scholarly journals KH-type splicing regulatory protein is a new component of chromatoid body

Reproduction ◽  
2017 ◽  
Vol 154 (6) ◽  
pp. 723-733 ◽  
Author(s):  
Huijuan Zhang ◽  
Guishuan Wang ◽  
Lin Liu ◽  
Xiaolin Liang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Germ Cell ◽  
Knockout Mice ◽  
Binding Protein ◽  
Regulatory Protein ◽  
Somatic Cells ◽  
Chromatoid Body ◽  
Mechanistic Insight ◽  
Insight Into

The chromatoid body (CB) is a specific cloud-like structure in the cytoplasm of haploid spermatids. Recent findings indicate that CB is identified as a male germ cell-specific RNA storage and processing center, but its function has remained elusive for decades. In somatic cells, KH-type splicing regulatory protein (KSRP) is involved in regulating gene expression and maturation of select microRNAs (miRNAs). However, the function of KSRP in spermatogenesis remains unclear. In this study, we showed that KSRP partly localizes in CB, as a component of CB. KSRP interacts with proteins (mouse VASA homolog (MVH), polyadenylate-binding protein 1 (PABP1) and polyadenylate-binding protein 2 (PABP2)), mRNAs (Tnp2 and Odf1) and microRNAs (microRNA-182) in mouse CB. Moreover, KSRP may regulate the integrity of CB via DDX5-miRNA-182 pathway. In addition, we found abnormal expressions of CB component in testes of Ksrp-knockout mice and of patients with hypospermatogenesis. Thus, our results provide mechanistic insight into the role of KSRP in spermatogenesis.

Abstract MP204: Pyruvate Dehydrogenase Kinase Isozyme Specific Regulation Of Protein Acetylation In Cardiac Tissue

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Chae-Myeong Ha ◽  
Adam R Wende
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
Knockout Mice ◽  
Pyruvate Dehydrogenase ◽  
Cardiac Tissue ◽  
Cell Protein ◽  
Protein Acetylation ◽  
Acetyl Coa ◽  
The Impact

Heart disease is the number one cause of death in developed countries. Metabolic diseases influence the severity of heart disease linked to risk factors which are thought to alter epigenetic mechanisms. Pyruvate dehydrogenase (PDH) kinases (PDK), which phosphorylate and reduce the activity of PDH the nexus of glucose oxidation and fatty acid oxidation are sensitive to metabolic status. Four isozymes of PDK (PDK1-4) exist with PDK2 and PDK4 as the major regulators in cardiac tissue. Owing to the role of PDH in regulating pyruvate to acetyl-CoA, we hypothesized that PDK inhibition may regulate protein acetylation through increasing acetyl-CoA because of PDH activation leading to post-translational modifications both directly to proteins in metabolic pathways as well as to histones associated with the genes encoding them. To test this, we utilized PDK2 germline knockout mice (P2KO), PDK4 germline knockout mice (P4KO), and PDK2 and PDK4 double knockout (DKO) mice for molecular analysis. Our results identify a novel increase in whole-cell protein acetylation in P2KO left ventricle tissue (LV). However, protein acetylation in P4KO LV was not changed compared to WT mice. The most robust protein acetylation was observed in the DKO LV. Furthermore, when we explored sub-cellular distribution of protein acetylation, the greatest increases were found on cytoplasmic proteins, with moderate changes in mitochondrial proteins. We also found PDK2 ablation induces histone H3 acetylation, which may also lead to changes in gene expression. Moreover, this protein acetylation in P2KO and DKO was not seen in other tissues examined (e.g., liver, skeletal muscle). The hyperacetylation is robust in male LV compared to female LV. In conclusion, our study supports a novel protein acetylation mechanism that is both tissue and PDK isozyme specific highlighting the role of PDK2, which is relatively understudied compared to PDK4 in heart disease. Further study will evaluate if the hyperacetylation has a beneficial effect in various heart disease settings as well as identify the impact on changes in gene expression. This study supports PDK isozyme-specific inhibition strategies will be required to develop therapeutic targets of cardiovascular disease with metabolic inflexibility.

Mechanistic insight into the role of metformin in Alzheimer's disease

Life Sciences ◽  
2022 ◽  
pp. 120299
Author(s):  
Mehdi Sanati ◽  
Samaneh Aminyavari ◽  
Amir R. Afshari ◽  
Amirhossein Sahebkar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mechanistic Insight ◽  
Insight Into

scholarly journals Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Suk Min Jang ◽  
Catherine Lachance ◽  
Wenyi Mi ◽  
Jie Lyu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Memory Impairment ◽  
Target Genes ◽  
Epigenetic Mark ◽  
Mechanistic Insight ◽  
Genomic Analyses ◽  
Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

Mechanistic insight into the role of immunocastration on eliminating skatole in boars

2019 ◽  
Vol 131 ◽  
pp. 32-40 ◽  
Author(s):  
Xingfa Han ◽  
Min Zhou ◽  
Xiaohan Cao ◽  
Xiaogang Du ◽  
Fengyan Meng ◽  
...  
Keyword(s):  
Mechanistic Insight ◽  
Insight Into

scholarly journals Atlas of gene expression in the mouse kidney: new features of glomerular parietal cells

