Structure, function and therapeutic implications of OB-fold proteins: A lesson from past to present

2020 ◽  
Vol 19 (5-6) ◽  
pp. 377-389
Author(s):  
Mohd Amir ◽  
Taj Mohammad ◽  
Ravins Dohare ◽  
Asimul Islam ◽  
Faizan Ahmad ◽  
...  
Keyword(s):  
Structure Function ◽  
Therapeutic Intervention ◽  
Protein Complexes ◽  
Underlying Mechanism ◽  
Therapeutic Implications ◽  
Dna Ligases ◽  
Cellular Processes ◽  
Ob Fold ◽  
Cycle Regulation

Abstract Oligonucleotide/oligosaccharide-binding (OB)-fold proteins play essential roles in the regulation of genome and its correct transformation to the subsequent generation. To maintain the genomic stability, OB-fold proteins are implicated in various cellular processes including DNA replication, DNA repair, cell cycle regulation and maintenance of telomere. The diverse functional spectrums of OB-fold proteins are mainly due to their involvement in protein–DNA and protein–protein complexes. Mutations and consequential structural alteration in the OB-fold proteins often lead to severe diseases. Here, we have investigated the structure, function and mode of action of OB-fold proteins (RPA, BRCA2, DNA ligases and SSBs1/2) in cellular pathways and their relationship with diseases and their possible use in therapeutic intervention. Due to the crucial role of OB-fold proteins in regulating the key physiological process, a detailed structural understanding in the context of underlying mechanism of action and cellular complexity offers a new avenue to target OB-proteins for therapeutic intervention.

scholarly journals Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

2020 ◽  
Vol 21 (18) ◽  
pp. 6841
Author(s):  
Mafalda Escobar-Henriques ◽  
Vincent Anton
Keyword(s):  
Membrane Fusion ◽  
Cell Cycle Regulation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Cellular Viability ◽  
Mitochondrial Quality Control ◽  
Cellular Processes ◽  
Mitochondrial Regulation ◽  
Cycle Regulation

Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.

scholarly journals The Interaction between Sgt1p and Skp1p Is Regulated by HSP90 Chaperones and Is Required for Proper CBF3 Assembly

2004 ◽  
Vol 24 (20) ◽  
pp. 8938-8950 ◽  
Author(s):  
Linda B. Lingelbach ◽  
Kenneth B. Kaplan
Keyword(s):  
Chromosome Segregation ◽  
Protein Complexes ◽  
Dependent Manner ◽  
Carboxy Terminus ◽  
Genetic Studies ◽  
Cellular Processes ◽  
Transient Interactions ◽  
Precise Relationship ◽  
Protein Complex Assembly

ABSTRACT Sgt1p is a well-conserved protein proposed to be involved in a number of cellular processes. Genetic studies of budding yeast suggest a role for SGT1 in signal transduction, cell cycle advance, and chromosome segregation. Recent evidence has linked Sgt1p to HSP90 chaperones, although the precise relationship between these proteins is unclear. To further explore the role of Sgt1p in these processes, we have characterized the interactions among Sgt1p, the inner kinetochore complex CBF3, and HSP90 chaperones. We show that the amino terminus of Sgt1p interacts with CBF3 subunits Skp1p and Ctf13p. HSP90 interacts with Sgt1p and, in combination with the carboxy terminus of Sgt1p, regulates the interaction between Sgt1p and Skp1p in a nucleotide-dependent manner. While the Sgt1p-Skp1p interaction is required for CBF3 assembly, mutations that stabilize this interaction prevent the turnover of protein complexes important for CBF3 assembly. We propose that HSP90 and Sgt1p act together as a molecular switch, maintaining transient interactions required to balance protein complex assembly with turnover.

scholarly journals Emerging Role of E2F Family in Cancer Stem Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Dan Xie ◽  
Qin Pei ◽  
Jingyuan Li ◽  
Xue Wan ◽  
Ting Ye
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Tumor Development ◽  
Transcriptional Repressors ◽  
Cellular Processes ◽  
Damage Response ◽  
Prevent Tumor Growth ◽  
Cycle Regulation

The E2F family of transcription factors (E2Fs) consist of eight genes in mammals. These genes encode ten proteins that are usually classified as transcriptional activators or transcriptional repressors. E2Fs are important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis, the DNA damage response and apoptosis. A growing body of evidence demonstrates that cancer stem cells (CSCs) are key players in tumor development, metastasis, drug resistance and recurrence. This review focuses on the role of E2Fs in CSCs and notes that many signals can regulate the activities of E2Fs, which in turn can transcriptionally regulate many different targets to contribute to various biological characteristics of CSCs, such as proliferation, self-renewal, metastasis, and drug resistance. Therefore, E2Fs may be promising biomarkers and therapeutic targets associated with CSCs pathologies. Finally, exploring therapeutic strategies for E2Fs may result in disruption of CSCs, which may prevent tumor growth, metastasis, and drug resistance.

