The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of Paper: Article
Title: In vivo Effect of Low Dose γ Rays on S-Nitrosylation in Presence and Absence of Iodine Contrast Agent
Author: Edouard Azzam
Affiliation: New Jersey Medical School Cancer Center, Newark, New Jersey 07103, USA
Abstract: The covalent addition of ‘nitric oxide (·NO)’ onto cysteine thiols (i.e. S-nitrosylation) modulates the activity of key proteins involved in essential signaling pathways. The dysregulation of normal S-nitrosylation contributes to cancer onset/progression, resistance to radio- or chemo-therapies, and abnormal cardio-vascular and nervous system functions among other effects. To gain insight into the biochemical changes induced by low dose ionizing radiation, we determined global S-nitrosylation by ‘Biotin Switch’ assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 10 cGy of 137Cs g rays delivered to the whole body in presence or absence of Iopamidol, a contrast agent used during computed tomography scans. To examine whether similar or distinct nitrosylation events are induced following high dose irradiation, mice were exposed in parallel to acute 400 cGy. Analyses of modulated SNO-proteins in freshly harvested organs of animals sacrificed 13 days after irradiation indicated significant radiation dose and contrast agent-dependent changes. An effect on numerous pathways including oxidative metabolism, DNA repair, Ras signaling and E3 ligase function was apparent. The data highlighted the impact of inherent radio-sensitivity of the organs that were investigated. The major results were as follows: i) Contrast agent alone had significant effects on S-nitrosylation in brain, lung and liver; ii) relative to control, exposure to 10 cGy without contrast agent resulted in significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood; iii) the presence of contrast agent did not alter the overall trend of changes in nitrosylation detected following exposure to 10 cGy; iv) whereas a significant decrease in S-nitrosylation occurred at 10 cGy for proteins of ~50 kDa in liver, an increase was detected at 400 cGy; v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential regulation of a large number of proteins by low and high dose irradiation; vi) Ingenuity pathway analyses identified major signaling networks that are differentially modulated in brain by low and high dose g-irradiation.
Type of Paper: Review
Title: The Role of Proteomics in the Understanding of Mechanisms of Non-Targeted Effects of Ionising Radiation: A Review
Author: Carmel Mothersill, Richard Smith and Colin Seymour
Affiliation: McMaster University, Hamilton, Ontario, Canada L8S 4K1
Abstract: This review considers data obtained using proteomics and other “omics” techniques to elucidate the mechanisms involved in the generation of non-targeted radiation effects (NTE). These occur in cells or organisms which have not received a direct energy deposition from an ionising track, but which receive signals from irradiated cells or organisms. The review is particularly topical now because there is intense debate about the implications of NTE in low dose radiobiology both in radiation protection and in diagnostic radiology. NTE are also important components of targeted radiotherapy approaches using medical microbeams, proton beams or antibody/peptide targeted therapies. A key focus of the review is to discuss how proteomics can help define adverse or beneficial bystander effects and help explain how communication of bystander signals can coordinate system level responses both in terms of spatial and temporal outcomes.
Type of Paper: Article
Title: A DDB2 protein interactome - a resource to understand DDB2 functions
Authors: Ling Zhang1, Abigail Lubin1, Hua Chen & Feng Gong*
Affiliation: University of Miami Miller School of Medicine, Miami, FL, USA
Abstract: Damage-specific DNA binding protein 2 (DDB2) is a subunit of the UV-DDB complex that is involved in DNA damage recognition in the nucleotide excision repair pathway (NER). DDB2 is a component of the CRL4DDB2 E3 ligase that targets XPC, histones and DDB2 itself for ubiquitination. Recently data show that, in addition to DNA damage recognition, DDB2 has other important functions in the cell, such as cell cycle regulation and regulation of gene expression as a transcription factor. The aim of this study was to identify potential DDB2 cellular partners in human cells to better understand its nuclear functions. Toward this aim, a yeast two-hybrid screening of a human cDNA library was performed followed by in silico database searches. We identified 70 proteins as potential DDB2 interacting partners, implicating DDB2 in a wide range of diverse processes. Our results suggest that DDB2 may have previously unknown roles in many cellular processes.
