The Diarylheptanoid Curcumin Induces MYC Inhibition and Cross-Links This Oncoprotein to the Coactivator TRRAP

The c-Myc protein (MYC) is a transcription factor with strong oncogenic potential controlling fundamental cellular processes. In most human tumors, MYC is overexpressed by enhanced transcriptional activation, gene amplification, chromosomal rearrangements, or increased protein stabilization. To pharmacologically suppress oncogenic MYC functions, multiple approaches have been applied either to inhibit transcriptional activation of the endogenous MYC gene, or to interfere with biochemical functions of aberrantly activated MYC. Other critical points of attack are targeted protein modification, or destabilization leading to a non-functional MYC oncoprotein. It has been claimed that the natural compound curcumin representing the principal curcumoid of turmeric (Curcuma longa) has anticancer properties although its specificity, efficacy, and the underlying molecular mechanisms have been controversially discussed. Here, we have tested curcumin’s effect on MYC-dependent cell transformation and transcriptional activation, and found that this natural compound interferes with both of these MYC activities. Furthermore, in curcumin-treated cells, the endogenous 60-kDa MYC protein is covalently and specifically cross-linked to one of its transcriptional interaction partners, namely the 434-kDa transformation/transcription domain associated protein (TRRAP). Thereby, endogenous MYC levels are strongly reduced and cells stop to proliferate. TRRAP is a multidomain adaptor protein of the phosphoinositide 3-kinase-related kinases (PIKK) family and represents an important component of many histone acetyltransferase (HAT) complexes. TRRAP is important to mediate transcriptional activation executed by the MYC oncoprotein, but on the other hand TRRAP also negatively regulates protein stability of the tumor suppressor p53 (TP53). Curcumin-mediated covalent binding of MYC to TRRAP reduces the protein amounts of both interaction partners but does not downregulate TP53, so that the growth-arresting effect of wild type TP53 could prevail. Our results elucidate a molecular mechanism of curcumin action that specifically and irreversibly targets two crucial multifunctional cellular players. With regard to their broad impact in cancer, our findings contribute to explain the pleiotropic functions of curcumin, and suggest that this natural spice, or more bioavailable derivatives thereof, may constitute useful adjuvants in the therapy of MYC-dependent and TRRAP-associated human tumors.

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The Role of Ubiquitin E3 Ligase in Atherosclerosis

Current Medicinal Chemistry ◽

10.2174/0929867327666200306124418 ◽

2020 ◽

Vol 28 (1) ◽

pp. 152-168

Author(s):

Zhi-Xiang Zhou ◽

Zhong Ren ◽

Bin-Jie Yan ◽

Shun-Lin Qu ◽

Zhi-Han Tang ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Smooth Muscle Cell ◽

Protein Modification ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Atherosclerotic Cardiovascular Disease ◽

E3 Ligases

: Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

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Xyloglucan processing machinery in Xanthomonas pathogens and its role in the transcriptional activation of virulence factors

Nature Communications ◽

10.1038/s41467-021-24277-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Plinio S. Vieira ◽

Isabela M. Bonfim ◽

Evandro A. Araujo ◽

Ricardo R. Melo ◽

Augusto R. Lima ◽

...

Keyword(s):

Virulence Factors ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Model Organism ◽

Citrus Canker ◽

Effector Proteins ◽

Glycoside Hydrolases ◽

Host Cells ◽

System A ◽

Enzymatic Machinery

AbstractXyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

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Curcuma Longa, the “Golden Spice” to Counteract Neuroinflammaging and Cognitive Decline—What Have We Learned and What Needs to Be Done

Nutrients ◽

10.3390/nu13051519 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1519

Author(s):

Alessandra Berry ◽

Barbara Collacchi ◽

Roberta Masella ◽

Rosaria Varì ◽

Francesca Cirulli

Keyword(s):

Molecular Structure ◽

Cognitive Decline ◽

Neurodegenerative Disorders ◽

Natural Compound ◽

Water Solubility ◽

Current Knowledge ◽

Curcuma Longa ◽

Biomedical Literature ◽

Global Increase ◽

New Strategies

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer’s disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.

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Curcumin: Modern Applications for a Versatile Additive

Coatings ◽

10.3390/coatings11050519 ◽

2021 ◽

Vol 11 (5) ◽

pp. 519

Author(s):

Florentina Monica Raduly ◽

Valentin Raditoiu ◽

Alina Raditoiu ◽

Violeta Purcar

Keyword(s):

Bacterial Infections ◽

Natural Compound ◽

Review Paper ◽

Curcuma Longa ◽

Antibacterial Properties ◽

Point Of View ◽

Nano Particles ◽

Synergistic Activity ◽

Quality Of Food

The recent development of several methods for extracting curcumin from the root of the plant Curcuma longa has led to intensified research on the properties of curcumin and its fields of application. Following the studies and the accreditation of curcumin as a natural compound with antifungal, antiviral, and antibacterial properties, new fields of application have been developed in two main directions—food and medical, respectively. This review paper aims to synthesize the fields of application of curcumin as an additive for the prevention of spoilage, safety, and quality of food. Simultaneously, it aims to present curcumin as an additive in products for the prevention of bacterial infections and health care. In both cases, the types of curcumin formulations in the form of (nano)emulsions, (nano)particles, or (nano)composites are presented, depending on the field and conditions of exploitation or their properties to be used. The diversity of composite materials that can be designed, depending on the purpose of use, leaves open the field of research on the conditioning of curcumin. Various biomaterials active from the antibacterial and antibiofilm point of view can be intuited in which curcumin acts as an additive that potentiates the activities of other compounds or has a synergistic activity with them.

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Structure and dynamics of the E. coli chemotaxis core signaling complex by cryo-electron tomography and molecular simulations

Communications Biology ◽

10.1038/s42003-019-0748-0 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 8

Author(s):

C. Keith Cassidy ◽

Benjamin A. Himes ◽

Dapeng Sun ◽

Jun Ma ◽

Gongpu Zhao ◽

...

Keyword(s):

Molecular Mechanisms ◽

Electron Tomography ◽

Conformational Dynamics ◽

Molecular Simulations ◽

Adaptor Protein ◽

Signaling Mechanism ◽

E Coli ◽

Signaling Complex ◽

Chemical Gradients ◽

Cryo Electron Tomography

AbstractTo enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Despite decades of study, important questions surrounding the molecular mechanisms of sensory signal transduction remain unresolved, owing especially to the lack of a high-resolution CSU structure. Here, we use cryo-electron tomography and sub-tomogram averaging to determine a structure of the Escherichia coli CSU at sub-nanometer resolution. Based on our experimental data, we use molecular simulations to construct an atomistic model of the CSU, enabling a detailed characterization of CheA conformational dynamics in its native structural context. We identify multiple, distinct conformations of the critical P4 domain as well as asymmetries in the localization of the P3 bundle, offering several novel insights into the CheA signaling mechanism.

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The binding of human complement proteins C5, factor B, β1H and properdin to complement fragment C3b on zymosan

Biochemical Journal ◽

10.1042/bj1990485 ◽

1981 ◽

Vol 199 (3) ◽

pp. 485-496 ◽

Cited By ~ 82

Author(s):

R G DiScipio

Keyword(s):

Protein Modification ◽

Alternative Pathway ◽

Covalent Binding ◽

Association Constants ◽

Affinity Constant ◽

Distinct Region ◽

Binding Studies ◽

Factor B ◽

Complement Proteins ◽

Competition Binding

The covalent binding of complement fragment C3b to zymosan by the action of the alternative-pathway C3 convertase and the reversible binding of several complement proteins (component C5, factor B, beta 1H and properdin) to C3b on zymosan have been investigated. When C3b is deposited on zymosan after activation by a surface-bound C3 convertase, the C3b molecules are deposited in foci around the C3 convertase site, with an average of 30 C3b molecules per site. The association constants of C5, factor B, beta 1H, and properdin for C3b bound to zymosan have been determined. The association constants ranged from 6.5 x 10(-5) M-1 for factor B to 2.9 x 10(7) M-1 for properdin. An approximate stoichiometry of 1 : 1 for C5, factor B, and properdin binding to C3b has been observed. Curvilinear Scatchard plots were observed for beta 1H binding to C3b, with the maximal extrapolated ratio of beta 1H to C3b of 0.32. Physiological amounts of properdin increase by 7-fold the affinity constant for factor B binding to C3b with no alteration in the stoichiometry. Similarly, physiological amounts of factor B increase the affinity constant of properdin to C3b about 4-fold with only a small measured difference in stoichiometry. Competition binding studies and protein modification suggest that C5, factor B, beta 1H, and properdin each bind to a distinct region on C3b.