scholarly journals Keeping the balance in NAD metabolism

2019 ◽  
Vol 47 (1) ◽  
pp. 119-130 ◽  
Author(s):  
Øyvind Strømland ◽  
Marc Niere ◽  
Andrey A. Nikiforov ◽  
Magali R. VanLinden ◽  
Ines Heiland ◽  
...  
Keyword(s):  
Calcium Signalling ◽  
Research Field ◽  
Therapeutic Effects ◽  
Nad Metabolism ◽  
Cellular Processes ◽  
Signalling Molecule ◽  
Cycle Regulation ◽  
Subcellular Level ◽  
Important Signalling Molecule

Abstract Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular processes. This includes DNA repair, cell cycle regulation, gene expression and calcium signalling, in which NAD is a substrate for several families of regulatory proteins, such as sirtuins and ADP-ribosyltransferases. At the molecular level, NAD-dependent signalling events differ from hydride transfer by cleavage of the dinucleotide into an ADP-ribosyl moiety and nicotinamide. Therefore, non-redox functions of NAD require continuous biosynthesis of the dinucleotide. Maintenance of cellular NAD levels is mainly achieved by nicotinamide salvage, yet a variety of other precursors can be used to sustain cellular NAD levels via different biosynthetic routes. Biosynthesis and consumption of NAD are compartmentalised at the subcellular level, and currently little is known about the generation and role of some of these subcellular NAD pools. Impaired biosynthesis or increased NAD consumption is deleterious and associated with ageing and several pathologies. Insults to neurons lead to depletion of axonal NAD and rapid degeneration, partial rescue can be achieved pharmacologically by administration of specific NAD precursors. Restoring NAD levels by stimulating biosynthesis or through supplementation with precursors also produces beneficial therapeutic effects in several disease models. In this review, we will briefly discuss the most recent achievements and the challenges ahead in this diverse research field.

scholarly journals Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2438 ◽  
Author(s):  
Sahar Sarmasti Emami ◽  
Derek Zhang ◽  
Xiaolong Yang
Keyword(s):  
Signaling Pathway ◽  
Hippo Pathway ◽  
Underlying Mechanism ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Cellular Processes ◽  
Wide Range ◽  
Future Direction ◽  
The Hippo Pathway

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

scholarly journals The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review

2020 ◽  
Author(s):  
Mislav Glibo ◽  
Alan Serman ◽  
Valentina Karin-Kujundzic ◽  
Ivanka Bekavac Vlatkovic ◽  
Berivoj Miskovic ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Glycogen Synthase ◽  
Alpha Helix ◽  
Glycogen Synthase Kinase ◽  
Cancer Development ◽  
Glycogen Synthase Kinase 3 ◽  
Serine Threonine Kinase ◽  
Therapeutic Implications ◽  
Cellular Processes

Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.

scholarly journals The Functional Role of Long Non-Coding RNAs in Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4848
Author(s):  
Michal Wozniak ◽  
Malgorzata Czyz
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Close Association ◽  
Response To Treatment ◽  
Rna Molecules ◽  
Cellular Processes ◽  
Molecular Events ◽  
Melanoma Treatment

Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse effects of immunotherapies are still a major challenge in melanoma treatment. Therefore, the elucidation of molecular mechanisms of melanomagenesis and cancer response to treatment is of great importance. Recently, many studies have revealed the close association of long noncoding RNAs (lncRNAs) with the development of many cancers, including melanoma. These RNA molecules are able to regulate a plethora of crucial cellular processes including proliferation, differentiation, migration, invasion and apoptosis through diverse mechanisms, and even slight dysregulation of their expression may lead to tumorigenesis. lncRNAs are able to bind to protein complexes, DNA and RNAs, affecting their stability, activity, and localization. They can also regulate gene expression in the nucleus. Several functions of lncRNAs are context-dependent. This review summarizes current knowledge regarding the involvement of lncRNAs in melanoma. Their possible role as prognostic markers of melanoma response to treatment and in resistance to therapy is also discussed

scholarly journals Mechanobiology of Autophagy: The Unexplored Side of Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Maria Paz Hernández-Cáceres ◽  
Leslie Munoz ◽  
Javiera M. Pradenas ◽  
Francisco Pena ◽  
Pablo Lagos ◽  
...  
Keyword(s):  
Cell Mechanics ◽  
Mechanical Response ◽  
Protein Complexes ◽  
Functional Integration ◽  
Cellular Responses ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
Physical Forces ◽  
Active Processes

