scholarly journals Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

2022 ◽  
Author(s):  
Yao Gong ◽  
Gaurav Behera ◽  
Luke Erber ◽  
Ang Luo ◽  
Yue Chen
Keyword(s):  
Protein Interactions ◽  
Critical Role ◽  
Network Connectivity ◽  
Integrated Analysis ◽  
Literature Mining ◽  
Structure Stability ◽  
Proteome Profiling ◽  
Specific Distribution ◽  
Functional Features ◽  
Proline Hydroxylation

Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.

Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

2019 ◽  
Vol 19 (6) ◽  
pp. 430-448 ◽  
Author(s):  
Khalid Bashir Dar ◽  
Aashiq Hussain Bhat ◽  
Shajrul Amin ◽  
Syed Anjum ◽  
Bilal Ahmad Reshi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Adaptor Proteins ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Beta Catenin ◽  
Protein Protein Interactions ◽  
Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

scholarly journals Integrated analysis of lncRNA, miRNA and mRNA profiles reveals potential lncRNA functions during early HIV infection

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lianwei Ma ◽  
Hui Zhang ◽  
Yue Zhang ◽  
Hailong Li ◽  
Minghui An ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Immune Activation ◽  
Expression Profiles ◽  
Critical Role ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Target Mrnas ◽  
Immunodeficiency Virus ◽  
Mirna Sequencing ◽  
Hiv 1

Abstract Background Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as “microRNA sponges”. However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. Methods 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. Results A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. Conclusions This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.

scholarly journals Coiled-coil networking shapes cell molecular machinery

2012 ◽  
Vol 23 (19) ◽  
pp. 3911-3922 ◽  
Author(s):  
Yongqiang Wang ◽  
Xinlei Zhang ◽  
Hong Zhang ◽  
Yi Lu ◽  
Haolong Huang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Critical Role ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Protein Protein Interactions ◽  
Full Spectrum ◽  
Kinetochore Assembly ◽  
Genome Wide ◽  
Molecular Machinery ◽  
Systematic Understanding

The highly abundant α-helical coiled-coil motif not only mediates crucial protein–protein interactions in the cell but is also an attractive scaffold in synthetic biology and material science and a potential target for disease intervention. Therefore a systematic understanding of the coiled-coil interactions (CCIs) at the organismal level would help unravel the full spectrum of the biological function of this interaction motif and facilitate its application in therapeutics. We report the first identified genome-wide CCI network in Saccharomyces cerevisiae, which consists of 3495 pair-wise interactions among 598 predicted coiled-coil regions. Computational analysis revealed that the CCI network is specifically and functionally organized and extensively involved in the organization of cell machinery. We further show that CCIs play a critical role in the assembly of the kinetochore, and disruption of the CCI network leads to defects in kinetochore assembly and cell division. The CCI network identified in this study is a valuable resource for systematic characterization of coiled coils in the shaping and regulation of a host of cellular machineries and provides a basis for the utilization of coiled coils as domain-based probes for network perturbation and pharmacological applications.

scholarly journals Integrated Analysis of Stemness-Related LncRNAs Helps Predict the Immunotherapy Responsiveness of Gastric Cancer Patients

2021 ◽  
Vol 9 ◽  
Author(s):  
Quan Jiang ◽  
Lingli Chen ◽  
Hao Chen ◽  
Zhaoqing Tang ◽  
Fenglin Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Independent Risk Factor ◽  
Critical Role ◽  
Tumor Biology ◽  
Integrated Analysis ◽  
Lasso Regression ◽  
Immune Microenvironment ◽  
Critical Feature ◽  
Non Coding Rnas ◽  
Gastric Cancer Patients

