E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer.
Abstract Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. Herein, we found the protein WNT5A, was significantly downregulated in BM tissues and EGFR-mutant samples. In addition, the overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared with the EGFR wide-type cells. ...
Source: Cellular and Molecular Life Sciences : CMLS - October 19, 2020 Category: Cytology Authors: Li H, Tong F, Meng R, Peng L, Wang J, Zhang R, Dong X Tags: Cell Mol Life Sci Source Type: research

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology.
z I, Benedito R Abstract Therapeutic modulation of vascular cell proliferation and migration is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The general view is that an increase in vascular growth factor levels or mitogenic stimulation is beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogenesis. This is due to the existence of intrinsic signaling feedback loops and cell cycle checkp...
Source: Cellular and Molecular Life Sciences : CMLS - October 19, 2020 Category: Cytology Authors: Mühleder S, Fernández-Chacón M, Garcia-Gonzalez I, Benedito R Tags: Cell Mol Life Sci Source Type: research

The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass.
Abstract The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to r...
Source: Cellular and Molecular Life Sciences : CMLS - October 19, 2020 Category: Cytology Authors: Romanello V, Sandri M Tags: Cell Mol Life Sci Source Type: research

New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis.
In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesi...
Source: Cellular and Molecular Life Sciences : CMLS - October 17, 2020 Category: Cytology Authors: Castillo AF, Orlando UD, Maloberti PM, Prada JG, Dattilo MA, Solano AR, Bigi MM, Ríos Medrano MA, Torres MT, Indo S, Caroca G, Contreras HR, Marelli BE, Salinas FJ, Salvetti NR, Ortega HH, Lorenzano Menna P, Szajnman S, Gomez DE, Rodríguez JB, Podesta E Tags: Cell Mol Life Sci Source Type: research

Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies.
Abstract Inflammation and cancerogenesis are strongly interconnected processes, not only because inflammation promotes DNA instability, but also because both processes are driven by pathways such as NF-kB, STAT3, mTOR and MAPKs. Interestingly, these pathways regulate the release of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β that in turn control their activation and play a crucial role in shaping immune response. The transcription factor p53 is the major tumor suppressor that is often mutated in cancer, contributing to tumor progression. In this overview, we highlight how the interplay betw...
Source: Cellular and Molecular Life Sciences : CMLS - October 17, 2020 Category: Cytology Authors: D'Orazi G, Cordani M, Cirone M Tags: Cell Mol Life Sci Source Type: research

Wip1 controls the translocation of the chromosomal passenger complex to the central spindle for faithful mitotic exit.
Abstract Dramatic cellular reorganization in mitosis critically depends on the timely and temporal phosphorylation of a broad range of proteins, which is mediated by the activation of the mitotic kinases and repression of counteracting phosphatases. The mitosis-to-interphase transition, which is termed mitotic exit, involves the removal of mitotic phosphorylation by protein phosphatases. Although protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) drive this reversal in animal cells, the phosphatase network associated with ordered bulk dephosphorylation in mitotic exit is not fully understood. Here, we d...
Source: Cellular and Molecular Life Sciences : CMLS - October 16, 2020 Category: Cytology Authors: Zhang X, Park JE, Kim EH, Hong J, Hwang KT, Kim YA, Jang CY Tags: Cell Mol Life Sci Source Type: research

Selective autophagy as a therapeutic target for neurological diseases.
Abstract The neurological diseases primarily include acute injuries, chronic neurodegeneration, and others (e.g., infectious diseases of the central nervous system). Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Recent studies have suggested that autophagy, particularly selective autophagy, such as mitophagy, pexophagy, ER-phagy, ribophagy, lipophagy, etc., is closely implicated in neurological diseases. These forms of selective autophagy are controlled by a group of important proteins, including PTEN...
Source: Cellular and Molecular Life Sciences : CMLS - October 16, 2020 Category: Cytology Authors: Xu W, Ocak U, Gao L, Tu S, Lenahan CJ, Zhang J, Shao A Tags: Cell Mol Life Sci Source Type: research

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling.
Abstract Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD1...
Source: Cellular and Molecular Life Sciences : CMLS - October 15, 2020 Category: Cytology Authors: Ciesielska A, Matyjek M, Kwiatkowska K Tags: Cell Mol Life Sci Source Type: research

