Impact of Ubiquitination Signaling Pathway Modifications on Oral Carcinoma

Among intra-cellular homeostasis mechanisms, ubiquitination plays a critical role in protein metabolism regulation by degrading proteins via activating a broad spectrum of ubiquitin chains. In fact, ubiquitination and sumoylation signaling pathways are characterized by increased complexity regarding the molecules and their interactions. The Ubiquitin-Proteasome System (Ub-PS) recognizes and targets a broad spectrum of protein substrates. Ubiquitin conjugation modifies each substrate protein determining its biochemical fate (degradation). A major functional activity of Ub-PS is autophagy mechanism regulation. Interestingly, Ub-PS promotesall stages of bulk autophagy (initiation, execution, and termination). Autophagy is a crucial catabolic process that provides protein degradation and for this reason the interaction with Ub-PS is crucial. Furthermore, ubiquitination controls and regulates specific types of protein targets. Ub-PS is also involved in oxidative cellular stress and DNA damage response. Additionally, the functional role of Ub-PS in ribosome machinery regulation seems to be crucial. Concerning carcinogenesis, Ub-PS is involved in malignant disease development and progression by negatively affecting the corresponding TGF-B-, MEEK/MAPK/ERK-JNK- dependent signaling pathways. In the current review article, we describe the role of Ub-PSbiochemicalmodifications and alterations in oral squamous cell carcinoma (OSCC).

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The Ubiquitin Proteasome System in Periodontal Disease: A Comprehensive Review

Frontiers in Dental Medicine ◽

10.3389/fdmed.2020.613080 ◽

2020 ◽

Vol 1 ◽

Author(s):

Vanessa Machado ◽

Rui Carvalho ◽

José João Mendes ◽

João Botelho

Keyword(s):

Periodontal Disease ◽

Periodontal Diseases ◽

Ubiquitin Proteasome System ◽

Substrate Protein ◽

Disease Therapy ◽

Intracellular Proteins ◽

Ubiquitin Proteasome ◽

Ubiquitin Conjugation ◽

Turn Over

The turnover of intracellular proteins is a highly selective and regulated process. This process is responsible for avoiding injury and irreparable breakdown of cellular constituents. Its impairment disrupts cellular stability, integrity, and homeostasis. The ubiquitin-proteasome system (UPS) is responsible for this programmed degradation of most intracellular proteins. This process involves a cascade of enzymes that involves the ubiquitin conjugation to a target substrate protein, its recognition and degradation by the proteasome. The turn-over of intracellular proteins is a non-stop ubiquitous process that regulates a series of mechanisms, for instance transcription, translation, endocytosis. In addition, proteasome act by releasing peptides that may serve to other purposes, such as antigen presentation in immune actions and enzymatic flagging toward biosynthesis and gluconeogenesis. The role of the UPS impairment in periodontal diseases is gaining growing. This acquaintance might contribute to the development of novel therapeutic applications. Thus, this review focuses on the latest progresses on the role of the UPS and its signaling pathways in Periodontal Medicine. Furthermore, we discuss the potential of UPS-based drugs development to be used in periodontal disease therapy.

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The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21176335 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6335 ◽

Cited By ~ 1

Author(s):

Gizem Celebi ◽

Hale Kesim ◽

Ebru Ozer ◽

Ozlem Kutlu

Keyword(s):

Protein Quality ◽

Ubiquitin Proteasome System ◽

Deubiquitinating Enzymes ◽

E3 Ligases ◽

Substrate Protein ◽

Common Diseases ◽

Ubiquitin Proteasome ◽

Ubiquitin Conjugating Enzymes ◽

Substrate Proteins

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Under physiological conditions, ubiquitination is highly reversible reaction, and deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by the removal of ubiquitin from substrate proteins, thus maintaining the protein quality control and homeostasis in the cell. The dysfunction or dysregulation of these multi-step reactions is closely related to pathogenic conditions; therefore, understanding the role of ubiquitination in diseases is highly valuable for therapeutic approaches. In this review, we first provide an overview of the molecular mechanism of ubiquitination and UPS; then, we attempt to summarize the most common diseases affecting the dysfunction or dysregulation of these mechanisms.

