FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications

FADD was initially described as an adaptor molecule for death receptor-mediated apoptosis, but subsequently it has been implicated in nonapoptotic cellular processes such as proliferation and cell cycle control. During the last decade, FADD has been shown to play a pivotal role in most of the signalosome complexes, such as the necroptosome and the inflammasome. Interestingly, various mechanisms involved in regulating FADD functions have been identified, essentially posttranslational modifications and secretion. All these aspects have been thoroughly addressed in previous reviews. However, FADD implication in cancer is complex, due to pleiotropic effects. It has been reported either as anti- or protumorigenic, depending on the cell type. Regulation of FADD expression in cancer is a complex issue since both overexpression and downregulation have been reported, but the mechanisms underlying such alterations have not been fully unveiled. Posttranslational modifications also constitute a relevant mechanism controlling FADD levels and functions in tumor cells. In this review, we aim to provide detailed, updated information on alterations leading to changes in FADD expression and function in cancer. The participation of FADD in various biological processes is recapitulated, with a mention of interesting novel functions recently proposed for FADD, such as regulation of gene expression and control of metabolic pathways. Finally, we gather all the available evidence regarding the clinical implications of FADD alterations in cancer, especially as it has been proposed as a potential biomarker with prognostic value.

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Hypoxia. 4. Hypoxia and ion channel function

AJP Cell Physiology ◽

10.1152/ajpcell.00512.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. C951-C967 ◽

Cited By ~ 57

Author(s):

Larissa A. Shimoda ◽

Jan Polak

Keyword(s):

Ion Channels ◽

Cell Function ◽

Critical Role ◽

Cardiac Contractility ◽

Cell Types ◽

Cellular Processes ◽

Oxygen Sensitive ◽

Sense And Respond ◽

And Function ◽

And Control

The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes.

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Long non-coding RNAs: novel regulators of cellular physiology and function

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-021-02641-z ◽

2021 ◽

Author(s):

James A. Oo ◽

Ralf P. Brandes ◽

Matthias S. Leisegang

Keyword(s):

Damage Control ◽

Regulation Of Gene Expression ◽

Cellular Processes ◽

Current Thinking ◽

Physiological Relevance ◽

Non Coding Rnas ◽

And Migration ◽

And Function ◽

Rna And Dna ◽

Proliferation And Migration

AbstractLong non-coding RNAs were once considered as “junk” RNA produced by aberrant DNA transcription. They are now understood to play central roles in diverse cellular processes from proliferation and migration to differentiation, senescence and DNA damage control. LncRNAs are classed as transcripts longer than 200 nucleotides that do not encode a peptide. They are relevant to many physiological and pathophysiological processes through their control of fundamental molecular functions. This review summarises the recent progress in lncRNA research and highlights the far-reaching physiological relevance of lncRNAs. The main areas of lncRNA research encompassing their characterisation, classification and mechanisms of action will be discussed. In particular, the regulation of gene expression and chromatin landscape through lncRNA control of proteins, DNA and other RNAs will be introduced. This will be exemplified with a selected number of lncRNAs that have been described in numerous physiological contexts and that should be largely representative of the tens-of-thousands of mammalian lncRNAs. To some extent, these lncRNAs have inspired the current thinking on the central dogmas of epigenetics, RNA and DNA mechanisms.

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Knockout of the Golgi stacking proteins GRASP55 and GRASP65 impairs Golgi structure and function

Molecular Biology of the Cell ◽

10.1091/mbc.e17-02-0112 ◽

2017 ◽

Vol 28 (21) ◽

pp. 2833-2842 ◽

Cited By ~ 47

Author(s):

Michael E. Bekier ◽

Leibin Wang ◽

Jie Li ◽

Haoran Huang ◽

Danming Tang ◽

...

Keyword(s):

Posttranslational Modifications ◽

Protein Trafficking ◽

Critical Role ◽

Hek293 Cells ◽

Double Knockout ◽

Knock Out ◽

Golgi Stack ◽

Cellular Processes ◽

Golgi Structure ◽

And Function

Golgi reassembly stacking protein of 65 kDa (GRASP65) and Golgi reassembly stacking protein of 55 kDa (GRASP55) were originally identified as Golgi stacking proteins; however, subsequent GRASP knockdown experiments yielded inconsistent results with respect to the Golgi structure, indicating a limitation of RNAi-based depletion. In this study, we have applied the recently developed clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology to knock out GRASP55 and GRASP65, individually or in combination, in HeLa and HEK293 cells. We show that double knockout of GRASP proteins disperses the Golgi stack into single cisternae and tubulovesicular structures, accelerates protein trafficking, and impairs accurate glycosylation of proteins and lipids. These results demonstrate a critical role for GRASPs in maintaining the stacked structure of the Golgi, which is required for accurate posttranslational modifications in the Golgi. Additionally, the GRASP knockout cell lines developed in this study will be useful tools for studying the role of GRASP proteins in other important cellular processes.