Vault RNAs: hidden gems in RNA and protein regulation.
Abstract Non-coding RNAs are important regulators of differentiation during embryogenesis as well as key players in the fine-tuning of transcription and furthermore, they control the post-transcriptional regulation of mRNAs under physiological conditions. Deregulated expression of non-coding RNAs is often identified as one major contribution in a number of pathological conditions. Non-coding RNAs are a heterogenous group of RNAs and they represent the majority of nuclear transcripts in eukaryotes. An evolutionary highly conserved sub-group of non-coding RNAs is represented by vault RNAs, named since firstly discov...
Source: Cellular and Molecular Life Sciences : CMLS - October 15, 2020 Category: Cytology Authors: Hahne JC, Lampis A, Valeri N Tags: Cell Mol Life Sci Source Type: research

Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks.
Abstract In the past decade, significant progress has been made in understanding the role of protein tyrosine phosphatase as a positive regulator of tumor progression. In this scenario, our group was one of the first to report the involvement of the low molecular weight protein tyrosine phosphatase (LMWPTP or ACP1) in the process of resistance and migration of tumor cells. Later, we and others demonstrated a positive correlation between the amount of this enzyme in human tumors and the poor prognosis. With this information in mind, we asked if LMWPTP contribution to metastasis, would it have an action beyond ...
Source: Cellular and Molecular Life Sciences : CMLS - October 14, 2020 Category: Cytology Authors: Faria AVS, Fonseca EMB, Cordeiro HG, Clerici SP, Ferreira-Halder CV Tags: Cell Mol Life Sci Source Type: research

Drugging the "undruggable" microRNAs.
Drugging the "undruggable" microRNAs. Cell Mol Life Sci. 2020 Oct 14;: Authors: Liu D, Wan X, Shan X, Fan R, Zha W Abstract As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summ...
Source: Cellular and Molecular Life Sciences : CMLS - October 14, 2020 Category: Cytology Authors: Liu D, Wan X, Shan X, Fan R, Zha W Tags: Cell Mol Life Sci Source Type: research

Emerging role of S100B protein implication in Parkinson's disease pathogenesis.
Abstract The exact etiology of Parkinson's disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidenc...
Source: Cellular and Molecular Life Sciences : CMLS - October 14, 2020 Category: Cytology Authors: Angelopoulou E, Paudel YN, Piperi C Tags: Cell Mol Life Sci Source Type: research

Dichotomic role of heparanase in a murine model of metabolic syndrome.
Abstract Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustainin...
Source: Cellular and Molecular Life Sciences : CMLS - October 13, 2020 Category: Cytology Authors: Hermano E, Carlotti F, Abecassis A, Meirovitz A, Rubinstein AM, Li JP, Vlodavsky I, Rabelink TJ, Elkin M Tags: Cell Mol Life Sci Source Type: research

Nontraditional systems in aging research: an update.
Abstract Research on the evolutionary and mechanistic aspects of aging and longevity has a reductionist nature, as the majority of knowledge originates from experiments on a relatively small number of systems and species. Good examples are the studies on the cellular, molecular, and genetic attributes of aging (senescence) that are primarily based on a narrow group of somatic cells, especially fibroblasts. Research on aging and/or longevity at the organismal level is dominated, in turn, by experiments on Drosophila melanogaster, worms (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and higher organisms...
Source: Cellular and Molecular Life Sciences : CMLS - October 9, 2020 Category: Cytology Authors: Mikuła-Pietrasik J, Pakuła M, Markowska M, Uruski P, Szczepaniak-Chicheł L, Tykarski A, Książek K Tags: Cell Mol Life Sci Source Type: research

Cell signaling pathways in autosomal-dominant leukodystrophy  (ADLD): the intriguing role of the astrocytes.
Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes. Cell Mol Life Sci. 2020 Oct 09;: Authors: Ratti S, Rusciano I, Mongiorgi S, Owusu Obeng E, Cappellini A, Teti G, Falconi M, Talozzi L, Capellari S, Bartoletti-Stella A, Guaraldi P, Cortelli P, Suh PG, Cocco L, Manzoli L, Ramazzotti G Abstract Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for ...
Source: Cellular and Molecular Life Sciences : CMLS - October 9, 2020 Category: Cytology Authors: Ratti S, Rusciano I, Mongiorgi S, Owusu Obeng E, Cappellini A, Teti G, Falconi M, Talozzi L, Capellari S, Bartoletti-Stella A, Guaraldi P, Cortelli P, Suh PG, Cocco L, Manzoli L, Ramazzotti G Tags: Cell Mol Life Sci Source Type: research

