The Identification of Protein Kinase C Iota as a Regulator of the Mammalian Heat Shock Response Using Functional Genomic Screens

BACKGROUND: The heat shock response is widely used as a surrogate of the general protein quality control system within the cell. This system plays a significant role in aging and many protein folding diseases as well as the responses to other physical and chemical stressors. METHODS/PRINCIPAL FINDINGS: In this study, a broad-based functional genomics approach was taken to identify potential regulators of the mammalian heat shock response. In the primary screen, a total of 13724 full-length genes in mammalian expression vectors were individually co-transfected into human embryonic kidney cells together with a human HSP70B promoter driving firefly luciferase. A subset of the full-length genes that showed significant activation in the primary screen were then evaluated for their ability to hyper-activate the HSP70B under heat shock conditions. Based on the results from the secondary assay and gene expression microarray analyses, eight genes were chosen for validation using siRNA knockdown. Of the eight genes, only PRKCI showed a statistically significant reduction in the heat shock response in two independent siRNA duplexes compared to scrambled controls. Knockdown of the PRKCI mRNA was confirmed using quantitative RT-PCR. Additional studies did not show a direct physical interaction between PRKCI and HSF1. CONCLUSIONS/SIGNIFICANCE: The results suggest that PRKCI is an indirect co-regulator of HSF1 activity and the heat shock response. Given the underlying role of HSF1 in many human diseases and the response to environmental stressors, PRKCI represents a potentially new candidate for gene-environment interactions and therapeutic intervention

The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

The role of Ti addition on the evolution and stability of γ/γ′ microstructure in a Co–30Ni–10Al–5Mo–2Ta alloy

The paper explores the influence of Ti addition to the Ta stabilized γ/γ′ two-phase Co-based superalloys having the compositions of Co-30Ni-10Al-5Mo-2Ta-xTi (x = 0, 1, 2 and 4 at.). The microstructure of the alloys after solutionizing (1300 °C for 25 h) and quenching show fine distribution of γ′ precipitates with spherical shape within the γ matrix. Aging of these alloys at 900 °C results in a morphological transition from spheroidal to cuboidal with a concomitant increase in γ/γ′ lattice misfit as compared to the solutionized alloys. However, the γ/γ′ lattice misfit of cuboidal particles decreases with an increase in Ti in the alloys. Atomic-scale compositional analysis by atom probe tomography across γ/γ′ interface for the aged alloys indicates a preferential partitioning of Ti to the γ′. This can be correlated with the observed increase in the γ′ solvus temperature up to 1166 °C for alloys with 4 at. Ti addition. The increase in Ti content also decreases the partitioning of Mo to the γ′. Despite the rise in solvus temperature, the coarsening study reveals an escalation in the γ′ coarsening rate at 900 and 950 °C with a maximum for the alloy containing the highest Ti content. The initial stages of γ′ coarsening follow diffusion-controlled LSW kinetics. However, during later stages, a propensity for particle coalescence could be observed. An addition of 3 and 4 at. Ti is shown to improve the high-temperature strength with 0.2 proof stress at 1000 °C of 360 and 400 MPa, respectively. © 2021 Acta Materialia Inc

On the effect of W addition on microstructural evolution and gamma' precipitate coarsening in a Co–30Ni–10Al–5Mo–2Ta–2Ti alloy

The effect of replacement of molybdenum with small amount of tungsten on the stability of cobalt based super-alloys of Co-Ni-Mo-Al-Ta-Ti class has been presented. A small addition of tungsten (W) in Co-30Ni-(5-x)Mo-10Al-2Ta-2Ti-2W alloys stabilizes the cuboidal morphology of precipitates and increases the gamma' volume fraction. A 2 at% addition of W causes an increase of 60 degrees C in solvus temperature of the base superalloy to reach a value of 1130 degrees C with a slight increase of mass density to 8.79 g/cc. Beside partitioning into gamma', W also shifts the partitioning preference of Mo from the gamma' phase in 0W alloy to that of equal partitioning in both gamma and gamma' phases in 2W alloy. An interfacial confinement of Mo atoms could be observed at the gamma/gamma' interfaces that reduces interface energy leading to enhanced microstructural stability. The experimentally determined temporal evolution of average precipitate size in the 2W alloy at the temperatures of 800, 900 and 950 degrees C suggests a matrix diffusion limited coarsening kinetics. The estimated coarsening rate constant at 900 degrees C follows a quasi-steady state model and is comparable to those observed for W and Re containing Co-based superalloys. The activation energy for gamma' precipitate coarsening is estimated to be 258 +/- 6 kJ/mole, which is comparable to the Mo diffusion in the gamma-Co matrix suggesting Mo diffusion still controls the precipitate coarsening in the 2W alloy

Addictive and other mental disorders : a call for a standardized definition of dual disorders

The persistent difficulty in conceptualizing the relationship between addictive and other mental disorders stands out among the many challenges faced by the field of Psychiatry. The different philosophies and schools of thought about, and the sheer complexity of these highly prevalent clinical conditions make progress inherently difficult, not to mention the profusion of competing and sometimes contradictory terms that unnecessarily exacerbate the challenge. The lack of a standardized term adds confusion, fuels stigma, and contributes to a "wrong door syndrome" that captures the difficulty of not only diagnosing but also treating addictive and other mental disorders in an integrated manner. The World Association on Dual Disorders (WADD) proposes the adoption of the term "Dual Disorder" which, while still arbitrary, would help harmonize various clinical and research efforts by rallying around a single, more accurate, and less stigmatizing designation

Food and drug reward: overlapping circuits in human obesity and addiction

Both drug addiction and obesity can be defined as disorders in which the saliency value of one type of reward (drugs and food, respectively) becomes abnormally enhanced relative to, and at the expense of others. This model is consistent with the fact that both drugs and food have powerful reinforcing effects - partly mediated by dopamine increases in the limbic system - that, under certain circumstances or in vulnerable individuals, could overwhelm the brain's homeostatic control mechanisms. Such parallels have generated significant interest in understanding the shared vulnerabilities and trajectories between addiction and obesity. Now, brain imaging discoveries have started to uncover common features between these two conditions and to delineate some of the overlapping brain circuits whose dysfunctions may explain stereotypic and related behavioral deficits in human subjects. These results suggest that both obese and drug addicted individuals suffer from impairments in dopaminergic pathways that regulate neuronal systems associated not only with reward sensitivity and incentive motivation, but also with conditioning (memory/learning), impulse control (behavioral inhibition), stress reactivity and interoceptive awareness. Here, we integrate findings predominantly derived from positron emission tomography that investigate the role of dopamine in drug addiction and in obesity and propose an updated working model to help identify treatment strategies that may benefit both of these conditions