Role In Autophagy Pathway Research Articles

Using SMOTE to Deal with Class-Imbalance Problem in Bioactivity Data to Predict mTOR Inhibitors

Machine learning algorithms give sub-optimal performance in the presence of class-imbalanced dataset. Mammalian target of rapamycin (mTOR) is one of the serine/threonine protein kinase, and plays an integral role in autophagy pathway. Autophagy is a cellular pathway for recycling of macromolecules (proteins, lipids, and organelles), which enables eukaryotic cells to adapt metabolism to survive during adverse growth conditions. Targeting mTOR through therapeutic interventions of autophagy pathway establishes mTOR a promising pharmacological target for autophagy modulation in cancer. The bioactivity dataset of mTOR in ChEMBL, a compound bioactivity database maintained by European Bioinformatics Institute, shows disproportionate distribution of active and inactive classes. The predictive models based on this skewed dataset are biased towards prediction of majority class. Hence, we have used Synthetic Minority Over-sampling TEchnique to deal with class-imbalance problem in bioactivity datasets. We have built and evaluated predictive models based on four commonly used classifiers using both class-imbalanced and class-balanced bioactivity datasets, and compared their performance based on various metrics like accuracy, sensitivity, specificity, F1-measure, and AUC. We observe that the classification models based on balanced dataset generally outperform those that are based on class-imbalanced dataset, irrespective of the classifiers used for classification task. We conclude that predictive models trained over class-balanced dataset can be used for screening large compound bioactivity datasets to predict mTOR inhibitors-like compounds.

New developments in mechanisms of prostate cancer progression.

Prostate cancer is the most prevalent type of cancer in men. The etiology of prostate cancer development and the mechanisms underlying androgen-independent progression remains to be further investigated. There are many known targets for prostate cancer therapy including the androgen receptor (AR) axis, but resistance eventually develops in advanced disease suggesting the need to better understand mechanisms of resistance and consideration of multi-targeted therapy. Mechanisms contributing to resistance may include gene amplifications, gene mutations, AR splice variants, and changes in expression of androgen receptor co-regulatory proteins. Given the limitations of approved therapies, further study of additional potential targets is warranted. This review focuses on the roles of autophagy pathway, p62, Yes-associated protein (YAP), cancer stem cells, and epigenetics. Therapies targeting these potential mechanisms of resistance may interact with currently approved therapies either additively or synergistically. Thus, the study of combination therapy against multiple targets may be critically important to achieve more impact against lethal forms of prostate cancer resistant to all approved current therapies.

Unc-51 like kinase 1 (ULK1) in silico analysis for biomarker identification: A vital component of autophagy

Autophagy is a degradation pathway involving lysosomal machinery for degradation of damaged organelles like the endoplasmic reticulum and mitochondria into their building blocks to maintain homeostasis within the cell. ULK1, a serine/threonine kinase, is conserved across species, from yeasts to mammals, and plays a central role in autophagy pathway. It receives signals from upstream modulators such as TIP60, mTOR and AMPK and relays them to its downstream substrates like Ambra1 and ZIP kinase. The activity of this complex is regulated through protein–protein interactions and post-translational modifications. Applying in silico analysis we identified (i) conserved patterns of ULK1 that showed its evolutionary relationship between the species which were closely related in a family compared to others. (ii) A total of 23 TFBS distributed throughout ULK1 and nuclear factor (erythroid-derived) 2 (NFE2) is of utmost significance because of its high importance rate. NEF2 has already been shown experimentally to play a role in the autophagy pathway. Most of these were of zinc coordinating class and we suggest that this information could be utilized to modulate this pathway by modifying interactions of these TFs with ULK1. (iii) CATTT haplotype was prominently found with frequency 0.774 in the studied population and nsSNPs which could have harmful effect on ULK1 protein and these could further be tested. (iv) A total of 83 phosphorylation sites were identified; 26 are already known and 57 are new that include one at tyrosine residue which could further be studied for its involvement in ULK1 regulation and hence autophagy. Furthermore, 4 palmitoylation sites at positions 426, 927, 1003 and 1049 were also found which could further be studied for protein–protein interactions as well as in trafficking.