Imaging and manipulating the segmentation clock.
Abstract During embryogenesis, the processes that control how cells differentiate and interact to form particular tissues and organs with precise timing and shape are of fundamental importance. One prominent example of such processes is vertebrate somitogenesis, which is governed by a molecular oscillator called the segmentation clock. The segmentation clock system is initiated in the presomitic mesoderm in which a set of genes and signaling pathways exhibit coordinated spatiotemporal dynamics to establish regularly spaced boundaries along the body axis; these boundaries provide a blueprint for the development of ...
Source: Cellular and Molecular Life Sciences : CMLS - October 3, 2020 Category: Cytology Authors: Yoshioka-Kobayashi K, Kageyama R Tags: Cell Mol Life Sci Source Type: research

Pluripotent stem cell-based gene therapy approach: human de novo synthesized chromosomes.
Abstract A novel approach in gene therapy was introduced 20 years ago since artificial non-integrative chromosome-based vectors containing gene loci size inserts were engineered. To date, different human artificial chromosomes (HAC) were generated with the use of de novo construction or "top-down" engineering approaches. The HAC-based therapeutic approach includes ex vivo gene transferring and correction of pluripotent stem cells (PSCs) or highly proliferative modified stem cells. The current progress in the technology of induced PSCs, integrating with the HAC technology, resulted in a novel platfor...
Source: Cellular and Molecular Life Sciences : CMLS - October 2, 2020 Category: Cytology Authors: Sinenko SA, Ponomartsev SV, Tomilin AN Tags: Cell Mol Life Sci Source Type: research

Long non-coding RNAs: the tentacles of chromatin remodeler complexes.
Abstract Chromatin remodeler complexes regulate gene transcription, DNA replication and DNA repair by changing both nucleosome position and post-translational modifications. The chromatin remodeler complexes are categorized into four families: the SWI/SNF, INO80/SWR1, ISWI and CHD family. In this review, we describe the subunits of these chromatin remodeler complexes, in particular, the recently identified members of the ISWI family and novelties of the CHD family. Long non-coding (lnc) RNAs regulate gene expression through different epigenetic mechanisms, including interaction with chromatin remodelers. For examp...
Source: Cellular and Molecular Life Sciences : CMLS - September 30, 2020 Category: Cytology Authors: Neve B, Jonckheere N, Vincent A, Van Seuningen I Tags: Cell Mol Life Sci Source Type: research

IDPology of the living cell: intrinsic disorder in the subcellular compartments of the human cell.
Abstract Intrinsic disorder can be found in all proteomes of all kingdoms of life and in viruses, being particularly prevalent in the eukaryotes. We conduct a comprehensive analysis of the intrinsic disorder in the human proteins while mapping them into 24 compartments of the human cell. In agreement with previous studies, we show that human proteins are significantly enriched in disorder relative to a generic protein set that represents the protein universe. In fact, the fraction of proteins with long disordered regions and the average protein-level disorder content in the human proteome are about 3 times higher ...
Source: Cellular and Molecular Life Sciences : CMLS - September 29, 2020 Category: Cytology Authors: Zhao B, Katuwawala A, Uversky VN, Kurgan L Tags: Cell Mol Life Sci Source Type: research

Cooperativity of membrane-protein and protein-protein interactions control membrane remodeling by epsin 1 and affects clathrin-mediated endocytosis.
Abstract Membrane remodeling is a critical process for many membrane trafficking events, including clathrin-mediated endocytosis. Several molecular mechanisms for protein-induced membrane curvature have been described in some detail. Contrary, the effect that the physico-chemical properties of the membrane have on these processes is far less well understood. Here, we show that the membrane binding and curvature-inducing ENTH domain of epsin1 is regulated by phosphatidylserine (PS). ENTH binds to membranes in a PI(4,5)P2-dependent manner but only induces curvature in the presence of PS. On PS-containing membranes, ...
Source: Cellular and Molecular Life Sciences : CMLS - September 29, 2020 Category: Cytology Authors: Kroppen B, Teske N, Yambire KF, Denkert N, Mukherjee I, Tarasenko D, Jaipuria G, Zweckstetter M, Milosevic I, Steinem C, Meinecke M Tags: Cell Mol Life Sci Source Type: research

Molecular and neurocircuitry mechanisms of social avoidance.
Abstract Humans and animals live in social relationships shaped by actions of approach and avoidance. Both are crucial for normal physical and mental development, survival, and well-being. Active withdrawal from social interaction is often induced by the perception of threat or unpleasant social experience and relies on adaptive mechanisms within neuronal networks associated with social behavior. In case of confrontation with overly strong or persistent stressors and/or dispositions of the affected individual, maladaptive processes in the neuronal circuitries and its associated transmitters and modulators lead to ...
Source: Cellular and Molecular Life Sciences : CMLS - September 29, 2020 Category: Cytology Authors: Gellner AK, Voelter J, Schmidt U, Beins EC, Stein V, Philipsen A, Hurlemann R Tags: Cell Mol Life Sci Source Type: research