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The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period

Journal of Biological Rhythms ◽

10.1177/0748730419878036 ◽

2019 ◽

Vol 34 (6) ◽

pp. 610-621 ◽

Cited By ~ 2

Author(s):

Tsedey Mekbib ◽

Ting-Chung Suen ◽

Aisha Rollins-Hairston ◽

Jason P. DeBruyne

Keyword(s):

Circadian Clock ◽

Critical Role ◽

Ubiquitin Proteasome System ◽

E3 Ligases ◽

Clock Proteins ◽

Ubiquitin Proteasome ◽

A Cell ◽

Circadian Clock Proteins ◽

The Stability

The time-dependent degradation of core circadian clock proteins is essential for the proper functioning of circadian timekeeping mechanisms that drive daily rhythms in gene expression and, ultimately, an organism’s physiology. The ubiquitin proteasome system plays a critical role in regulating the stability of most proteins, including the core clock components. Our laboratory developed a cell-based functional screen to identify ubiquitin ligases that degrade any protein of interest and have started screening for those ligases that degrade circadian clock proteins. This screen identified Spsb4 as a putative novel E3 ligase for RevErbα. In this article, we further investigate the role of Spsb4 and its paralogs in RevErbα stability and circadian rhythmicity. Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbα ubiquitination and degradation and regulate circadian clock periodicity.

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Degradation and beyond: Control of androgen receptor activity by the proteasome system

Cellular & Molecular Biology Letters ◽

10.2478/s11658-006-0011-9 ◽

2006 ◽

Vol 11 (1) ◽

Cited By ~ 27

Author(s):

Tomasz Jaworski

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Critical Role ◽

Ubiquitin Proteasome System ◽

Cancer Therapies ◽

The Family ◽

Prostate Cancer Development ◽

Androgen Receptor Activity ◽

Ubiquitin Proteasome

AbstractThe androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.

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Current Understanding on the Role of Standard and Immunoproteasomes in Inflammatory/Immunological Pathways of Multiple Sclerosis

Autoimmune Diseases ◽

10.1155/2014/739705 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Elena Bellavista ◽

Aurelia Santoro ◽

Daniela Galimberti ◽

Cristoforo Comi ◽

Fabio Luciani ◽

...

Keyword(s):

Multiple Sclerosis ◽

Current Knowledge ◽

Ex Vivo ◽

Critical Role ◽

Proteasome Inhibitors ◽

Cell Types ◽

Ubiquitin Proteasome System ◽

Ubiquitin Proteasome ◽

Molecular Machinery

The ubiquitin-proteasome system is the major intracellular molecular machinery for protein degradation and maintenance of protein homeostasis in most human cells. As ubiquitin-proteasome system plays a critical role in the regulation of the immune system, it might also influence the development and progression of multiple sclerosis (MS). Bothex vivoanalyses and animal models suggest that activity and composition of ubiquitin-proteasome system are altered in MS. Proteasome isoforms endowed of immunosubunits may affect the functionality of different cell types such as CD8+and CD4+T cells and B cells as well as neurons during MS development. Furthermore, the study of proteasome-related biomarkers, such as proteasome antibodies and circulating proteasomes, may represent a field of interest in MS. Proteasome inhibitors are already used as treatment for cancer and the recent development of inhibitors selective for immunoproteasome subunits may soon represent novel therapeutic approaches to the different forms of MS. In this review we describe the current knowledge on the potential role of proteasomes in MS and discuss thepro et contraof possible therapies for MS targeting proteasome isoforms.

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The role of the ubiquitin–proteasome system in ER quality control

Essays in Biochemistry ◽

10.1042/eb0410099 ◽

2005 ◽

Vol 41 (1) ◽

pp. 99 ◽

Cited By ~ 10

Author(s):

Yihong Ye

Keyword(s):

Quality Control ◽

Ubiquitin Proteasome System ◽

Er Quality Control ◽

Ubiquitin Proteasome

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183 Role of the ubiquitin-proteasome system in the development of myocardial hypertrophy

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(03)90110-x ◽

2003 ◽

Vol 2 (1) ◽

pp. 36

Author(s):

K STANGL ◽

H DREGER ◽

V STANGL ◽

G BAUMANN ◽

S MEINERS

Keyword(s):

Myocardial Hypertrophy ◽

Ubiquitin Proteasome System ◽

Ubiquitin Proteasome

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Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

Author(s):

Namrata Khurana ◽

Suresh C. Sikka

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Critical Role ◽

Castration Resistant Prostate Cancer ◽

Form Complex ◽

Androgen Receptor Signaling ◽

Castration Resistant ◽

Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01060-z ◽

2021 ◽

Author(s):

Xu Zhou ◽

Xiongjin Chen ◽

Tingting Hong ◽

Miaoping Zhang ◽

Yujie Cai ◽

...

Keyword(s):

Quality Control ◽

Cognitive Impairment ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Research Progress ◽

Repeat Domain ◽

Ubiquitin Proteasome ◽

Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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