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BAG-1 in carcinogenesis

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399404007537 ◽

2004 ◽

Vol 6 (7) ◽

pp. 1-15 ◽

Cited By ~ 21

Author(s):

Adam Sharp ◽

Simon J. Crabb ◽

Ramsey I. Cutress ◽

Matthew Brimmell ◽

Xiu-hong Wang ◽

...

Keyword(s):

Human Cancer ◽

Predictive Marker ◽

Nuclear Hormone Receptor ◽

Response To Therapy ◽

Clinical Implications ◽

Multifunctional Protein ◽

Cellular Processes ◽

Wide Range ◽

Cancer Types ◽

And Function

BAG-1 is a multifunctional protein that exists as several differentially localised and functionally distinct isoforms. BAG-1 isoforms interact with a diverse array of molecular targets and regulate a wide range of cellular processes, including proliferation, survival, transcription, apoptosis, metastasis and motility. The BAG domain of BAG-1 interacts with chaperone molecules and this is considered important for many BAG-1 functions. The ability of BAG-1 to regulate such a wide variety of cellular processes suggests it might play an important role in many cancer types. For example, regulation of nuclear hormone receptor function and susceptibility to apoptosis might have a major impact on cancer development, progression and response to therapy. There is also increasing evidence that BAG-1 expression is altered in a variety of human malignancies relative to normal cells, and with further understanding of BAG-1 function it might become a powerful prognostic/predictive marker in human cancer. This review describes the structure and function of BAG-1 isoforms and the potential clinical implications of their expression in tumour cells.

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Posttranslational modifications in proteins: resources, tools and prediction methods

Database ◽

10.1093/database/baab012 ◽

2021 ◽

Author(s):

Shahin Ramazi ◽

Javad Zahiri

Keyword(s):

Computational Methods ◽

Posttranslational Modifications ◽

Side Chain ◽

Amino Acid Side Chain ◽

Cellular Processes ◽

Online Databases ◽

Different Types ◽

Protein Functions ◽

And Function ◽

Molecular Regulatory Mechanisms

Abstract Posttranslational modifications (PTMs) refer to amino acid side chain modification in some proteins after their biosynthesis. There are more than 400 different types of PTMs affecting many aspects of protein functions. Such modifications happen as crucial molecular regulatory mechanisms to regulate diverse cellular processes. These processes have a significant impact on the structure and function of proteins. Disruption in PTMs can lead to the dysfunction of vital biological processes and hence to various diseases. High-throughput experimental methods for discovery of PTMs are very laborious and time-consuming. Therefore, there is an urgent need for computational methods and powerful tools to predict PTMs. There are vast amounts of PTMs data, which are publicly accessible through many online databases. In this survey, we comprehensively reviewed the major online databases and related tools. The current challenges of computational methods were reviewed in detail as well.

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Reciprocal Changes in miRNA Expression with Pigmentation and Decreased Proliferation Induced in Mouse B16F1 Melanoma Cells by l-Tyrosine and 5-Bromo-2′-Deoxyuridine

International Journal of Molecular Sciences ◽

10.3390/ijms22041591 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1591

Author(s):

Hernán Mauricio Rivera ◽

Esther Natalia Muñoz ◽

Daniel Osuna ◽

Mauro Florez ◽

Michael Carvajal ◽

...

