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International Journal of Molecular... Jun 2024Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized...
Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized endoplasmic reticulum (ER) in fibroblasts from COPD with different responses to chemical stressors compared to healthy subjects. Here, we aimed to investigate differences in stress-related gene expressions within lung cells from COPD and healthy subjects. Bronchoalveolar lavage (BAL) cells were collected from seven COPD and 35 healthy subjects. Lung fibroblasts were derived from 19 COPD and 24 healthy subjects and exposed to cigarette smoke extract (CSE). Gene and protein expression and cell proliferation were investigated. Compared to healthy subjects, we found lower gene expression of CHOP in lung fibroblasts from COPD subjects. Exposure to CSE caused inhibition of lung fibroblast proliferation in both groups, though the changes in ER stress-related gene expressions (ATF6, IRE1, PERK, ATF4, CHOP, BCL2L1) and genes relating to proteasomal subunits mostly occurred in healthy lung fibroblasts. No differences were found in BAL cells. In this study, we have found that lung fibroblasts from COPD subjects have an atypical ER stress gene response to CSE, particularly in genes related to apoptosis. This difference in response to CSE may be a contributing factor to COPD progression.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Fibroblasts; Endoplasmic Reticulum Stress; Male; Female; Middle Aged; Lung; Bronchoalveolar Lavage Fluid; Aged; Cell Proliferation; Gene Expression Regulation; Cells, Cultured; Apoptosis; Case-Control Studies
PubMed: 38928305
DOI: 10.3390/ijms25126600 -
International Journal of Molecular... Jun 2024The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids,... (Review)
Review
The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.
Topics: Humans; Antineoplastic Agents; Peripheral Nervous System Diseases; Ion Channels; Animals; Neurotoxicity Syndromes; Membrane Transport Proteins; Neoplasms
PubMed: 38928257
DOI: 10.3390/ijms25126552 -
International Journal of Molecular... Jun 2024Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this...
Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this study, we cloned the of and analyzed its expression pattern. was identified on the Z chromosome of , which is considered an interesting candidate gene for spermatogenesis. qRT-PCR and FISH experiments showed that the gene was significantly highly expressed in the testes. It is worth noting that the expression level of in male fish testes is significantly higher than that in pseudomales. In order to further explore the role of in spermatogenesis, a male testicular cell line was used as the experimental material. The results of the -RNAi and overexpression experiments showed that had a synergistic effect with spermatogenesis-related genes , , and , but had an antagonistic effect with . Our findings offer a scientific foundation for comprehending the role of in the spermatogenesis regulatory network of .
Topics: Animals; Spermatogenesis; Male; Testis; Sex Chromosomes; Fish Proteins; Proteasome Endopeptidase Complex; Cloning, Molecular
PubMed: 38928079
DOI: 10.3390/ijms25126372 -
Genes Jun 2024We conducted transcriptome sequencing on salt-tolerant mutants X5 and X3, and a control (Ctr) strain of after treatment with artificial seawater at varying salinities...
We conducted transcriptome sequencing on salt-tolerant mutants X5 and X3, and a control (Ctr) strain of after treatment with artificial seawater at varying salinities (30‱, 45‱, and 60‱) for 3 weeks. Differentially expressed genes were identified and a weighted co-expression network analysis was conducted. The blue, red, and tan modules were most closely associated with salinity, while the black, cyan, light cyan, and yellow modules showed a close correlation with strain attributes. KEGG enrichment of genes from the aforementioned modules revealed that the key enrichment pathways for salinity attributes included the proteasome and carbon fixation in photosynthesis, whereas the key pathways for strain attributes consisted of lipid metabolism, oxidative phosphorylation, soluble N-ethylmaleimide-sensitive factor-activating protein receptor (SNARE) interactions in vesicular transport, and porphyrin and chlorophyll metabolism. Gene expression for the proteasome and carbon fixation in photosynthesis was higher in all strains at 60‱. In addition, gene expression in the proteasome pathway was higher in the X5-60 than Ctr-60 and X3-60. Based on the above data and relevant literature, we speculated that mutant X5 likely copes with high salt stress by upregulating genes related to lysosome and carbon fixation in photosynthesis. The proteasome may be reset to adjust the organism's proteome composition to adapt to high-salt environments, while carbon fixation may aid in maintaining material and energy metabolism for normal life activities by enhancing carbon dioxide uptake via photosynthesis. The differences between the X5-30 and Ctr-30 expression of genes involved in the synthesis of secondary metabolites, oxidative phosphorylation, and SNARE interactions in vesicular transport suggested that the X5-30 may differ from Ctr-30 in lipid metabolism, energy metabolism, and vesicular transport. Finally, among the key pathways with good correlation with salinity and strain traits, the key genes with significant correlation with salinity and strain traits were identified by correlation analysis.
Topics: Salt Tolerance; Transcriptome; Gene Regulatory Networks; Salinity; Photosynthesis; Osmotic Pressure; Proteasome Endopeptidase Complex; Gene Expression Profiling; Lipid Metabolism
PubMed: 38927717
DOI: 10.3390/genes15060781 -
Biomedicines Jun 2024We explored differences in the DNA methylation statuses of , , , and gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR)...
We explored differences in the DNA methylation statuses of , , , and gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR) stages. Study subjects included individuals with no DR (NDR, = 41), those with non-proliferative DR (NPDR, = 27), and individuals with proliferative DR or those who underwent laser photocoagulation (PDR/LPC, = 46). DNA methylation was determined by Zymo OneStep qMethyl technique. The methylation of (NDR 5.9 (3.9-8.7) %, NPDR 4.5 (3.8-5.7) %, PDR/LPC 6.6 (4.7-10.7) %, = 0.003) and (NDR 2.2 (1.9-3.7) %, NPDR 2.2 (1.9-3.0) %, PDR/LPC 3.2 (2.5-7.1) %, < 0.01) differed across the groups. Consistent correlations were observed between the methylation levels of and in all study groups. DNA methylation levels of , , and genes were positively correlated with the duration of diabetes, HbA1c, and albuminuria in certain study groups. Univariate regression models revealed a significant association between the methylation level z-scores of , , and and severe DR (: OR = 1.96 (1.15; 3.33), = 0.013; : OR = 1.90 (1.14; 3.16), = 0.013; : OR = 3.19 (1.26; 8.06), = 0.014). remained significantly associated with DR in multivariate analysis. Our findings suggest significant associations between the severity of DR and the DNA methylation levels of the genes , , and , but not gene.
PubMed: 38927561
DOI: 10.3390/biomedicines12061354 -
Biomolecules May 2024The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations... (Review)
Review
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
Topics: Humans; Tumor Suppressor Protein p53; Neoplasms; Tumor Microenvironment; Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Animals; Mutation; Lysosomes; Carcinogenesis
PubMed: 38927053
DOI: 10.3390/biom14060649 -
Scientific Reports Jun 2024Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones...
Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones are degraded by the proteasome mediated via the DNA damage response factor Rad53. Histone expression, therefore, is tightly regulated at the protein level. Our understanding of the transcriptional regulation of histone genes is far from complete. In this study, we found that calcineurin inhibitor treatment increased histone protein levels, and that the transcription factor NFATc1 (nuclear factor of activated T cells 1) repressed histone transcription and acts downstream of the calcineurin. We further revealed that NFATc1 binds to the promoter regions of many histone genes and that histone transcription is downregulated in a manner dependent on intracellular calcium levels. Indeed, overexpression of histone H3 markedly inhibited cell proliferation. Taken together, these findings suggest that NFATc1 prevents the detrimental effects of histone H3 accumulation by inhibiting expression of histone at the transcriptional level.
Topics: NFATC Transcription Factors; Histones; Calcineurin; Humans; Cell Proliferation; Gene Expression Regulation; Promoter Regions, Genetic; Signal Transduction; Transcription, Genetic; Calcium
PubMed: 38926604
DOI: 10.1038/s41598-024-65769-9 -
Scientific Reports Jun 2024The oxygen-labile transcription factor called hypoxia-inducible factor (HIF) is responsible for the cellular and organismal adaptive response to reduced oxygen...
The oxygen-labile transcription factor called hypoxia-inducible factor (HIF) is responsible for the cellular and organismal adaptive response to reduced oxygen availability. Deregulation of HIF is associated with the pathogenesis of major human diseases including cardiovascular disease and cancer. Under normoxia, the HIFα subunit is hydroxylated on conserved proline residues within the oxygen-dependent degradation domain (ODD) that labels HIFα for proteasome-mediated degradation. Despite similar oxygen-dependent degradation machinery acting on HIF1α and HIF2α, these two paralogs have been shown to exhibit unique kinetics under hypoxia, which suggests that other regulatory processes may be at play. Here, we characterize the protease activity found in rabbit reticulocytes that specifically cleaves the ODD of HIF1α but not HIF2α. Notably, the cleavage product is observed irrespective of the oxygen-dependent prolyl-hydroxylation potential of HIF1α, suggesting independence from oxygen. HIF1α M561T substitution, which mimics an evolutionary substitution that occurred during the duplication and divergence of HIF1α and HIF2α, diminished the cleavage of HIF1α. Protease inhibitor screening suggests that cysteine proteases cathepsins L and B preferentially cleave HIF1αODD, thereby revealing an additional layer of differential HIF regulation.
Topics: Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Cathepsin L; Proteolysis; Rabbits; Oxygen; Humans; Reticulocytes; Basic Helix-Loop-Helix Transcription Factors; Hydroxylation
PubMed: 38926538
DOI: 10.1038/s41598-024-65537-9 -
Nature Communications Jun 2024Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a...
Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCF ligase for FKBP12 degradation. Target engagement occurs via covalent adduction of Cys326 in the FBXO22 C-terminal domain, which is critical for ternary complex formation, ubiquitylation and degradation. This mechanism is conserved for two recently reported alkylamine-based degraders of NSD2 and XIAP, thus establishing alkylamine tethering and covalent hijacking of FBXO22 as a generalizable TPD strategy.
Topics: Humans; Proteolysis; Ubiquitination; F-Box Proteins; HEK293 Cells; Tacrolimus Binding Protein 1A; Ubiquitin-Protein Ligases; Amines; Proteasome Endopeptidase Complex; Ligands; Receptors, Cytoplasmic and Nuclear
PubMed: 38926334
DOI: 10.1038/s41467-024-49739-3 -
Current Issues in Molecular Biology Jun 2024Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential...
Bioinformatics Analysis Reveals E6 and E7 of HPV 16 Regulate Metabolic Reprogramming in Cervical Cancer, Head and Neck Cancer, and Colorectal Cancer through the PHD2-VHL-CUL2-ELOC-HIF-1α Axis.
Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1β to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.
PubMed: 38921041
DOI: 10.3390/cimb46060370