E3 ubiquitin ligases: key regulators of TGF beta signaling in cancer progression

Transforming growth factor beta (TGF beta) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGF beta signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGF beta is dependent on cellular context, and TGF beta can perform both anti- and pro-oncogenic roles. TGF beta acts by binding to specific cell surface TGF beta type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGF beta signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGF beta receptor and intracellular signaling components. E3 ligases regulate TGF beta signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGF beta's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGF beta-induced pro-oncogenic responses.Cancer Signaling networks and Molecular Therapeutic

Optical symmetries and anisotropic transport in high-Tc superconductors

A simple symmetry analysis of in-plane and out-of-plane transport in a family of high temperature superconductors is presented. It is shown that generalized scaling relations exist between the low frequency electronic Raman response and the low frequency in-plane and out-of-plane conductivities in both the normal and superconducting states of the cuprates. Specifically, for both the normal and superconducting state, the temperature dependence of the low frequency $B_{1g}$ Raman slope scales with the $c-$axis conductivity, while the $B_{2g}$ Raman slope scales with the in-plane conductivity. Comparison with experiments in the normal state of Bi-2212 and Y-123 imply that the nodal transport is largely doping independent and metallic, while transport near the BZ axes is governed by a quantum critical point near doping $p\sim 0.22$ holes per CuO$_{2}$ plaquette. Important differences for La-214 are discussed. It is also shown that the $c-$ axis conductivity rise for $T\ll T_{c}$ is a consequence of partial conservation of in-plane momentum for out-of-plane transport.Comment: 16 pages, 8 Figures (3 pages added, new discussion on pseudogap and charge ordering in La214

Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis

Therapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a highly active DUBs in TNBC may lead to novel therapies.\n biochemical methods. A specific inhibitor was synthesised and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.\nTwo DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in TNBC patient sera, and highly enriched in sera exosomes as well as TNBC cell conditioned media. UCHL1 enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.\nOur DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment.Toxicolog

A review of advanced air distribution methods - theory, practice, limitations and solutions

Ventilation and air distribution methods are important for indoor thermal environments and air quality. Effective distribution of airflow for indoor built environments with the aim of simultaneously offsetting thermal and ventilation loads in an energy efficient manner has been the research focus in the past several decades. Based on airflow characteristics, ventilation methods can be categorized as fully mixed or non-uniform. Non-uniform methods can be further divided into piston, stratified and task zone ventilation. In this paper, the theory, performance, practical applications, limitations and solutions pertaining to ventilation and air distribution methods are critically reviewed. Since many ventilation methods are buoyancy driving that confines their use for heating mode, some methods suitable for heating are discussed. Furthermore, measuring and evaluating methods for ventilation and air distribution are also discussed to give a comprehensive framework of the review

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex

© 2020, The Author(s). Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity

Bone morphogenetic protein receptor signal transduction in human disease

Cancer Signaling networks and Molecular Therapeutic

OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-beta type I receptor

Ovo-like transcriptional repressor 1 (OVOL1) is a key mediator of epithelial lineage determination and mesenchymal-epithelial transition (MET). The cytokines transforming growth factor-beta (TGF-beta) and bone morphogenetic proteins (BMP) control the epithelial-mesenchymal plasticity (EMP) of cancer cells, but whether this occurs through interplay with OVOL1 is not known. Here, we show that OVOL1 is inversely correlated with the epithelial-mesenchymal transition (EMT) signature, and is an indicator of a favorable prognosis for breast cancer patients. OVOL1 suppresses EMT, migration, extravasation, and early metastatic events of breast cancer cells. Importantly, BMP strongly promotes the expression of OVOL1, which enhances BMP signaling in turn. This positive feedback loop is established through the inhibition of TGF-beta receptor signaling by OVOL1. Mechanistically, OVOL1 interacts with and prevents the ubiquitination and degradation of SMAD family member 7 (SMAD7), which is a negative regulator of TGF-beta type I receptor stability. Moreover, a small-molecule compound 6-formylindolo(3,2-b)carbazole (FICZ) was identified to activate OVOL1 expression and thereby antagonizing (at least in part) TGF-beta-mediated EMT and migration in breast cancer cells. Our results uncover a novel mechanism by which OVOL1 attenuates TGF-beta/SMAD signaling and maintains the epithelial identity of breast cancer cells.Therapeutic cell differentiatio

Author Correction: c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression (Nature Communications, (2019), 10, 1, (4349), 10.1038/s41467-019-12241-2)

© 2019, The Author(s). The original version of this Article contained an error in the spelling of the author Azad Saei, which was incorrectly given as Azad Saie. This has now been corrected in both the PDF and HTML versions of the Article