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Investigating the functions and molecular mechanisms of DTX3L in cancer progression.

In the field of tumor research, the process by which E3 ubiquitin ligases specifically ubiquitinate substrate proteins and promote their degradation has garnered significant attention. DTX3L, an emerging E3 ubiquitin ligase of the Deltex family, is closely associated with the development and progression of various malignant tumors. Through multiple mechanisms such as epigenetic modifications, signal pathway activation, and protein interaction networks, DTX3L precisely regulates key biological processes, including cell proliferation, cycle progression, migration, invasion, and apoptosis. This r

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… When DTX3L approaches p53, it can polyubiquitinate p53 and target it for proteasomal degradation, thereby regulating the stability and function of p53 ( 25 ). …

Paeoniflorin Ameliorates BiPN by Reducing IL6 Levels and Regulating PARKIN-Mediated Mitochondrial Autophagy.

BACKGROUND: Bortezomib-induced peripheral neuropathy (BiPN) is a common complication of multiple myeloma (MM) treatment that seriously affects the quality of life of patients. The purpose of the present study was to explore the therapeutic effect of paeoniflorin on BiPN and its possible mechanism. METHODS: ELISA was used to measure the level of interleukin-6 (IL6) in the plasma of MM patients, and bioinformatics analysis was used to predict the mechanism underlying the effect of paeoniflorin on peripheral neuropathy. Cell and animal models of BiPN were constructed to evaluate mitochondrial fu

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… Many studies have shown that proteasome inhibition can cause mitochondrial damage by inducing the accumulation of polyubiquitinated proteins, and mitochondrial dysfunction is the main factor that promotes the development and maintenance of PN. 8–10 Cavaletti et al 11 observed mitochondrial swelling in …

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease.

The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin-proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and c

TGF-β: an active participant in the immune and metabolic microenvironment of multiple myeloma : TGF-β in the microenvironment of multiple myeloma.

Although substantial quantities of potent therapies for multiple myeloma (MM) have been established, MM remains an incurable disease. In recent years, our understanding of the initiation, development, and metastasis of cancers has made a qualitative leap. Cancers attain the abilities to maintain proliferation signals, escape growth inhibitors, resist cell death, induce angiogenesis, and more importantly, escape anti-tumor immunity and reprogram metabolism, which are the hallmarks of cancers. Besides, different cancers have different tumor microenvironments (TME), thus, we pay more attention to

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… SMAD6, acting as an inhibitory factor, recruits E3-ubiquitin ligases, causing MYD88 polyubiquitination and sequestering adapter protein spelling-1, thus fostering inflammatory responses. This inhibition is crucial for immune evasion, MM growth, and drug resistance [ 19 , 57 ]. …

Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies.

Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of re

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… It has been observed that phosphorylation of both MYC and MYCN affects polyubiquitination and by extension, proteasomal degradation, but no such regulatory mechanism has been reported for MYCL ( Sjostrom et al., 2005 ; Malempati et al., 2006 ; Brockmann et al., 2013 ). …

The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in

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… Cleavage of polyubiquitin chains enables Ub recycling into the cellular pool ( Budenholzer et al., 2017 ; Pathare et al., 2014 ) and it is carried out mostly by Rpn11, a Zn 2+ de-ubiquitinase essential for proteasome functions and cell viability located above the translocation channel, which removes … As a matter of fact, the close proximity of the N-terminal domain ring of the AAA + ATPases sterically prevents the cleavage inside ubiquitin moieties by Rpn11, which, therefore, removes polyubiquitin chains by hydrolysing the isopeptide bond (located at the base of the chain) between the lysine residue …

LAMP5 modulates IRF4 stability and nuclear transport: a critical mechanism in myeloma progression and therapy.