The immune microenvironment plays a critical role in tumor biology. As a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancers (GCs). Long non-coding RNAs (lncRNAs) have been revealed to participate in this process. In this study, we aimed to develop a stemness-related lncRNA signature (SRLncSig) with guiding significance for immunotherapy. Three cohorts (TCGA, Zhongshan, and IMvigor210) were enrolled for analysis. A list of stemness-related lncRNAs (SRlncRNAs) was collected by co-expression strategy under the threshold of coefficient value >0.35 and p-value < 0.05. Cox and Lasso regression analysis was further applied to find out the SRlncRNAs with prognosis-predictive value to establish the SRLncSig in the TCGA cohort. IPS and TIDE algorithms were further applied to predict the efficacy of SRLncSig in TCGA and Zhongshan cohorts. IMvigor210 was composed of patients with clinical outcomes of immunotherapy. The results indicated that SRLncSig not only was confirmed as an independent risk factor for GCs but also identified as a robust indicator for immunotherapy. The patient with a lower SRLncSig score was more likely to benefit from immunotherapy, and the results were highly consistent in three cohorts. In conclusion, our study not only could clarify the correlations between stemness and immunotherapy in GC patients but also provided a model to guide the applications of immunotherapy in clinical practice.

scholarly journals Mitochondria: Regulators of Cell Death and Survival

2002 ◽  
Vol 2 ◽  
pp. 1569-1578 ◽  
Author(s):  
David J. Granville ◽  
Roberta A. Gottlieb
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Death Process ◽  
Protein Protein Interactions ◽  
Ionic Changes ◽  
A Cell ◽  
Cyt C

The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.

scholarly journals Thermal proteome profiling for interrogating protein interactions

2020 ◽  
Vol 16 (3) ◽  
Author(s):  
André Mateus ◽  
Nils Kurzawa ◽  
Isabelle Becher ◽  
Sindhuja Sridharan ◽  
Dominic Helm ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Proteome Profiling

scholarly journals Guide snoRNAs: Drivers or Passengers in Human Disease?

Biology ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 1 ◽  
Author(s):  
Manisha Deogharia ◽  
Mrinmoyee Majumder
Keyword(s):  
Protein Interactions ◽  
Human Disease ◽  
Critical Role ◽  
Mrna Translation ◽  
Causal Link ◽  
Rna Modification ◽  
Disease Manifestation ◽  
The Stability ◽  
Nucleoside Modification ◽  
Host Genes

In every domain of life, RNA-protein interactions play a significant role in co- and post-transcriptional modifications and mRNA translation. RNA performs diverse roles inside the cell, and therefore any aberrancy in their function can cause various diseases. During maturation from its primary transcript, RNA undergoes several functionally important post-transcriptional modifications including pseudouridylation and ribose 2′-O-methylation. These modifications play a critical role in the stability of the RNA. In the last few decades, small nucleolar RNAs (snoRNAs) were revealed to be one of the main components to guide these modifications. Due to their active links to the nucleoside modification, deregulation in the snoRNA expressions can cause multiple disorders in humans. Additionally, host genes carrying snoRNA-encoding sequences in their introns also show differential expression in disease. Although few reports support a causal link between snoRNA expression and disease manifestation, this emerging field will have an impact on the way we think about biomarkers or identify novel targets for therapy. This review focuses on the intriguing aspect of snoRNAs that function as a guide in post-transcriptional RNA modification, and regulation of their host genes in human disease.

Neocortical pathological high-frequency oscillations are associated with frequency-dependent alterations in functional network topology

2013 ◽  
Vol 110 (10) ◽  
pp. 2475-2483 ◽  
Author(s):  
George M. Ibrahim ◽  
Ryan Anderson ◽  
Tomoyuki Akiyama ◽  
Ayako Ochi ◽  
Hiroshi Otsubo ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
High Frequency ◽  
Phase Locking ◽  
Critical Role ◽  
Intractable Epilepsy ◽  
Network Connectivity ◽  
Relative Increase ◽  
High Frequencies ◽  
High Frequency Oscillations ◽  
Cortical Regions