Keyword(s):

Cell Cycle ◽

Expression Profiles ◽

Cell Cycle Control ◽

Network Models ◽

Bioinformatic Analysis ◽

Melanoma Cells ◽

Cellular Processes ◽

And Control ◽

Molecular Bases ◽

Small Rnaseq

Background: Many microRNAs have been identified as critical mediators in the progression of melanoma through its regulation of genes involved in different cellular processes such as melanogenesis, cell cycle control, and senescence. However, microRNAs’ concurrent participation in syngeneic mouse B16F1 melanoma cells simultaneously induced decreased proliferation and differential pigmentation by exposure to 5-Brd-2′-dU (5’Bromo-2-deoxyuridine) and L-Tyr (L-Tyrosine) respectively, is poorly understood. Aim: To evaluate changes in the expression of microRNAs and identify which miRNAs in-network may contribute to the functional bases of phenotypes of differential pigmentation and reduction of proliferation in B16F1 melanoma cells exposed to 5-Brd-2′-dU and L-Tyr. Methods: Small RNAseq evaluation of the expression profiles of miRNAs in B16F1 melanoma cells exposed to 5-Brd-2′-dU (2.5 μg/mL) and L-Tyr (5 mM), as well as the expression by qRT-PCR of some molecular targets related to melanogenesis, cell cycle, and senescence. By bioinformatic analysis, we constructed network models of regulation and co-expression of microRNAs. Results: We confirmed that stimulation or repression of melanogenesis with L-Tyr or 5-Brd-2′-dU, respectively, generated changes in melanin concentration, reduction in proliferation, and changes in expression of microRNAs 470-3p, 470-5p, 30d-5p, 129-5p, 148b-3p, 27b-3p, and 211-5p, which presented patterns of coordinated and reciprocal co-expression, related to changes in melanogenesis through their putative targets Mitf, Tyr and Tyrp1, and control of cell cycle and senescence: Cyclin D1, Cdk2, Cdk4, p21, and p27. Conclusions: These findings provide insights into the molecular biology of melanoma of the way miRNAs are coordinated and reciprocal expression that may operate in a network as molecular bases for understanding changes in pigmentation and decreased proliferation induced in B16F1 melanoma cells exposed to L-Tyr and 5-Brd-2′-dU.

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Microtubule Regulation and Function during Virus Infection

Journal of Virology ◽

10.1128/jvi.00538-17 ◽

2017 ◽

Vol 91 (16) ◽

Cited By ~ 34

Author(s):

Mojgan H. Naghavi ◽

Derek Walsh

Keyword(s):

Posttranslational Modifications ◽

Intracellular Transport ◽

Spatial Organization ◽

Virus Particles ◽

Cellular Processes ◽

Wide Range ◽

Associated Proteins ◽

And Function ◽

Induced Changes ◽

Growth Pause

ABSTRACT Microtubules (MTs) form a rapidly adaptable network of filaments that radiate throughout the cell. These dynamic arrays facilitate a wide range of cellular processes, including the capture, transport, and spatial organization of cargos and organelles, as well as changes in cell shape, polarity, and motility. Nucleating from MT-organizing centers, including but by no means limited to the centrosome, MTs undergo rapid transitions through phases of growth, pause, and catastrophe, continuously exploring and adapting to the intracellular environment. Subsets of MTs can become stabilized in response to environmental cues, acquiring distinguishing posttranslational modifications and performing discrete functions as specialized tracks for cargo trafficking. The dynamic behavior and organization of the MT array is regulated by MT-associated proteins (MAPs), which include a subset of highly specialized plus-end-tracking proteins (+TIPs) that respond to signaling cues to alter MT behavior. As pathogenic cargos, viruses require MTs to transport to and from their intracellular sites of replication. While interactions with and functions for MT motor proteins are well characterized and extensively reviewed for many viruses, this review focuses on MT filaments themselves. Changes in the spatial organization and dynamics of the MT array, mediated by virus- or host-induced changes to MT regulatory proteins, not only play a central role in the intracellular transport of virus particles but also regulate a wider range of processes critical to the outcome of infection.

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Defining the AHR regulated transcriptome in NK cells reveal gene expression program relevant to development and function

Blood Advances ◽

10.1182/bloodadvances.2021004533 ◽

2021 ◽

Author(s):

Prashant Trikha ◽

Jena Moseman ◽

Aarohi Thakkar ◽

Amanda l Campbell ◽

Ezgi Elmas ◽

...