Multiple myeloma is a malignant hematopoietic neoplasm characterized by unclear molecular mechanisms and lack of highly effective targeted therapies for clinical application. Interferon regulatory factor 4 (IRF4) is a well-known core transcription factor that regulates the progression of myeloma, but the molecular mechanisms underlying its protein homeostasis regulation are unknown. Our research shows that lysosomal-associated membrane protein 5 (LAMP5) interacts with IRF4 and prevents its degradation through the autophagy-lysosome pathway, thereby facilitating the progression of myeloma. Addi

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… Cell lysates were subjected to immunoprecipitation, and western blot analysis revealed a substantial increase in IRF4 polyubiquitination, and p62 and LC3B-II protein levels in sh LAMP5 cells compared with sh Ctrl cells (Fig. 4L ). …

Гипоксия в множестве склерозов.

Низкая доступность кислорода (гипоксии) является заметной, но плохо понимаемой особенностью множественного склероза (МС). Неизвестно, вызывает ли гипоксия патологию и симптомы MS или она является следствием других патологических явлений, таких, как воспаление и сосудистая дисфункция. Здесь мы резюмируем имеющуюся литературу о взаимосвязи между гипоксией и как патологическими, так и симптомными характеристиками MS. Острая экологическая гипоксия (т.е. высота) может вызвать или облегчить события, связанные с MS, возможно, путем усиления гипоксии тканей в центральной нервной системе. Соответственн

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… Among them is the oxygen-dependent regulation via HIF prolyl hydroxylases (PHDs), which hydroxylate (OH) HIF α subunits, allowing recognition by the von Hippel Lindau (VHL) tumor suppression protein, polyubiquitination (Ub) and proteasomal degradation under normoxic conditions. …

Benzyl isothiocyanate suppresses development of thyroid carcinoma by regulating both autophagy and apoptosis pathway.

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, characterized by rapid growth and invasion and poor prognosis. Due to its rarity and aggressive nature, ATC is a difficult condition to treat, thus knowledge of the mechanisms underlying its progression represents important research challenges. Benzyl isothiocyanate (BITC) is a natural compound that has shown promising anticancer properties. The aim of this study was to evaluate the antitumor effect of BITC in ATC, highlighting signaling pathways involved in BITC mechanism of action. This work included in vitro a

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… P62 recognizes polyubiquitin chains through its C-terminal domain and binds to LC3, thus promoting autophagic degradation of ubiquitinated loads. …

Management of refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: current perspectives.

Autoimmune hemolytic anemia (AIHA) is increasingly observed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reported incidence between 4% and 6%. The disease is generally severe and refractory to standard therapy, with high mortality, and there are neither defined therapies, nor prospective clinical trials addressing the best treatment. Most of the knowledge on the therapy of AIHAs derives from primary forms, which are highly heterogeneous as well, further complicating the management of post-allo-HSCT forms. The review addresses the risk factors associated with pos

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… The drug leads to the accumulation of polyubiquitinated proteins, inducing the death of both short- and long-lived plasma cells by activation of the terminal-unfolded protein response. …

Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma.

Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of

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… Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137 721–735. 10.1016/j.cell.2009.03.015 Johnson G. L., Nakamura K. (2007). The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim. …

Molecular Approaches To Target GPCRs in Cancer Therapy

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… FTY720 efficiently induces internalization and polyubiquitination of S1P receptor 1 leading to its proteasomal degradation. As a result, lymphocytes become unresponsive to S1P [ 69 ]. …

Role of nuclear factor-kappa B in feline injection site sarcoma.

BackgroundChronic inflammation has been implicated in sarcomagenesis. Among various factors, activation of nuclear factor-kappa B (NF-κB) signaling pathway has been documented being able to target genes associated with tumor progression and up-regulate the expression of tumor-promoting cytokines and survival genes in several human solid tumors. Feline injection sites sarcomas (FISS) are malignant entities derived from the mesenchymal origin. The disease has been considered to be associated with vaccine adjuvant, aluminum, which serves as a stimulus continuously inducing overzealous inflammator

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… This phosphorylation is a prerequisite for subsequent polyubiquitination, which in turn leads to proteasomal disintegration of IκB. …

Targeting the proteasome in cancer therapy: development and future opportunities in natural products.