Antioxidant functions of DHHC3 suppress anti-cancer drug activities.
Abstract Ablation of protein acyltransferase DHHC3 selectively enhanced the anti-cancer cell activities of several chemotherapeutic agents, but not kinase inhibitors. To understand why this occurs, we used comparative mass spectrometry-based palmitoyl-proteomic analysis of breast and prostate cancer cell lines, ± DHHC3 ablation, to obtain the first comprehensive lists of candidate protein substrates palmitoylated by DHHC3. Putative substrates included 22-28 antioxidant/redox-regulatory proteins, thus predicting that DHHC3 should have antioxidant functions. Consistent with this, DHHC3 ablation ...
Source: Cellular and Molecular Life Sciences : CMLS - September 27, 2020 Category: Cytology Authors: Sharma C, Yang W, Steen H, Freeman MR, Hemler ME Tags: Cell Mol Life Sci Source Type: research

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations.
dai A, Hegedűs T Abstract Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed...
Source: Cellular and Molecular Life Sciences : CMLS - September 25, 2020 Category: Cytology Authors: Nagy T, Tóth Á, Telbisz Á, Sarkadi B, Tordai H, Tordai A, Hegedűs T Tags: Cell Mol Life Sci Source Type: research

Twenty years of research on HPV vaccines based on genetically modified lactic acid bacteria: an overview on the gut-vagina axis.
Mohseni AH Abstract Most cervical cancer (CxCa) are related to persistent infection with high-risk human papillomavirus (HR-HPV) in the cervical mucosa, suggesting that an induction of mucosal cell-mediated immunity against HR-HPV oncoproteins can be a promising strategy to fight HPV-associated CxCa. From this perspective, many pre-clinical and clinical trials have proved the potential of lactic acid bacteria (LAB) genetically modified to deliver recombinant antigens to induce mucosal, humoral and cellular immunity in the host. Altogether, the outcomes of these studies suggest that there are several key factors t...
Source: Cellular and Molecular Life Sciences : CMLS - September 25, 2020 Category: Cytology Authors: Taghinezhad-S S, Keyvani H, Bermúdez-Humarán LG, Donders GGG, Fu X, Mohseni AH Tags: Cell Mol Life Sci Source Type: research

TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF- κB signaling pathway in macrophages.
TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages. Cell Mol Life Sci. 2020 Sep 25;: Authors: Roh KH, Lee Y, Yoon JH, Lee D, Kim E, Park E, Lee IY, Kim TS, Song HK, Shin J, Lim DS, Choi EJ Abstract Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway assoc...
Source: Cellular and Molecular Life Sciences : CMLS - September 24, 2020 Category: Cytology Authors: Roh KH, Lee Y, Yoon JH, Lee D, Kim E, Park E, Lee IY, Kim TS, Song HK, Shin J, Lim DS, Choi EJ Tags: Cell Mol Life Sci Source Type: research

miR-490 suppresses telomere maintenance program and associated hallmarks in glioblastoma.
Abstract Glioblastoma (GBM) is the most aggressive cancer of central nervous system with worst patient outcome. Telomere maintenance is a crucial mechanism governing GBM initiation and progression making it an attractive target. microRNAs (miRNAs) have shown therapeutic potential in GBM. Earlier, we showed miR-490 is downregulated in GBM patients and plays a tumor suppressive role. Here, we show that miR-490 regulates telomere maintenance program in GBM by directly targeting Telomeric Repeat-binding Factor 2 (TERF2) of the shelterin complex, Tankyrase 2 (TNKS2) and Serine/Threonine-protein kinase, SMG1. Overexpres...
Source: Cellular and Molecular Life Sciences : CMLS - September 23, 2020 Category: Cytology Authors: Vinchure OS, Whittemore K, Kushwah D, Blasco MA, Kulshreshtha R Tags: Cell Mol Life Sci Source Type: research

Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies.
This article provides a comprehensive review of research findings on the association between DM and AF and critically analyzes the effect of different pharmacological classes of antidiabetic drugs on AF. PMID: 32965513 [PubMed - as supplied by publisher] (Source: Cellular and Molecular Life Sciences : CMLS)
Source: Cellular and Molecular Life Sciences : CMLS - September 22, 2020 Category: Cytology Authors: Lee TW, Lee TI, Lin YK, Chen YC, Kao YH, Chen YJ Tags: Cell Mol Life Sci Source Type: research

Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation.
Abstract The gut microbiota has a crucial effect on regulating the intestinal mucosal immunity and maintaining intestinal homeostasis both in health and in disease state. Many effects are mediated by gut microbiota-derived metabolites and tryptophan, an essential aromatic amino acid, is considered important among many metabolites in the crosstalk between gut microbiota and the host. Kynurenine, serotonin, and indole derivatives are derived from the three major tryptophan metabolism pathways modulated by gut microbiota directly or indirectly. Aryl hydrocarbon receptor (AHR) is a cytoplasmic ligand-activated transcr...
Source: Cellular and Molecular Life Sciences : CMLS - September 22, 2020 Category: Cytology Authors: Liu JR, Miao H, Deng DQ, Vaziri ND, Li P, Zhao YY Tags: Cell Mol Life Sci Source Type: research

Diversity of intrinsically photosensitive retinal ganglion cells: circuits and functions.
Abstract The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are a relatively recently discovered class of atypical ganglion cell photoreceptor. These ipRGCs are a morphologically and physiologically heterogeneous population that project widely throughout the brain and mediate a wide array of visual functions ranging from photoentrainment of our circadian rhythms, to driving the pupillary light reflex to improve visual function, to modulating our mood, alertness, learning, sleep/wakefulness, regulation of body temperature, and even our visual perception. The presence of melanops...
Source: Cellular and Molecular Life Sciences : CMLS - September 22, 2020 Category: Cytology Authors: Aranda ML, Schmidt TM Tags: Cell Mol Life Sci Source Type: research

Biological activity versus physiological function of proinsulin C-peptide.
l H Abstract Proinsulin C-peptide (C-peptide) has drawn much research attention. Even if the peptide has turned out not to be important in the treatment of diabetes, every phase of C-peptide research has changed our view on insulin and peptide hormone biology. The first phase revealed that peptide hormones can be subject to processing, and that their pro-forms may involve regulatory stages. The second phase revealed the possibility that one prohormone could harbor more than one activity, and that the additional activities should be taken into account in the development of hormone-based therapies. In the third phas...
Source: Cellular and Molecular Life Sciences : CMLS - September 20, 2020 Category: Cytology Authors: Landreh M, Jörnvall H Tags: Cell Mol Life Sci Source Type: research

Long-term plasticity of inhibitory synapses in the hippocampus and spatial learning depends on matrix metalloproteinase 3.
Abstract Learning and memory are known to depend on synaptic plasticity. Whereas the involvement of plastic changes at excitatory synapses is well established, plasticity mechanisms at inhibitory synapses only start to be discovered. Extracellular proteolysis is known to be a key factor in glutamatergic plasticity but nothing is known about its role at GABAergic synapses. We reveal that pharmacological inhibition of MMP3 activity or genetic knockout of the Mmp3 gene abolishes induction of postsynaptic iLTP. Moreover, the application of exogenous active MMP3 mimics major iLTP manifestations: increased mIPSCs amplit...
Source: Cellular and Molecular Life Sciences : CMLS - September 20, 2020 Category: Cytology Authors: Wiera G, Lebida K, Lech AM, Brzdąk P, Van Hove I, De Groef L, Moons L, Petrini EM, Barberis A, Mozrzymas JW Tags: Cell Mol Life Sci Source Type: research

The tumor-promoting effects of the adaptive immune system: a cause of hyperprogressive disease in cancer?
We describe the basic mechanisms that underlie tumor-promoting adaptive immune responses and try to identify the variables that induce the switching of a tumor-inhibitory, cellular or humoral immune response, into a tumor-promoting one. We suggest that tumor-promoting adaptive immune responses may be at the origin of at least a fraction of hyperprogressive diseases (HPD) that are observed in cancer patients during therapy with immune checkpoint inhibitors (ICI) and, less frequently, with single-agent chemotherapy. We also propose the use of non-invasive biomarkers allowing to predict which patients may undergo HPD during I...
Source: Cellular and Molecular Life Sciences : CMLS - September 16, 2020 Category: Cytology Authors: Marcucci F, Rumio C Tags: Cell Mol Life Sci Source Type: research

Immune landscape and therapeutic strategies: new insights into PD-L1 in tumors.
Abstract PD-1/PD-L1 axis represents an important target for renormalizing and resetting anti-tumor immunity in cancer patients. Currently, anti-PD-1/PD-L1 therapy has been applied in a broad spectrum of tumors and has yielded durable remission in patients. However, how to further broaden the application, guide personalized therapeutic strategies, and improve clinical responses remains a vital task. At present, PD-L1 expression is an important parameter of clinical indications for immune checkpoint blockade in many types of cancers, a strategy based on the supposition that positive PD-L1 expression reflects local T...
Source: Cellular and Molecular Life Sciences : CMLS - September 16, 2020 Category: Cytology Authors: Wei Y, Xiao X, Lao XM, Zheng L, Kuang DM Tags: Cell Mol Life Sci Source Type: research