2011 ◽  
Vol 43 (3) ◽  
pp. 161-173 ◽  
Author(s):  
Lydie Cheval ◽  
Fabien Pierrat ◽  
Carole Dossat ◽  
Mathieu Genete ◽  
Martine Imbert-Teboul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Kidney ◽  
Thick Ascending Limb ◽  
Proliferating Cells ◽  
Quantitative Expression ◽  
Nephron Segments ◽  
Nephron Segment ◽  
Mrna Markers ◽  
Insight Into

To gain molecular insight into kidney function, we performed a high-resolution quantitative analysis of gene expression in glomeruli and nine different nephron segments dissected from mouse kidney using Serial Analysis of Gene Expression (SAGE). We also developed dedicated bioinformatics tools and databases to annotate mRNA tags as transcripts. Over 800,000 mRNA SAGE tags were sequenced corresponding to >20,000 different mRNA tags present at least twice in at least one library. Hierarchical clustering analysis of tags demonstrated similarities between the three anatomical subsegments of the proximal tubule, between the cortical and medullary segments of the thick ascending limb of Henle's loop, and between the three segments constituting the aldosterone-sensitive distal nephron segments, whereas the glomerulus and distal convoluted tubule clusterized independently. We also identified highly specific mRNA markers of each subgroup of nephron segments and of most nephron segments. Tag annotation also identified numbers of putative antisense mRNAs. This database constitutes a reference resource in which the quantitative expression of a given gene can be compared with that of other genes in the same nephron segment, or between different segments of the nephron. To illustrate possible applications of this database, we performed a deeper analysis of the glomerulus transcriptome that unexpectedly revealed expression of several ion and water carriers; within the glomerulus, they were found to be preferentially expressed in the parietal sheet. It also revealed the major role of the zinc finger transcription factor Wt1 in the specificity of gene expression in the glomerulus. Finally, functional annotation of glomerulus-specific transcripts suggested a high proliferation activity of glomerular cells. Immunolabeling for PCNA confirmed a high percentage of proliferating cells in the glomerulus parietal sheet.

scholarly journals Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

2009 ◽  
Vol 37 (10) ◽  
pp. 1176-1185.e21 ◽  
Author(s):  
Cristina Cellai ◽  
Anna Laurenzana ◽  
Elisa Bianchi ◽  
Sara Sdelci ◽  
Rossella Manfredini ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Crucial Role ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Mechanistic Insight ◽  
Acute Myelogenous ◽  
Induced Apoptosis ◽  
Insight Into

scholarly journals Integrative Omic Profiling Reveals Unique Hypoxia Induced Signatures in Gastric Cancer Associated Myofibroblasts

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 263
Author(s):  
Hanna Najgebauer ◽  
Andrew Jarnuczak ◽  
Andrea Varro ◽  
Christopher Sanderson
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Normal Tissue ◽  
Tumour Progression ◽  
Cancer Cell Migration ◽  
Hypoxic Conditions ◽  
Mechanistic Insight ◽  
Functional Characterisation ◽  
Induced Changes ◽  
Insight Into

Although hypoxia is known to contribute to several aspects of tumour progression, relatively little is known about the effects of hypoxia on cancer-associated myofibroblasts (CAMs), or the consequences that conditional changes in CAM function may have on tumour development and metastasis. To investigate this issue in the context of gastric cancer, a comparative multiomic analysis was performed on populations of patient-derived myofibroblasts, cultured under normoxic or hypoxic conditions. Data from this study reveal a novel set of CAM-specific hypoxia-induced changes in gene expression and secreted proteins. Significantly, these signatures are not observed in either patient matched adjacent tissue myofibroblasts (ATMs) or non-cancer associated normal tissue myofibroblasts (NTMs). Functional characterisation of different myofibroblast populations shows that hypoxia-induced changes in gene expression not only enhance the ability of CAMs to induce cancer cell migration, but also confer pro-tumorigenic (CAM-like) properties in NTMs. This study provides the first global mechanistic insight into the molecular changes that contribute to hypoxia-induced pro-tumorigenic changes in gastric stromal myofibroblasts.

Poly(A)-binding protein (PABP): a common viral target

2010 ◽  
Vol 426 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Richard W. P. Smith ◽  
Nicola K. Gray
Keyword(s):  
Gene Expression ◽  
Binding Protein ◽  
Intracellular Localization ◽  
Mrna Translation ◽  
Dna Viruses ◽  
Multifunctional Protein ◽  
Wide Range ◽  
Viral Target ◽  
Rna And Dna

Cytoplasmic PABP [poly(A)-binding protein] is a multifunctional protein with well-studied roles in mRNA translation and stability. In the present review, we examine recent evidence that the activity of PABP is altered during infection with a wide range of viruses, bringing about changes in its stability, complex formation and intracellular localization. Targeting of PABP by both RNA and DNA viruses highlights the role of PABP as a central regulator of gene expression.

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