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Analysis of Saccharomyces cerevisiae his3 transcription in vitro: biochemical support for multiple mechanisms of transcription

Molecular and Cellular Biology ◽

10.1128/mcb.10.6.2832-2839.1990 ◽

1990 ◽

Vol 10 (6) ◽

pp. 2832-2839

Author(s):

A S Ponticelli ◽

K Struhl

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcriptional Activation ◽

Transcription Initiation ◽

Molecular Mechanisms ◽

Initiation Site ◽

Activator Proteins ◽

Nuclear Extracts ◽

Transcription In Vitro

The promoter region of the Saccharomyces cerevisiae his3 gene contains two TATA elements, TC and TR, that direct transcription initiation to two sites designated +1 and +13. On the basis of differences between their nucleotide sequences and their responsiveness to upstream promoter elements, it has previously been proposed that TC and TR promote transcription by different molecular mechanisms. To begin a study of his3 transcription in vitro, we used S. cerevisiae nuclear extracts together with various DNA templates and transcriptional activator proteins that have been characterized in vivo. We demonstrated accurate transcription initiation in vitro at the sites used in vivo, transcriptional activation by GCN4, and activation by a GAL4 derivative on various gal-his3 hybrid promoters. In all cases, transcription stimulation was dependent on the presence of an acidic activation region in the activator protein. In addition, analysis of promoters containing a variety of TR derivatives indicated that the level of transcription in vitro was directly related to the level achieved in vivo. The results demonstrated that the in vitro system accurately reproduced all known aspects of in vivo his3 transcription that depend on the TR element. However, in striking contrast to his3 transcription in vivo, transcription in vitro yielded approximately 20 times more of the +13 transcript than the +1 transcript. This result was not due to inability of the +1 initiation site to be efficiently utilized in vitro, but rather it reflects the lack of TC function in vitro. The results support the idea that TC and TR mediate transcription from the wild-type promoter by distinct mechanisms.

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Elicitor Recognition and Signal Transduction in Plant Defense Gene Activation

Zeitschrift für Naturforschung C ◽

10.1515/znc-1990-0601 ◽

1990 ◽

Vol 45 (6) ◽

pp. 569-575 ◽

Cited By ~ 56

Author(s):

Dierk Scheel ◽

Jane E. Parker

Keyword(s):

Signal Transduction ◽

Plant Defense ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Plant Protection ◽

Plant Cells ◽

Defense Responses ◽

Plant Defense Responses ◽

Defense Genes ◽

Plant Defense Genes

Abstract Plants defend themselves against pathogen attack by activating a whole set of defense responses, most of them relying on transcriptional activation of plant defense genes. The same responses are induced by treatment of plant cells with elicitors released from the pathogen or from the plant surface. Several plant/elicitor combinations have been used successfully as experimental systems to investigate the molecular basis of plant defense responses. Receptor-like structures on the plasma membrane of plant cells appear to bind the elicitors. Thereby, intracellular signal transduction chains are initiated which finally result in the activation of plant defense genes. A better understanding of the molecular mechanisms of early processes in plant defense responses, as provided by these studies, may in the long term help to develop environmentally safe plant protection methods for agriculture.

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Curcumin: Could This Compound Be Useful in Pregnancy and Pregnancy-Related Complications?

Nutrients ◽

10.3390/nu12103179 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3179 ◽

Cited By ~ 1

Author(s):

Tiziana Filardi ◽

Rosaria Varì ◽

Elisabetta Ferretti ◽

Alessandra Zicari ◽

Susanna Morano ◽

...

Keyword(s):

Molecular Mechanisms ◽

Curcuma Longa ◽

Growth Disorders ◽

Beneficial Effects ◽

Toxic Agents ◽

Health Promoting ◽

Short And Long Term ◽

The Impact ◽

In Pregnancy

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin’s effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes.

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The Role of Curcumin in Cancer Treatment

Biomedicines ◽

10.3390/biomedicines9091086 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1086

Author(s):

Vasiliki Zoi ◽

Vasiliki Galani ◽

Georgios D. Lianos ◽

Spyridon Voulgaris ◽

Athanasios P. Kyritsis ◽

...

Keyword(s):

Clinical Trials ◽

Molecular Mechanisms ◽

Curcuma Longa ◽

Immune Modulators ◽

Anticancer Properties ◽

Stat3 Signaling ◽

Anticancer Effects ◽

Transcription 3 ◽

Light Chain Enhancer

Curcumin is a polyphenol extracted from the rhizomes of the turmeric plant, Curcuma longa which has anti-inflammatory, and anticancer properties. Chronic inflammation is associated with the development of cancer. Curcumin acts on the regulation of various immune modulators, including cytokines, cyclooxygenase-2 (COX-2), and reactive oxygen species (ROS), which partly explains its anticancer effects. It also takes part in the downregulation of growth factors, protein kinases, oncogenic molecules and various signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (STAT3) signaling. Clinical trials of curcumin have been completed or are ongoing for various types of cancer. This review presents the molecular mechanisms of curcumin in different types of cancer and the evidence from the most recent clinical trials.

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