Keyword(s):

Nk Cells ◽

Immune Cell ◽

Altered Expression ◽

Chip Sequencing ◽

Cellular Processes ◽

Aryl Hydrocarbon ◽

Cd56 Expression ◽

And Function ◽

Transcriptional Elements ◽

Expression Program

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular processes in cancer and immunity, including innate immune cell development and effector function. However, the transcriptional repertoire through which AHR mediates these effects remains largely unexplored. To elucidate the transcriptional elements directly regulated by AHR in NK cells, we performed RNA- and ChIP-sequencing on NK cells exposed to AHR agonist or antagonist. We show that mature peripheral blood NK cells lack AHR, but its expression is induced by Stat3 during IL-21-driven activation and proliferation, coincident with increased NCAM1 (CD56) expression resulting in a CD56bright phenotype. Compared to control conditions, NK cells expanded in the presence of the AHR antagonist, StemRegenin-1, were unaffected in proliferation or cytotoxicity, had no increase in NCAM1 transcription and maintained the CD56dim phenotype. However, it showed altered expression of 1,004 genes including those strongly associated with signaling pathways. In contrast, NK cells expanded in the presence of the AHR agonist, kynurenine, showed decreased cytotoxicity and altered expression of 97 genes including those strongly associated with oxidative stress and cellular metabolism. By overlaying these differentially expressed genes with AHR chromatin binding we identified 160 genes directly regulated by AHR, including hallmark AHR targets AHRR and CYP1B1, and known regulators of phenotype, development, metabolism, and function such as NCAM1, KIT, NQO1, and TXN. In summary, we define the AHR transcriptome in NK cells, propose a model of AHR and Stat3 coregulation, and identify potential pathways that may be targeted to overcome AHR-mediated immune suppression.

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Cancers ◽

10.3390/cancers13040741 ◽

2021 ◽

Vol 13 (4) ◽

pp. 741

Author(s):

Nayden Naydenov ◽

Susana Lechuga ◽

Emina Huang ◽

Andrei Ivanov

Keyword(s):

Colorectal Cancer ◽

Cancer Development ◽

Altered Expression ◽

Common Cause ◽

Functional Roles ◽

Cellular Processes ◽

The Third ◽

Tissue Invasion ◽

Myosin Motors ◽

And Control

Colorectal cancer (CRC) remains the third most common cause of cancer and the second most common cause of cancer deaths worldwide. Clinicians are largely faced with advanced and metastatic disease for which few interventions are available. One poorly understood aspect of CRC involves altered organization of the actin cytoskeleton, especially at the metastatic stage of the disease. Myosin motors are crucial regulators of actin cytoskeletal architecture and remodeling. They act as mechanosensors of the tumor environments and control key cellular processes linked to oncogenesis, including cell division, extracellular matrix adhesion and tissue invasion. Different myosins play either oncogenic or tumor suppressor roles in breast, lung and prostate cancer; however, little is known about their functions in CRC. This review focuses on the functional roles of myosins in colon cancer development. We discuss the most studied class of myosins, class II (conventional) myosins, as well as several classes (I, V, VI, X and XVIII) of unconventional myosins that have been linked to CRC development. Altered expression and mutations of these motors in clinical tumor samples and their roles in CRC growth and metastasis are described. We also evaluate the potential of using small molecular modulators of myosin activity to develop novel anticancer therapies.

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Ca2+-Activated K+ Channels: From Protein Complexes to Function

Physiological Reviews ◽

10.1152/physrev.00049.2009 ◽

2010 ◽

Vol 90 (4) ◽

pp. 1437-1459 ◽

Cited By ~ 156

Author(s):

Henrike Berkefeld ◽

Bernd Fakler ◽

Uwe Schulte

Keyword(s):

Protein Interactions ◽

Muscle Tone ◽

Protein Complexes ◽

Neuronal Firing ◽

Protein Protein Interactions ◽

Cellular Processes ◽

And Function ◽

And Control ◽

Proteomic Research ◽

Partner Proteins

Molecular research on ion channels has demonstrated that many of these integral membrane proteins associate with partner proteins, often versatile in their function, or even assemble into stable macromolecular complexes that ensure specificity and proper rate of the channel-mediated signal transduction. Calcium-activated potassium (KCa) channels that link excitability and intracellular calcium concentration are responsible for a wide variety of cellular processes ranging from regulation of smooth muscle tone to modulation of neurotransmission and control of neuronal firing pattern. Most of these functions are brought about by interaction of the channels' pore-forming subunits with distinct partner proteins. In this review we summarize recent insights into protein complexes associated with KCa channels as revealed by proteomic research and discuss the results available on structure and function of these complexes and on the underlying protein-protein interactions. Finally, the results are related to their significance for the function of KCa channels under cellular conditions.

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