scholarly journals Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 598 ◽  
Author(s):  
Kateryna Kubaichuk ◽  
Thomas Kietzmann
Keyword(s):  
Cancer Progression ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Specific Treatment ◽  
Stress Factors ◽  
Cellular Functions ◽  
Α Subunit ◽  
E3 Ligases ◽  
Cellular Processes ◽  
The Impact

The ubiquitin and hypoxia-inducible factor (HIF) pathways are cellular processes involved in the regulation of a variety of cellular functions. Enzymes called ubiquitin E3 ligases perform protein ubiquitylation. The action of these enzymes can be counteracted by another group of enzymes called deubiquitinases (DUBs), which remove ubiquitin from target proteins. The balanced action of these enzymes allows cells to adapt their protein content to a variety of cellular and environmental stress factors, including hypoxia. While hypoxia appears to be a powerful regulator of the ubiquitylation process, much less is known about the impact of DUBs on the HIF system and hypoxia-regulated DUBs. Moreover, hypoxia and DUBs play crucial roles in many diseases, such as cancer. Hence, DUBs are considered to be promising targets for cancer cell-specific treatment. Here, we review the current knowledge about the role DUBs play in the control of HIFs, the regulation of DUBs by hypoxia, and their implication in cancer progression.

scholarly journals Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

2017 ◽  
Vol 24 (10) ◽  
pp. R349-R366 ◽  
Author(s):  
Catherine Zabkiewicz ◽  
Jeyna Resaul ◽  
Rachel Hargest ◽  
Wen Guo Jiang ◽  
Lin Ye
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Bone Morphogenetic Proteins ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Breast Tumour ◽  
Cellular Functions ◽  
Foetal Development ◽  
Key Factor ◽  
The Right

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

scholarly journals TFEB Signalling-Related MicroRNAs and Autophagy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 985
Author(s):  
Davide Corà ◽  
Federico Bussolino ◽  
Gabriella Doronzo
Keyword(s):  
Transcriptional Regulation ◽  
Stress Factors ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Factor Deficiency ◽  
Transcription Factor Eb ◽  
Important Regulator ◽  
Response To Stress ◽  
Post Transcriptional Regulation

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.

scholarly journals Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

2021 ◽  
Vol 22 (13) ◽  
pp. 7220
Author(s):  
Thuy-Hang Nguyen ◽  
Stephanie Conotte ◽  
Alexandra Belayew ◽  
Anne-Emilie Declèves ◽  
Alexandre Legrand ◽  
...  
Keyword(s):  
Cell Function ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Hypoxia Inducible Factor ◽  
Muscular Dystrophies ◽  
Compensatory Mechanisms ◽  
Hypoxia Response ◽  
Muscle Disorders ◽  
Almost All ◽  
The Impact

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

scholarly journals SUMO conjugation susceptibility of Akt/protein kinase B affects the expression of the pluripotency transcription factor Nanog in embryonic stem cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254447
Author(s):  
Marcos Francia ◽  
Martin Stortz ◽  
Camila Vazquez Echegaray ◽  
Camila Oses ◽  
Paula Verneri ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Sumo Conjugation ◽  
Heterologous System ◽  
Canonical Pathways ◽  
The Impact

Akt/PKB is a kinase involved in the regulation of a wide variety of cell processes. Its activity is modulated by diverse post-translational modifications (PTMs). Particularly, conjugation of the small ubiquitin-related modifier (SUMO) to this kinase impacts on multiple cellular functions, such as proliferation and splicing. In embryonic stem (ES) cells, this kinase is key for pluripotency maintenance. Among other functions, Akt is known to promote the expression of Nanog, a central pluripotency transcription factor (TF). However, the relevance of this specific PTM of Akt has not been previously analyzed in this context. In this work, we study the effect of Akt1 variants with differential SUMOylation susceptibility on the expression of Nanog. Our results demonstrate that both, the Akt1 capability of being modified by SUMO conjugation and a functional SUMO conjugase activity are required to induce Nanog gene expression. Likewise, we found that the common oncogenic E17K Akt1 mutant affected Nanog expression in ES cells also in a SUMOylatability dependent manner. Interestingly, this outcome takes places in ES cells but not in a non-pluripotent heterologous system, suggesting the presence of a crucial factor for this induction in ES cells. Remarkably, the two major candidate factors to mediate this induction, GSK3-β and Tbx3, are non-essential players of this effect, suggesting a complex mechanism probably involving non-canonical pathways. Furthermore, we found that Akt1 subcellular distribution does not depend on its SUMOylatability, indicating that Akt localization has no influence on the effect on Nanog, and that besides the membrane localization of E17K Akt mutant, SUMOylation is also required for its hyperactivity. Our results highlight the impact of SUMO conjugation in the function of a kinase relevant for a plethora of cellular processes, including the control of a key pluripotency TF.

scholarly journals Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Vascular Function ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
E3 Ligase ◽  
Small Gtpases ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Cytoskeletal Dynamics

