Role of c-Abl in the DNA damage stress response

c-Abl has been implicated in many cellular processes including differentiation, division, adhesion, death, and stress response, c-Abl is a latent tyrosine kinase that becomes activated in response to numerous extra- and intra-cellular stimuli. Here we briefly review the current knowledge about c-Abl involvement in the DNA-damage stress response and its implication on cell physiology.     

20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1

Ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, is a very labile protein. ODC is a homodimeric enzyme that undergoes ubiquitin-independent proteasomal degradation via direct interaction with antizyme, a polyamine-induced protein. Binding of antizyme promotes the dissociation of ODC homodimers and marks ODC for degradation by the 26S proteasomes. We describe here an alternative pathway for ODC degradation that is regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). We show that NQO1 binds and stabilizes ODC. Dicoumarol, an inhibitor of NQO1, dissociates ODC-NQO1 interaction and enhances ubiquitin-independent ODC proteasomal degradation. We further show that dicoumarol sensitizes ODC monomers to proteasomal degradation in an antizyme-independent manner. This process of NQO1-regulated ODC degradation was recapitulated in vitro by using purified 20S proteasomes. Finally, we show that the regulation of ODC stability by NQO1 is especially prominent under oxidative stress. Our findings assign to NQO1 a role in regulating ubiquitin-independent degradation of ODC by the 20S proteasomes.     

Reproductive division of labor, dominance, and ecdysteroid levels in hemolymph and ovary of the bumble bee Bombus terrestris

To determine whether ecdysteroids are associated with reproductive division of labor in Bombus terrestris, we measured their levels in hemolymph and ovaries of queens and workers. Queens heading colonies had large active ovaries with high ecdysteroid content, whereas virgin gynes and mated queens before and after diapause had undeveloped ovaries with low ecdysteroid content. The hemolymph ecdysteroid titer was rather variable, but in a pooled analysis of mated queens before and after diapause versus colony-heading queens, ecdysteroid titers were higher in the latter group. In workers, agonistic behavior, ovarian activity, ovarian ecdysteroid content, and hemolymph ecdysteroid titers were positively correlated, and were lowest when a queen was present. In queenless workers, ecdysteroid levels were elevated in dominant workers, and were also influenced by the presence of brood and by group demography; hormone levels were higher in bees kept in larger groups. These findings are consistent with the premise that in B. terrestris the ovary is the primary site of ecdysteroid synthesis, and they show that ecdysteroids levels vary with the social environment.     

Carbon:chlorophyll <Emphasis Type="Italic">a</Emphasis> ratio,assimilation numbers and turnover times of Lake Kinneret phytoplankton

Carbon to chlorophyll a (C:Chl) ratios, assimilation numbers (A.N.) and turnover times of natural populations of individual species and taxonomic groups were extracted from a long-term database of phytoplankton wet-weight biomass, chlorophyll a concentrations, and primary production in Lake Kinneret, Israel. From a database spanning more than a decade, we selected data for samples dominated by a single species or taxonomic group. The overall average of C:Chl was highest for cyanophytes and lowest for diatoms, while chlorophytes and dinoflagellates showed intermediate values. When converting chlorophyll a to algal cellular carbon this variability should be taken into account. The variability in C:Chl within each phylum and species (when data were available) was high and the variability at any particular sampling date tended to be greater than the temporal variability. The average chlorophyll a-normalized rate of photosynthetic activity of cyanophytes was higher and that of the dinoflagellates lower than that of other phyla. Turnover time of phytoplankton, calculated using primary productivity data at the depth of maximal photosynthetic rate, was longest in dinoflagellates and shortest in cyanophytes, with diatoms and chlorophytes showing intermediate values. The more extreme C:Chl and turnover times of dinoflagellates and cyanobacteria in comparison with chlorophytes and diatoms should be taken into consideration when employed in ecological modeling.     

On the mechanisms of the reaction of dodecatungstophosphate with alkyl radicals in aqueous solutions

The reduced lacunary polyoxotungstate, [PW₁₁O₃₉]⁸⁻, reacts with the ^.CH₂CH(OH)CH₃ and ^.CH₂C(CH₃)₂OH radicals via a mechanism involving β-hydroxide elimination to yield propene and 2-methyl propene respectively, and [PW₁₁O₃₉]⁷⁻. [PW₁₁O₃₉]⁸⁻ is also oxidized by methyl radicals in a reaction which yields methane as the major product. It is proposed that the reactions proceed via the formation of short lived transients with W-C σ bonds.     

RNA interference for antiviral therapy

Silencing gene expression through a process known as RNA interference (RNAi) has been known in the plant world for many years. In recent years, knowledge of the prevalence of RNAi and the mechanism of gene silencing through RNAi has started to unfold. It is now believed that RNAi serves in part as an innate response against invading viral pathogens and, indeed, counter silencing mechanisms aimed at neutralizing RNAi have been found in various viral pathogens. During the past few years, it has been demonstrated that RNAi, induced by specifically designed double-stranded RNA (dsRNA) molecules, can silence gene expression of human viral pathogens both in acute and chronic viral infections. Furthermore, it is now apparent that in in vitro and in some in vivo models, the prospects for this technology in developing therapeutic applications are robust. However, many key questions and obstacles in the translation of RNAi into a potential therapeutic platform still remain, including the specificity and longevity of the silencing effect, and, most importantly, the delivery of the dsRNA that induces the system. It is expected that for the specific examples in which the delivery issue could be circumvented or resolved, RNAi may hold promise for the development of gene-specific therapeutics.     

Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases

When appended to the epidermal growth factor receptor (EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases.