IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy

Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1α and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1α-proficient and in IRE1α-deficient cells, by pharmacological inhibition with 4μ8 C or down-regulation by specific siRNA. We show that either type of IRE1α deficiency affects eIF2α expression and causes cell death increase. GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2α down-regulation and restore cell survival. Degradation of this protein is due to autophagy, as it is prevented by bafilomycin and not by proteasome inhibition. Furthermore, activation of the autophagy flux is PERK dependent. Also the Cathepsin B inhibitor CA074 prevents eIF2α from degradation and reduces cell death. Altogether, these results show that IRE1α deficiency in ER stressed cells leads to an unexpected decrease of eIF2α, an important molecule for protein translation, through PERK dependent autophagy. Thus, IRE1/XBP1 inhibitors may represent a feasible strategy for tumor therapy, while PERK inhibitors may vanish the goal

Nonequilibrium ionization states and cooling rates of the photoionized enriched gas

Nonequilibrium (time-dependent) cooling rates and ionization state calculations are presented for low-density gas enriched with heavy elements (metals) and photoionized by external ultraviolet/X-ray radiation. We consider a wide range of gas densities and metallicities and also two types of external radiation field: a power-law and the extragalactic background spectra. We have found that both cooling efficiencies and ionic composition of enriched photoionized gas depend significantly on the gas metallicity and density, the flux amplitude, and the shape of ionizing radiation spectrum. The cooling rates and ionic composition of gas in nonequilibrium photoionization models differ strongly (by a factor of several) from those in photoequilibrium due to overionization of the ionic states in the nonequilibrium case. The difference is maximal at low values of the ionization parameter and similar in magnitude to that between the equlibrium and nonequilibrium cooling rates in the collisionally controlled gas. In general, the nonequilibrium effects are notable at T\simlt 10^6 K. In this temperature range, the mismatch of the ionic states and their ratios between the photoequilibrium and the photo-nonequilibrium models reach a factor of several. The net result is that the time-dependent energy losses due to each chemical element (i.e. the contributions to the total cooling rate) differ singificantly from the photoequilibrium ones. We advocate the use of nonequilibrium cooling rates and ionic states for gas with near-solar (and above) metallicity exposed to an arbitrary ionizing radiation flux. We provide a parameter space (in terms of temperature, density, metallicity and ionizing radiation flux), where the nonequilibrium cooling rates are to be used. (abridged)Comment: 14 pages, 11 figures, accepted to MNRA

Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. We previously showed that the inhibition of placental growth factor (PlGF) exerts antitumour effects and induces vessel normalisation, possibly reducing hypoxia. However, the exact mechanism underlying these effects remains unclear. Because hypoxia and endoplasmic reticulum stress, which activates the unfolded protein response (UPR), have been implicated in HCC progression, we assessed the interactions between PlGF and these microenvironmental stresses. Methods: PlGF knockout mice and validated monoclonal anti-PlGF antibodies were used in a diethylnitrosamine-induced mouse model for HCC. We examined the interactions among hypoxia, UPR activation and PlGF induction in HCC cells. Results: Both the genetic and pharmacological inhibitions of PlGF reduced the chaperone levels and the activation of the PKR-like endoplasmic reticulum kinase (PERK) pathway of the UPR in diethylnitrosamine-induced HCC. Furthermore, we identified that tumour hypoxia was attenuated, as shown by reduced pimonidazole binding. Interestingly, hypoxic exposure markedly activated the PERK pathway in HCC cells in vitro, suggesting that PlGF inhibition may diminish PERK activation by improving oxygen delivery. We also found that PlGF expression is upregulated by different chemical UPR inducers via activation of the inositol-requiring enzyme 1 pathway in HCC cells. Conclusions: PlGF inhibition attenuates PERK activation, likely by tempering hypoxia in HCC via vessel normalisation. The UPR, in turn, is able to regulate PlGF expression, suggesting the existence of a feedback mechanism for hypoxia-mediated UPR that promotes the expression of the angiogenic factor PlGF. These findings have important implications for our understanding of the effect of therapies normalising tumour vasculature

Generalised Perk--Schultz models: solutions of the Yang-Baxter equation associated with quantised orthosymplectic superalgebras

The Perk--Schultz model may be expressed in terms of the solution of the Yang--Baxter equation associated with the fundamental representation of the untwisted affine extension of the general linear quantum superalgebra $U_q[sl(m|n)]$, with a multiparametric co-product action as given by Reshetikhin. Here we present analogous explicit expressions for solutions of the Yang-Baxter equation associated with the fundamental representations of the twisted and untwisted affine extensions of the orthosymplectic quantum superalgebras $U_q[osp(m|n)]$. In this manner we obtain generalisations of the Perk--Schultz model.Comment: 10 pages, 2 figure

Effects of keratin filaments on ERK signaling during Fas-induced death of cervical cancer (HeLa) cells

Survival of cancer cells is influenced by a variety of factors, including physical elements such as keratin filaments. We know HeLa cells containing or lacking keratin 8/18 intermediate filaments (K+ and K- cells, respectively) are more sensitive to the death-inducing effects of Fas agonist compared to the cytokines tumor necrosis factor alpha (TNF-α) or TNF-related apoptosis-inducing ligand. Additionally, K- cells are more sensitive to Fas-induced death than K+ as shown by previous studies using mitochondrial activity and caspase activation assays. In the current study we tested the hypothesis that keratin filaments associate with the mitogen activated protein kinase (MAPK) cascade to protect cells from Fas-induced death. To do this, K+ and K- cells were exposed to Fas agonist in the absence or presence of human epidermal growth factor (EGF) (known to stimulate MAPK) and then downstream phosphorylation of extracellular signal-regulated kinase (pERK) was measured. Fas agonist reduced pERK expression in both cell types (~32% less pERK compared to non-EGF-treated controls, n= 3 expts.). Conversely, EGF (50ng/ml) reversed this outcome, but again did so equally in K+ and K- cells. Intriguingly, K- cells were more responsive to EGF stimulation alone than K+ cells, regardless of EGF dose (pERK ~27% higher in K- than K+ cells, n= 3 expts.). The results suggest keratin 8/18 filaments do associate with the MAPK cascade to influence cell survival. Supported by the Hamel Center for Undergraduate Research (AB) and the COLSA Karabelas Fund (DHT)

A Rent Extraction View of Employee Discounts and Benefits

We offer a novel view of employee discounts and in kind compensation. In our theory, bundling perks and cash compensation allows a firm to extract information rents from employees who have private information about their preferences for the perk and about their outside opportunities. We show that in maximizing profit with heterogeneous workers, the firm creates different bundles of the perk and salary in response to different employee characteristics and marginal costs of the perk. Our key result is that strategic bundling can lead firms to provide perks even in the absence of any cost advantage over the outside market and to deviate from the standard marginal cost pricing rule. We study how this deviation depends upon the set of feasible contracts, upon the perk's marginal cost, and upon the correlation between the agents' preferences for the good and their reservation utilities.In Kind Compensation, Bundling, Optimal Employment Contracts

The exact equivalence of the two-flavour strong coupling lattice Schwinger model with Wilson fermions to a vertex model

In this paper a method previously employed by Salmhofer to establish an exact equivalence of the one-flavour strong coupling lattice Schwinger model with Wilson fermions to some 8-vertex model is applied to the case with two flavours. As this method is fairly general and can be applied to strong coupling QED and purely fermionic models with any (sufficiently small) number of Wilson fermions in any dimension the purpose of the present study is mainly a methodical one in order to gain some further experience with it. In the paper the vertex model equivalent to the two-flavour strong coupling lattice Schwinger model with Wilson fermions is found. It turns out to be some modified 3-state 20-vertex model on the square lattice, which can also be understood as a regular 6-state vertex model. In analogy with the one- flavour case, this model can be viewed as some loop model.Comment: 22 pages LaTe