Serotonin functions as a bidirectional guidance molecule regulating growth cone motility.
In this study, we asked if serotonin acts as a guidance cue by examining how serotonin alters growth cone motility of rodent sensory neurons in vitro. Using a growth cone motility assay, we found that serotonin acted as both an attractive and repulsive guidance cue through a narrow concentration range. Extracellular gradients of 50 µM serotonin elicited attraction, mediated by the serotonin 5-HT2a receptor while 100 µM serotonin elicited repulsion mediated by the 5-HT1b receptor. Importantly, high resolution imaging of growth cones indicated that these receptors signalled through their canonical pathw...
Source: Cellular and Molecular Life Sciences : CMLS - September 15, 2020 Category: Cytology Authors: Vicenzi S, Foa L, Gasperini RJ Tags: Cell Mol Life Sci Source Type: research

Induction and transmission of oncogene-induced senescence.
Abstract Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we di...
Source: Cellular and Molecular Life Sciences : CMLS - September 15, 2020 Category: Cytology Authors: Rattanavirotkul N, Kirschner K, Chandra T Tags: Cell Mol Life Sci Source Type: research

Disorder in a two-domain neuronal Ca2+-binding protein regulates domain stability and dynamics using ligand mimicry.
In this study, we examine the role of a disordered tail in the overall properties of the two-domain, calcium-sensing protein neuronal calcium sensor 1 (NCS-1). We show that loss of just six of the 190 residues at the flexible C-terminus is sufficient to severely affect stability, dynamics, and folding behavior of both ordered domains. We identify specific hydrophobic contacts mediated by the disordered tail that may be responsible for stabilizing the distal N-terminal domain. Moreover, sequence analyses indicate the presence of an LSL-motif in the tail that acts as a mimic of native ligands critical to the observed order-d...
Source: Cellular and Molecular Life Sciences : CMLS - September 15, 2020 Category: Cytology Authors: Staby L, Kemplen KR, Stein A, Ploug M, Clarke J, Skriver K, Heidarsson PO, Kragelund BB Tags: Cell Mol Life Sci Source Type: research

Epsins in vascular development, function and disease.
Abstract Epsins are a family of adaptor proteins involved in clathrin-dependent endocytosis. In the vasculature, epsins 1 and 2 are functionally redundant members of this family that are expressed in the endothelial cells of blood vessels and the lymphatic system throughout development and adulthood. These proteins contain a number of peptide motifs that allow them to interact with lipid moieties and a variety of proteins. These interactions facilitate the regulation of a wide range of cell signaling pathways. In this review, we focus on the involvement of epsins 1 and 2 in controlling vascular endothelial growth ...
Source: Cellular and Molecular Life Sciences : CMLS - September 14, 2020 Category: Cytology Authors: Bhattacharjee S, Lee Y, Zhu B, Wu H, Chen Y, Chen H Tags: Cell Mol Life Sci Source Type: research

Differential effects of putative N-glycosylation sites in human Tau on Alzheimer's disease-related neurodegeneration.
Abstract Amyloid assemblies of Tau are associated with Alzheimer's disease (AD). In AD Tau undergoes several abnormal post-translational modifications, including hyperphosphorylation and glycosylation, which impact disease progression. N-glycosylated Tau was reported to be found in AD brain tissues but not in healthy counterparts. This is surprising since Tau is a cytosolic protein whereas N-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated that N-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specif...
Source: Cellular and Molecular Life Sciences : CMLS - September 13, 2020 Category: Cytology Authors: Losev Y, Frenkel-Pinter M, Abu-Hussien M, Viswanathan GK, Elyashiv-Revivo D, Geries R, Khalaila I, Gazit E, Segal D Tags: Cell Mol Life Sci Source Type: research

Intercellular trafficking via plasmodesmata: molecular layers of complexity.
Abstract Plasmodesmata are intercellular pores connecting together most plant cells. These structures consist of a central constricted form of the endoplasmic reticulum, encircled by some cytoplasmic space, in turn delimited by the plasma membrane, itself ultimately surrounded by the cell wall. The presence and structure of plasmodesmata create multiple routes for intercellular trafficking of a large spectrum of molecules (encompassing RNAs, proteins, hormones and metabolites) and also enable local signalling events. Movement across plasmodesmata is finely controlled in order to balance processes requiring co...
Source: Cellular and Molecular Life Sciences : CMLS - September 11, 2020 Category: Cytology Authors: Li ZP, Paterlini A, Glavier M, Bayer EM Tags: Cell Mol Life Sci Source Type: research