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.

scholarly journals Plant-Microbe Interactions in Alleviating Abiotic Stress—A Mini Review

2021 ◽  
Vol 3 ◽  
Author(s):  
Michael Prabhu Inbaraj
Keyword(s):  
Abiotic Stress ◽  
Plant Growth ◽  
Mycorrhizal Fungi ◽  
Abiotic Stresses ◽  
Current Knowledge ◽  
Crop Plants ◽  
Stress Factors ◽  
Limiting Factors ◽  
Nutrient Deficiencies ◽  
The Impact

Crop plants are continuously exposed to various abiotic stresses like drought, salinity, ultraviolet radiation, low and high temperatures, flooding, metal toxicities, nutrient deficiencies which act as limiting factors that hampers plant growth and low agricultural productivity. Climate change and intensive agricultural practices has further aggravated the impact of abiotic stresses leading to a substantial crop loss worldwide. Crop plants have to get acclimatized to various environmental abiotic stress factors. Though genetic engineering is applied to improve plants tolerance to abiotic stresses, these are long-term strategies, and many countries have not accepted them worldwide. Therefore, use of microbes can be an economical and ecofriendly tool to avoid the shortcomings of other strategies. The microbial community in close proximity to the plant roots is so diverse in nature and can play an important role in mitigating the abiotic stresses. Plant-associated microorganisms, such as endophytes, arbuscular mycorrhizal fungi (AMF), and plant growth-promoting rhizobacteria (PGPR), are well-documented for their role in promoting crop productivity and providing stress tolerance. This mini review highlights and discusses the current knowledge on the role of various microbes and it's tolerance mechanisms which helps the crop plants to mitigate and tolerate varied abiotic stresses.

scholarly journals Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8162
Author(s):  
Guang Yang ◽  
Rachel Shi ◽  
Qing Zhang
Keyword(s):  
Gene Regulation ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Oxygen Homeostasis ◽  
Jmjc Domain ◽  
Encoding Protein

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

scholarly journals Embryo–Maternal Interactions Underlying Reproduction in Mammals

2020 ◽  
Vol 21 (14) ◽  
pp. 4872
Author(s):  
Stefan Bauersachs ◽  
Carmen Almiñana
Keyword(s):  
Current Knowledge ◽  
Mammalian Species ◽  
Stress Factors ◽  
Research Articles ◽  
Future Research ◽  
Original Research ◽  
Special Issue ◽  
New Findings ◽  
As Stress ◽  
The Impact

This Special Issue, “Embryo-Maternal Interactions Underlying Reproduction in Mammals”, gathers a collection of 23 articles, 16 original research articles and 7 up-to-date reviews, providing new findings or summarizing current knowledge on embryo–maternal interactions in seven different mammalian species including humans. Considering the different players involved in these embryo-maternal interactions, articles are mainly focused on one of these different players: the oviduct, the uterus, the embryo or the emergent extracellular vesicles. Additionally, a few articles bring up the impact of reproductive, but also non-reproductive, diseases, as well as stress factors, on the establishment of pregnancy. We hope the readers enjoy this collection of articles and that the knowledge assembled here will support and inspire current and future research investigations. We would like to thank all authors for their contributions to this Special Issue.

scholarly journals HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 532 ◽  
Author(s):  
Valentina Condelli ◽  
Fabiana Crispo ◽  
Michele Pietrafesa ◽  
Giacomo Lettini ◽  
Danilo Swann Matassa ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Chaperones ◽  
Heat Shock Protein 90 ◽  
Anticancer Therapy ◽  
Cellular Functions ◽  
Master Regulators ◽  
Cellular Processes ◽  
Direct Binding ◽  
Client Proteins ◽  
The Relationship

Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.

scholarly journals Control of Toxin-Antitoxin Systems by Proteases in Mycobacterium Tuberculosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Patricia Bordes ◽  
Pierre Genevaux
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Growth ◽  
Current Knowledge ◽  
Human Pathogen ◽  
Cellular Functions ◽  
Genetic Elements ◽  
Cellular Processes ◽  
Bacterial Chromosomes ◽  
Activation Mechanisms ◽  
Activation Cycle

Toxin-antitoxin (TA) systems are small genetic elements composed of a noxious toxin and a counteracting cognate antitoxin. Although they are widespread in bacterial chromosomes and in mobile genetic elements, their cellular functions and activation mechanisms remain largely unknown. It has been proposed that toxin activation or expression of the TA operon could rely on the degradation of generally less stable antitoxins by cellular proteases. The resulting active toxin would then target essential cellular processes and inhibit bacterial growth. Although interplay between proteases and TA systems has been observed, evidences for such activation cycle are very limited. Herein, we present an overview of the current knowledge on TA recognition by proteases with a main focus on the major human pathogen Mycobacterium tuberculosis, which harbours multiple TA systems (over 80), the essential AAA + stress proteases, ClpC1P1P2 and ClpXP1P2, and the Pup-proteasome system.

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