Synchronization of neural oscillations is thought to integrate distributed neural populations into functional cell assemblies. Epilepsy is widely regarded as a disorder of neural synchrony. Knowledge is scant, however, regarding whether ictal changes in synchrony involving epileptogenic cortex are expressed similarly across various frequency ranges. Cortical regions involved in epileptic networks also exhibit pathological high-frequency oscillations (pHFOs, >80 Hz), which are increasingly utilized as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to epileptic network connectivity. By calculating phase-locking values among intracranial electrodes implanted in children with intractable epilepsy, we constructed ictal connectivity networks and performed graph theoretical analysis to characterize their network properties at distinct frequency bands. Ictal data from 17 children were analyzed with a hierarchical mixed-effects model adjusting for patient-level covariates. Epileptogenic cortex was defined in two ways: 1) a hypothesis-driven method using the visually defined seizure-onset zone and 2) a data-agnostic method using the high-frequency amplitude of each electrode. Epileptogenic cortex exhibited a logarithmic decrease in interregional functional connectivity at high frequencies (>30 Hz) during seizure initiation and propagation but not at termination. At slower frequencies, conversely, epileptogenic cortex expressed a relative increase in functional connectivity. Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding theoretical support for their utility in the presurgical evaluation of intractable epilepsy. The view that abnormal network synchronization plays a critical role in ictogenesis and seizure dynamics is supported by the observation that functional isolation of epileptogenic cortex at high frequencies is absent at seizure termination.

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

2020 ◽  
Author(s):  
Yajun Xie ◽  
Aaron T. Kuan ◽  
Wengang Wang ◽  
Zachary T. Herbert ◽  
Olivia Mosto ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Critical Role ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Cortical Astrocytes ◽  
Functional Features ◽  
And Function ◽  
Circuit Assembly

SUMMARYNeuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

scholarly journals Functional Characterization of Brain Tumor-Initiating Cells: Implications for Preclinical Models and Drug Development

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Cesar A Garcia ◽  
Adip Guruprasad Bhargav ◽  
Sujan K Mondal ◽  
Karim ReFaey ◽  
Natanael Zarco ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Critical Role ◽  
Functional Characterization ◽  
Tumor Initiating Cells ◽  
Retroviral Transduction ◽  
Significant Difference ◽  
Brain Tumor Initiating Cells ◽  
Functional Features

Abstract INTRODUCTION Glioblastoma (GBM) is the deadliest and most common primary brain cancer in adults. Brain tumor-initiating cells (BTICs) are a heterogeneous subset of stem-like, invasive cells that play a critical role in treatment failure and recurrence. METHODS Here, we propose a system to functionally characterize patient-derived BTICs to identify features that will guide assessment of therapeutics in a BTIC subpopulation-specific manner. We established and evaluated 5 BTIC populations based on (1) proliferation, (2) stemness, (3) migration, (4) tumorigenesis, (5) clinical characteristics, and (6) therapeutic sensitivity. RESULTS Overall, in Vitro growth trends reflected in Vivo growth rates. However, a significant difference was found between tumor growth in male versus female mice in 3 BTIC lines (QNS108 P = .0011; QNS120 P < .0001; QNS 140 P < .0001). Differences in survival were observed, where BTICs derived from male and female patients produced faster morbidity in mice of the opposite sex (male derived QNS108 male vs female P = .0039; female derived QNS203 male vs female P = .029). QNS203, which was isolated from a tumor in contact with the anterior subventricular zone, decreased survival at a faster rate compared to other cell lines (n = 10 per line, 5 males/5 females, P < .0001). Stem-like properties of BTICs were assessed via differentiation marker expression, sphere-forming capacity, and detection of canonical marker CD133. Higher CD133 expression correlated with faster in Vitro doubling time and greater tumor burden. Histology reflected similar patient tumor features such as migration across the corpus callosum and cystic formation. BTICs revealed varying responses to therapies (TMZ, Radiation, TRAIL, BMP4) and varied competence to retroviral transduction. CONCLUSION By studying the functional features of BTICs within our model of GBM heterogeneity, it was shown that several factors influenced tumorigenesis and survival. These included original tumor location, stemness, variation in therapeutic sensitivity, and a critical finding for the role of sex, an unexplored area for creating next-generation, sex-specific, and BTIC-specific therapeutics.

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