BACKGROUND: The ubiquitin-proteasome pathway is a critical therapeutic target in malignancies, particularly multiple myeloma. The development of proteasome inhibitors (PIs) has marked a milestone in multiple myeloma therapy and now constitutes the backbone of frontline treatment regimens. However, primary and acquired resistance remain a major challenge, underscoring the need to identify new PIs as well as agents that can resensitize resistant cells. METHOD: This review provides an overview of the current clinical applications of PIs and offers a comprehensive summary of natural products that

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… Its proper function relies on the precise coordination of several steps, such as polyubiquitination, deubiquitination, and the eventual degradation of target proteins, ensuring the timely removal of damaged, misfolded, or unnecessary proteins ( Manasanch and Orlowski, 2017 ). … Notably, 2a retained activity against BTZ-resistant KMS-11/BTZ and OPM-2/BTZ cells and, like BTZ, induced accumulation of phosphorylated and polyubiquitinated IκBɑ. It was also well tolerated in mice, highlighting its therapeutic promise ( Chiba et al., 2014 ; Yoshida et al., 2016 ). …

The IL-17 family in diseases: from bench to bedside.

The interleukin-17 (IL-17) family comprises six members (IL-17A-17F), and recently, all of its related receptors have been discovered. IL-17 was first discovered approximately 30 years ago. Members of this family have various biological functions, including driving an inflammatory cascade during infections and autoimmune diseases, as well as boosting protective immunity against various pathogens. IL-17 is a highly versatile proinflammatory cytokine necessary for vital processes including host immune defenses, tissue repair, inflammatory disease pathogenesis, and cancer progression. However, ho

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… This causes conjugation of a K63-linked polyubiquitin chain with TRAF6. 40 Ubiquitinated TRAF6 activates the expression of inflammatory transcription factor-induced genes through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and contributes to the activation of three … A20 (also known as tumor necrosis factor alpha-induced protein 3, Tnfaip3 ), which is upregulated by IL-17A via NF-κB, binds to the CBAD of IL-17RA and removes polyubiquitin chains on TRAF6, thereby inhibiting IL-17 signaling through negative feedback regulation. 59 , 60 Similarly, ubiquitin-specific …

MicroRNAs and Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies.

The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The

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… PTEN is also negatively regulated by the anti-apoptotic XIAP (X-linked inhibitor of apoptosis) that promotes PTEN for polyubiquitination and proteosomal degradation [ 309 ]. … USP9X removes degradative Lys48-linked polyubiquitin chains on Mcl-1. High levels of Mcl-1 correlated with elevated USP9X expression in follicular lymphoma, diffuse large B-cell lymphoma, and some other cancer samples. …

Modulation of Lonp1 Activity by Small Compounds.

The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizin

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… By inhibiting the chymotrypsin-like activity of the proteasome catalytic 20S core, MG132 prevents the degradation of polyubiquitinated proteins, leading to their accumulation within the cell. …

AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation.

BackgroundMultiple myeloma (MM) is the second most common hematological malignancy. An overwhelming majority of patients with MM progress to serious osteolytic bone disease. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) participates in several steps during cancer development and osteoclast differentiation. This study aimed to explore its role in MM.MethodsThe gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis. Enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotti

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… Additionally, these proteins mainly possess protein polyubiquitin and histone‐binding functions (Figure 5C ). …

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in r

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… Bortezomib-Encapsulated CuS/Carbon Dot Nanocomposites for Enhanced Photothermal Therapy via Stabilization of Polyubiquitinated Substrates in the Proteasomal Degradation Pathway ACS Nano 2020 14 10688 10703 10.1021/acsnano.0c05332 32790339 131. Min J. Moon H. Yang H.J. Shin H.H. Hong S.Y. Kang S. …

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B.

Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have revolutionized therapy for chronic myeloid leukemia (CML), paving the way for clinical development in other diseases. Despite success, targeting leukemic stem cells and overcoming drug resistance remain challenges for curative cancer therapy. To identify drivers of kinase-independent TKI resistance in CML, we performed genome-wide expression analyses on TKI-resistant versus sensitive CML cell lines, revealing a nuclear factor-kappa B (NF-κB) expression signature. Nucleocytoplasmic fractionation and luciferase reporter assays confirmed i

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… Saccani et al. [ 71 ] previously reported that the proteasome represses NF-κB transcriptional activity by direct polyubiquitination and degradation of p65 in the nucleus. …