Interplay between HMGA and TP53 in cell cycle control along tumor progression.
Abstract The high mobility group A (HMGA) proteins are found to be aberrantly expressed in several tumors. Studies (in vitro and in vivo) have shown that HMGA protein overexpression has a causative role in carcinogenesis process. HMGA proteins regulate cell cycle progression through distinct mechanisms which strongly influence its normal dynamics along malignant transformation. Tumor protein p53 (TP53) is the most frequently altered gene in cancer. The loss of its activity is recognized as the fall of a barrier that enables neoplastic transformation. Among the different functions, TP53 signaling pathway is tightly...
Source: Cellular and Molecular Life Sciences : CMLS - September 11, 2020 Category: Cytology Authors: Meireles Da Costa N, Palumbo A, De Martino M, Fusco A, Ribeiro Pinto LF, Nasciutti LE Tags: Cell Mol Life Sci Source Type: research

Motile cilia genetics and cell biology: big results from little mice.
Abstract Our understanding of motile cilia and their role in disease has increased tremendously over the last two decades, with critical information and insight coming from the analysis of mouse models. Motile cilia form on specific epithelial cell types and typically beat in a coordinated, whip-like manner to facilitate the flow and clearance of fluids along the cell surface. Defects in formation and function of motile cilia result in primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder with a well-characterized phenotype but no effective treatment. A number of model systems, ranging from unicel...
Source: Cellular and Molecular Life Sciences : CMLS - September 10, 2020 Category: Cytology Authors: Lee L, Ostrowski LE Tags: Cell Mol Life Sci Source Type: research

NEAT1 polyA-modulating antisense oligonucleotides reveal opposing functions for both long non-coding RNA isoforms in neuroblastoma.
Abstract Many long non-coding RNAs (lncRNA) are highly dysregulated in cancer and are emerging as therapeutic targets. One example is NEAT1, which consists of two overlapping lncRNA isoforms, NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb), that are functionally distinct. The longer NEAT1_2 is responsible for scaffolding gene-regulatory nuclear bodies termed paraspeckles, whereas NEAT1_1 is involved in paraspeckle-independent function. The NEAT1 isoform ratio is dependent on the efficient cleavage and polyadenylation of NEAT1_1 at the expense of NEAT1_2. Here, we developed a targeted antisense oligonucleotide (ASO)...
Source: Cellular and Molecular Life Sciences : CMLS - September 9, 2020 Category: Cytology Authors: Naveed A, Cooper JA, Li R, Hubbard A, Chen J, Liu T, Wilton SD, Fletcher S, Fox AH Tags: Cell Mol Life Sci Source Type: research

FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK.
Abstract It is critical to specify a signal that directly drives the transition that occurs between cell states. However, such inferences are often confounded by indirect intercellular communications or secondary transcriptomic changes due to primary transcription factors. Although FGF is known for its importance during mesoderm-to-endothelium differentiation, its specific role and signaling mechanisms are still unclear due to the confounding factors referenced above. Here, we attempted to minimize the secondary artifacts by manipulating FGF and its downstream mediators with a short incubation time ...
Source: Cellular and Molecular Life Sciences : CMLS - September 9, 2020 Category: Cytology Authors: Chen PC, Hsueh YW, Lee YH, Tsai HW, Tsai KJ, Chiang PM Tags: Cell Mol Life Sci Source Type: research

Hedgehog signaling regulates regenerative patterning and growth in Harmonia axyridis leg.
Abstract Appendage regeneration has been widely studied in many species. Compared to other animal models, Harmonia axyridis has the advantage of a short life cycle, is easily reared, has strong regeneration capacity and contains systemic RNAi, making it a model organism for research on appendage regeneration. Here, we performed transcriptome analysis, followed by gene functional assays to reveal the molecular mechanism of H. axyridis leg regenerative growth process. Signaling pathways including Decapentaplegic (Dpp), Wingless (Wg), Ds/Ft/Hippo, Notch, Egfr, and Hedgehog (Hh) were all upregulated during the leg reg...
Source: Cellular and Molecular Life Sciences : CMLS - September 8, 2020 Category: Cytology Authors: Zhou H, Ma Z, Wang Z, Yan S, Wang D, Shen J Tags: Cell Mol Life Sci Source Type: research

Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition.
Abstract Cerebral ischemia-reperfusion increases intraneuronal levels of ubiquitinated proteins, but the factors driving ubiquitination and whether it results from altered proteostasis remain unclear. To address these questions, we used in vivo and in vitro models of cerebral ischemia-reperfusion, in which hippocampal slices were transiently deprived of oxygen and glucose to simulate ischemia followed by reperfusion, or the middle cerebral artery was temporarily occluded in mice. We found that post-ischemic ubiquitination results from two key steps: restoration of ATP at reperfusion, which allows initiation of pro...
Source: Cellular and Molecular Life Sciences : CMLS - September 4, 2020 Category: Cytology Authors: Kahles T, Poon C, Qian L, Palfini V, Srinivasan SP, Swaminathan S, Blanco I, Rodney-Sandy R, Iadecola C, Zhou P, Hochrainer K Tags: Cell Mol Life Sci Source Type: research

P53 in acute respiratory distress syndrome.
Abstract P53 is a tumor suppressor protein, associated with strong anti-inflammatory activities. Recent evidence suggest that this transcription factor counteracts lung inflammatory diseases, including the lethal acute respiratory distress syndrome. Herein we provide a brief discussion on the relevant topic. PMID: 32886127 [PubMed - as supplied by publisher] (Source: Cellular and Molecular Life Sciences : CMLS)
Source: Cellular and Molecular Life Sciences : CMLS - September 3, 2020 Category: Cytology Authors: Barabutis N Tags: Cell Mol Life Sci Source Type: research

Cellular prion protein dysfunction in a prototypical inherited metabolic myopathy.
Abstract Inherited fatty acid oxidation diseases in their mild forms often present as metabolic myopathies. Carnitine Palmitoyl Transferase 2 (CPT2) deficiency, one such prototypical disorder is associated with compromised myotube differentiation. Here, we show that CPT2-deficient myotubes exhibit defects in focal adhesions and redox balance, exemplified by increased SOD2 expression. We document unprecedented alterations in the cellular prion protein PrPC, which directly arise from the failure in CPT2 enzymatic activity. We also demonstrate that the loss of PrPC function in normal myotubes recapitulates the defect...
Source: Cellular and Molecular Life Sciences : CMLS - August 31, 2020 Category: Cytology Authors: Boufroura FZ, Tomkiewicz-Raulet C, Poindessous V, Castille J, Vilotte JL, Bastin J, Mouillet-Richard S, Djouadi F Tags: Cell Mol Life Sci Source Type: research

DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis.
Abstract Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual kinase that can phosphorylate its own activation loop on tyrosine residue and phosphorylate its substrates on threonine and serine residues. It is the most studied member of DYRK kinases, because its gene maps to human chromosome 21 within the Down syndrome critical region (DSCR). DYRK1A overexpression was found to be responsible for the phenotypic features observed in Down syndrome such as mental retardation, early onset neurodegenerative, and developmental heart defects. Besides its dual activity in phosphorylation, DYRK1A ...
Source: Cellular and Molecular Life Sciences : CMLS - August 31, 2020 Category: Cytology Authors: Laham AJ, Saber-Ayad M, El-Awady R Tags: Cell Mol Life Sci Source Type: research

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.
Abstract Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing glo...
Source: Cellular and Molecular Life Sciences : CMLS - August 25, 2020 Category: Cytology Authors: Jeitany M, Prabhu A, Dakle P, Pathak E, Madan V, Kanojia D, Mukundan V, Jiang YY, Landesman Y, Tam WL, Kappei D, Koeffler HP Tags: Cell Mol Life Sci Source Type: research

The pro-apoptotic domain of BIM protein forms toxic amyloid fibrils.
Abstract BIM is a key apoptotic protein, participating in diverse cellular processes. Interestingly, recent studies have hypothesized that BIM is associated with the extensive neuronal cell death encountered in protein misfolding diseases, such as Alzheimer's disease. Here, we report that the core pro-apoptotic domain of BIM, the BIM-BH3 motif, forms ubiquitous amyloid fibrils. The BIM-BH3 fibrils exhibit cytotoxicity, disrupt mitochondrial functions, and modulate the structures and dynamics of mitochondrial membrane mimics. Interestingly, a slightly longer peptide in which BIM-BH3 was flanked by four additional r...
Source: Cellular and Molecular Life Sciences : CMLS - August 24, 2020 Category: Cytology Authors: Malishev R, Ben-Zichri S, Oren O, Shauloff N, Peretz T, Taube R, Papo N, Jelinek R Tags: Cell Mol Life Sci Source Type: research