Proper execution of cellular function, maintenance of cellular homeostasis and cell survival depend on functional integration of cellular processes and correct orchestration of cellular responses to stresses. Cancer transformation is a common negative consequence of mismanagement of coordinated response by the cell. In this scenario, by maintaining the balance among synthesis, degradation, and recycling of cytosolic components including proteins, lipids, and organelles the process of autophagy plays a central role. Several environmental stresses activate autophagy, among those hypoxia, DNA damage, inflammation, and metabolic challenges such as starvation. In addition to these chemical challenges, there is a requirement for cells to cope with mechanical stresses stemming from their microenvironment. Cells accomplish this task by activating an intrinsic mechanical response mediated by cytoskeleton active processes and through mechanosensitive protein complexes which interface the cells with their mechano-environment. Despite autophagy and cell mechanics being known to play crucial transforming roles during oncogenesis and malignant progression their interplay is largely overlooked. In this review, we highlight the role of physical forces in autophagy regulation and their potential implications in both physiological as well as pathological conditions. By taking a mechanical perspective, we wish to stimulate novel questions to further the investigation of the mechanical requirements of autophagy and appreciate the extent to which mechanical signals affect this process.

scholarly journals Analysis of biological networks in the endothelium with biomimetic microsystem platform

2019 ◽  
Vol 317 (3) ◽  
pp. L392-L401 ◽  
Author(s):  
Kevin Kruse ◽  
Jeff Klomp ◽  
Mitchell Sun ◽  
Zhang Chen ◽  
Dianicha Santana ◽  
...  
Keyword(s):  
Biological Networks ◽  
Protein Complexes ◽  
Single Point ◽  
Point Mutations ◽  
Cellular Processes ◽  
Signal Transduction Networks ◽  
Protein Interactome ◽  
Health And Disease ◽  
Cell To Cell Adhesion

Here we describe a novel method for studying the protein “interactome” in primary human cells and apply this method to investigate the effect of posttranslational protein modifications (PTMs) on the protein’s functions. We created a novel “biomimetic microsystem platform” (Bio-MSP) to isolate the protein complexes in primary cells by covalently attaching purified His-tagged proteins to a solid microscale support. Using this Bio-MSP, we have analyzed the interactomes of unphosphorylated and phosphomimetic end-binding protein-3 (EB3) in endothelial cells. Pathway analysis of these interactomes demonstrated the novel role of EB3 phosphorylation at serine 162 in regulating the protein’s function. We showed that phosphorylation “switches” the EB3 biological network to modulate cellular processes such as cell-to-cell adhesion whereas dephosphorylation of this site promotes cell proliferation. This novel technique provides a useful tool to study the role of PTMs or single point mutations in activating distinct signal transduction networks and thereby the biological function of the protein in health and disease.

The lncRNA TUG1 promotes cell growth and migration via the TUG1/miR-145-5p/TRPC6 pathway in colorectal cancer

2020 ◽  
Author(s):  
Xiaoqiang Wang ◽  
Xiaomin Bai ◽  
Zhonghui Yan ◽  
Xinyu Guo ◽  
Youcheng Zhang
Keyword(s):  
Colorectal Cancer ◽  
Underlying Mechanism ◽  
Clinical Samples ◽  
Cell Growth And Migration ◽  
Cellular Processes ◽  
Non Coding Rna ◽  
And Migration ◽  
Long Non Coding Rna ◽  
Taurine Upregulated Gene 1

Colorectal cancer (CRC) is the third most prevalent malignant tumor. Taurine upregulated gene 1 (TUG1), a long non-coding RNA (lncRNA), has been shown to be involved in the physiological and pathological processes of CRC. However, the role of TUG1 in the progression of CRC and its underlying mechanism are largely unknown. Here, we measured TUG1 expression in clinical samples from CRC patients and found that TUG1 expression was higher in CRC tissues as compared to that in normal adjacent tissues. We then inhibited TUG1 with siRNAs in two CRC cell lines and found that TUG1 knockdown inhibited the viability, proliferation, and migration of CRC cells and lowered the ability of CRC cells to form subcutaneous tumors. Furthermore, we revealed that TUG1 affected the cellular processes in CRC cells by sponging miR-145-5p. We further found that miR-145-5p inhibited TRPC6 expression, and overexpression of TRPC6 restored the role of miR-145-5p in CRC cells. Collectively, we illustrated that TUG1 manifests its functions by modulating the TUG1/miR-145-5p/TRPC6 regulatory axis. In conclusion, our study revealed a novel molecular mechanism of TUG1 in CRC progression and suggested the potential of the TUG1/miR-145-5p/TRPC6 pathway to serve as a target for the diagnosis and treatment of CRC.

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