of Bcr-Abl signaling. NF-κB-regulated genes, therefore, likely play a role in transformation by Bcr-Abl and thus in Bcr- Abl-associated human leukemias

Lithium ceramics as the solid breeder material in fusion reactors

Fusion blanket designs have for almost a decade considered the use of a solid breeder relying on available data and assumed performance. The conclusion from these studies is that acceptable neutronic and thermal hydraulic performance can be achieved. In the future, it will be necessary to establish that a particular material can tolerate the thermal and irradiation environment of the fusion blanket while still providing the required functions of tritium recovery, power production and neutron shielding

Caracteres agronómicos en el cultivo de espárrago de diferentes edades y manejos Agronomic characters in asparagus of different ages and crop systems

El objetivo del trabajo fue evaluar el efecto de la edad de la planta y la respuesta a los manejos en 11 híbridos de espárrago (Asparagus officinalis L.). Se utilizó un diseño en bloques completos aleatorios con tres repeticiones de 20 plantas por parcela, con tres y cuatro años de edad, según dos sistemas de manejo: con surcos alomados para la producción de espárrago blanco y surcos sin alomar para espárrago verde. Con el manejo para espárrago blanco se obtuvieron mayores valores promedio para días a brotación, rendimiento de mercado, rendimiento total, número de turiones y peso promedio del turión. Sin embargo, la tasa de incremento del primer al segundo año de cosecha para rendimiento de mercado y rendimiento total resultó superior en el manejo verde debido a una tasa de incremento superior para número de turiones. Para días a brotación y peso promedio del turión, la respuesta debida al efecto del manejo y de la edad del cultivo fue similar, mientras que días al 50% de parcela brotada se vio afectada principalmente por la edad de la planta.<br>Age and crop system effects on agronomic response were evaluated in 11 hybrids of Asparagus officinalis L. The experimental design was a complete randomized block with three replicates of 20 plants of 3 or 4 years old, conducted either in mounded soil over plants for blanched asparagus, or in raised beds without ridging for green asparagus. The highest mean values were obtained under the blanched production for days to harvest, market yield, total yield, spears number and the spear mean weight. However, under the green production, the rate of increment from first to second year was superior for market yield and total yield due to an augmented rate of increment of spears number. Type and year of production effects were similar for days to first harvest and spears mean weight, meanwhile days to 50% of sprout plot was affected mainly by the year of production

Suppression of Integrin Activation by Activated Ras or Raf Does Not Correlate with Bulk Activation of ERK MAP Kinase

The rapid modulation of ligand-binding affinity (“activation”) is a central property of the integrin family of cell adhesion receptors. The Ras family of small GTP-binding proteins and their downstream effectors are key players in regulating integrin activation. H-Ras can suppress integrin activation in fibroblasts via its downstream effector kinase, Raf-1. In contrast, to H-Ras, a closely related small GTP-binding protein R-Ras has the opposite activity, and promotes integrin activation. To gain insight into the regulation of integrin activation by Ras GTPases, we created a series of H-Ras/R-Ras chimeras. We found that a 35-amino acid stretch of H-Ras was required for full suppressive activity. Furthermore, the suppressive chimeras were weak activators of the ERK1/2 MAP kinase pathway, suggesting that the suppression of integrin activation may be independent of the activation of the bulk of ERK MAP kinase. Additional data demonstrating that the ability of H-Ras or Raf-1 to suppress integrin activation was unaffected by inhibition of bulk ERK1/2 MAP kinase activation supported this hypothesis. Thus, the suppression of integrin activation is a Raf kinase induced regulatory event that can be mediated independently of bulk activation of the ERK MAP-kinase pathway

Deregulation of the Egfr/Ras Signaling Pathway Induces Age-related Brain Degeneration in the Drosophila Mutant vap

Ras signaling has been shown to play an important role in promoting cell survival in many different tissues. Here we show that upregulation of Ras activity in adult Drosophila neurons induces neuronal cell death, as evident from the phenotype of vacuolar peduncle (vap) mutants defective in the Drosophila RasGAP gene, which encodes a Ras GTPase-activating protein. These mutants show age-related brain degeneration that is dependent on activation of the EGF receptor signaling pathway in adult neurons, leading to autophagic cell death (cell death type 2). These results provide the first evidence for a requirement of Egf receptor activity in differentiated adult Drosophila neurons and show that a delicate balance of Ras activity is essential for the survival of adult neurons

Membrane Targeting of Grb2-associated Binder-1 (Gab1) Scaffolding Protein through Src Myristoylation Sequence Substitutes for Gab1 Pleckstrin Homology Domain and Switches an Epidermal Growth Factor Response to an Invasive Morphogenic Program

The hepatocyte growth factor receptor tyrosine kinase Met promotes cell dissociation and the inherent morphogenic program of epithelial cells. In a search for substrates downstream from Met, we have previously identified the Grb2-associated binder-1 (Gab1) as critical for the morphogenic program. Gab1 is a scaffold protein that acts to diversify the signal downstream from the Met receptor through its ability to couple with multiple signal transduction pathways. Gab1 contains a pleckstrin homology (PH) domain with specificity for phosphatidylinositol 3,4,5-trisphosphate. The phospholipid binding capacity of the Gab1 PH domain is required for the localization of Gab1 at sites of cell-cell contact in colonies of epithelial cells and for epithelial morphogenesis, suggesting that PH domain-dependent subcellular localization of Gab1 is a prerequisite for function. We have investigated the requirement for membrane localization of Gab1 for biological activity. We show that substitution of the Gab1 PH domain with the myristoylation signal from the c-Src protein is sufficient to replace the Gab1 PH domain for epithelial morphogenesis. The membrane targeting of Gab1 enhances Rac activity in the absence of stimulation and switches a nonmorphogenic noninvasive response to epidermal growth factor to a morphogenic invasive program. These results suggest that the subcellular localization of Gab1 is a critical determinant for epithelial morphogenesis and invasiveness