A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-κB activity in T-cells

Background!#!Human T-cell leukemia virus type 1 (HTLV-1) infects primarily CD4!##!Results!#!Here we found that Tax mutants which are defective in NF-κB signaling showed diminished protein expression levels compared to Tax wildtype in T-cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF-κB signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK-β), IKK2-EE, rescued protein expression of the NF-κB defective Tax mutants M22 and K1-10R and even increased protein levels of Tax wildtype in various T-cell lines while Tax transcript levels were only slightly affected. Using several Tax expression constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12-O-Tetradecanoylphorbol-13-Acetate [TPA; Phorbol 12-myristate 13-acetate (PMA)]/ ionomycin, inducers of NF-κB and cytokine signaling, but not by tumor necrosis factor alpha (TNF-α). On the other hand, co-expression of Tax with a dominant negative inhibitor of κB, IκBα-DN, or specific inhibition of IKK2 by the compound ACHP, led to a vast decrease in Tax protein levels to some extent independent of Tax transcripts in transiently transfected and Tax-transformed T-cells. Cycloheximide chase experiments revealed that co-expression of IKK2-EE prolongs the half-life of M22, and constant repression of NF-κB signaling by IκBα-DN strongly reduces protein stability of Tax wildtype suggesting that NF-κB activity is required for Tax protein stability. Finally, protein expression of Tax and M22 could be recovered by NH!##!Conclusions!#!Together, these findings suggest that Tax's capability to induce NF-κB is critical for protein expression and stabilization of Tax itself. Overall, identification of this novel positive feedback loop between Tax and NF-κB in T-cells improves our understanding of Tax-driven transformation

Shock-induced formation of wüstite and fayalite in a magnetite-quartz target rock

Projectile–target interactions as a result of a large bolide impact are important issues, as abundant extraterrestrial material has been delivered to the Earth throughout its history. Here, we report results of shock-recovery experiments with a magnetite-quartz target rock positioned in an ARMCO iron container. Petrography, synchrotron-assisted X-ray powder diffraction, and micro-chemical analysis confirm the appearance of wüstite, fayalite, and iron in targets subjected to 30 GPa. The newly formed mineral phases occur along shock veins and melt pockets within the magnetite-quartz aggregates, as well as along intergranular fractures. We suggest that iron melt formed locally at the contact between ARMCO container and target, and intruded the sample causing melt corrosion at the rims of intensely fractured magnetite and quartz. The strongly reducing iron melt, in the form of μm-sized droplets, caused mainly a diffusion rim of wüstite with minor melt corrosion around magnetite. In contact with quartz, iron reacted to form an iron-enriched silicate melt, from which fayalite crystallized rapidly as dendritic grains. The temperatures required for these transformations are estimated between 1200 and 1600 °C, indicating extreme local temperature spikes during the 30 GPa shock pressure experiments