Tu1934 Whole-Genome Sequencing and Transcriptome Analysis of Mice With Progressive Crohn's Disease-Like Ileitis

Background: Autophagy has been implicated in the pathogenesis of CD. ATG12-ATG5ATG16L1 conjugate protein complex plays a critical role in autophagy pathway. We previously reported that rs26538 in ATG12 correlated with CD at a modest level, and genetic interaction between this SNP and the focal SNP rs2241880 in ATG16L1 could contribute to CD susceptibility. Our study aimed to explore expression association of the three genes in terminal ileum biopsies in an East Anglia CD cohort. Methods: TaqMan expression & genotyping assays were all ordered from Applied Biosystems. Both expression correlation regardless of genotype and eQTL experiments for a particular SNP were undertaken in a control panel. This panel comprised 97 healthy volunteers from Addenbrooke's hospital endoscopy centre. Blood DNA of normal controls was genotyped for the SNPs. mRNA was extracted from terminal ileum biopsies and then reverse-transcribed into cDNA, which was used to measure gene expression by qPCR (2-ddCt, normalised to GAPDH). A case-control study was designed to compare gene expression between control panel and case panel with non-inflamed (24) and inflamed (22) CD cases (Kruskal-Wallis test). Results: In this study ATG5, ATG12 and ATG16L1 gene expression significantly correlated one another in normal controls regardless of genotype (p 0.05). ATG12 expression was not significantly different among inflamed CD, non-inflamed CD and controls (p=0.17395); ATG12 expression also was not significantly different for any pair (all p-values >0.05). ATG16L1 expression was significantly different among inflamed CD, non-inflamed CD and controls (p=0.0003); ATG16L1 expression was significantly different for any pair comparison (all p-values <0.05). Conclusion: ATG5, ATG12 and ATG16L1 gene expression levels significantly correlated with one another in normal controls. ATG5 and ATG16L1 expression significantly differed among noninflamed, inflamed and controls. Together with our previously reported genetic findings, it can be hypothesized that the three autophagy genes may work together to contribute to CD susceptibility.

Autophagy in COPD

Autophagy is an important cellular homeostatic process, where cell self-degrades long-lived proteins and damaged sub cellular organelles and proteins with the help of lysosomes in eukaryotic cells. In the past decade, remarkable advances have been made in describing autophagy as clinically relevant target to the treatment of pulmonary diseases. In this review I attempt to provide an overview of autophagy signaling pathway and also summarize the recent studies that suggest direct relevancy and function of autophagy pathway in the Chronic Obstructive Pulmonary Disease (COPD). However, further resolution of autophagic proteins and mechanisms is warranted in specifically designing autophagy-based therapeutic targets in COPD. Introduction Autophagy in COPD Mammalian macroautophagy (hereafter referred as autophagy) is evolutionary conserved degradative pathway that involves the fusion of double membrane autophagosomes and lysosomes for the turnover of free amino acids and fatty acids [1,2]. In addition to this, two other forms of autophagy mechanisms have been described. One type involves the invagination of lysosomal membrane to engulf cytosolic components into intralysosomal vesicles termed as microautophagy [3]. In chaperone-mediated autophagy, proteins with a particular consensus motif (KFERQ) are selectively delivered across the lysosomal membrane for degradation [4]. Autophagy can be upregulated in response to multiple forms of physiological stress including starvation [5], growth factor deprivation [6], reactive oxygen species [7], hypoxia [8], hyperoxia [9,10], endoplasmic reticulum stress [11], DNA damage [12], protein aggregates [13] or pathogens [14]. Therefore, autophagy can be predominantly viewed as a cellular response pathway to a variety of stress stimuli rather than a VRI Cell Signaling, Volume 1, Issue 2, October 2013 nutrient deprivation response pathway. Chronic or acute exposure of the aforementioned stimuli can result in dysregulated or deranged autophagy pathway with the development of several pathological conditions. In this regard stimulant cigarette smoke upon chronic exposure has recently demonstrated an increased expression of autophagy markers in the development of COPD [15,16]. A better understanding for the role of autophagy pathway in COPD will help support in the design of the therapies for the cure of COPD. eISSN 2330-0302 I S S N 2 3 3 0 0 3 0 2 ( O n l i i n e ) ; C O D E N : V R I C A O , V R I C e l l S i g n a l i n g , V e d i c Mini Review DOI: http://dx.doi.org/10.14259/cs.v1i2.68 Article Info: Received: September 25th, 2013; Accepted: October 1st, 2013

Neuronal Autophagy and Neurodevelopmental Disorders

Neurodevelopmental disorders include a wide range of diseases such as autism spectrum disorders and mental retardation. Mutations in several genes that regulate neural development and synapse function have been identified in neurodevelopmental disorders. Interestingly, some affected genes and pathways in these diseases are associated with the autophagy pathway. Autophagy is a complex, bulky degradative process that involves the sequestration of cellular proteins, RNA, lipids, and cellular organelles into lysosomes. Despite recent progress in elucidating the genetics and molecular pathogenesis of these disorders, little is known about the pathogenic mechanisms and autophagy-related pathways involved in common neurodevelopmental disorders. Therefore, in this review, we focus on the current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagy pathway in common neurodevelopmental disorders.