Type of Paper: Article
Title: Role of membrane-bound Hsp70 in the Cripto and apoptosis pathway after irradiation
Authors: T.E.Schmid, I. Braun, S. Weinberger, M. Zitzelsberger, M. Gehrmann and G. Multhoff
Affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, München, Germany
Abstract: The major stress-inducible heat shock protein Hsp70 is frequently overexpressed and presented on the cell membrane of tumor but not normal cells. Hsp70 membrane-positive tumor cells were found to be more resistant to ionizing irradiation compared to their Hsp70 membrane-negative counterparts. Furthermore, following ionizing irradiation, the density of membrane-bound Hsp70 (mHSP70) increases in tumor cells with an initially low mHsp70 expression density. Although elevated cytosolic Hsp70 levels are associated with anti-apoptotic mechanisms, little is known about the role of mHsp70-mediated radiation resistance. A better understanding of pathways that are involved in the regulation of the Hsp70 membrane expression following irradiation might contribute to the development of novel strategies to increase the radiosensitivity of tumor cells. The effects of a non-lethal irradiation on mHsp70 and its interaction with the apoptosis- and Cripto-1-signalling were examined within an isogenic tumor cell system derived from the colorectal adenocarcinoma cell line CX-2. The advantage of this isogenic system is that the tumor cell sublines CX+ and CX- differ only with respect to their Hsp70 membrane expression pattern. With respect to the mRNA and cytosolic Hsp70 protein levels, no significant differences were observed in the two CX-2 derived tumor sublines under physiological conditions. Functionally, CX- tumor cells were found to be more radiosensitive than CX+ tumor cells and following sublethal irradiation the density of Hsp70 increased in CX- but not CX- tumor cells. An RT-qPCR analysis revealed that ionizing radiation alters the expression of several genes (e.g. GRP78, Nodal, SMAD4, TNF, BCL2, CASP10) that are related to the Cripto-1 and apoptosis signaling. These findings could be confirmed by Western blot analysis. In summary, the two CX-2 derived sublines showed characteristic differences in the expression of genes and proteins that are related to Cripto-1 and apoptosis signaling following irradiation. These differences not only can contribute to cell survival of tumor cells, but also might influence the translocation of Hsp70 from the cytosol to the cell membrane. We speculate that elevated mHsp70 levels might protect tumor cells against radiation-induced damage.
Type of the Paper: Review
Title: DNA damage response: the utility of proteaomic to identify new key factors
Authors: Imane Abdellaoui Maane, Hassan Ait Benhassou Hassan Sefrioui and Abdeladim Moumen
Affiliations: Moroccan Foundation for science, Innovation and research.
Abstract: Maintenance of genomic integrity is one of the elementary features of life. The DNA damage response (DDR) has evolved to deal with all these sources of damaging factors that threat the integrity of our genome. The DDR has been a fertile ground for proteomics, as it involves a plethora of molecular changes that are ideally captured by systems-wide analysis. In these review we emphasize the value of proteomics in the identification of key elements involved in the cellular response to DNA damage. We give examples of proteins which have been identified via proteomic analysis and play an elementary role in the DDR.
Type of Paper: Review
Title: The role of translational regulation in survival after radiation damage; an opportunity for proteomics analysis.
Authors: Stefanie Stickel1, Nathan Gomes3 and Tin Tin Su1,2,3
1Molecular, Cellular and Developmental Biology Department, University of Colorado at Boulder, CO, USA
2University of Colorado Comprehensive Cancer Center, Aurora, CO, USA
3SuviCa, Inc., Boulder, CO, USA
Abstract: In this review, we will summarize the data from different model systems that illustrate the need for proteome-wide analyses of the biological consequences of ionizing radiation (IR). IR remains one of three main therapy choices for oncology, the other two being surgery and chemotherapy. Understanding how cells and tissues respond to IR is integral to improving therapeutic regimes against cancer. Numerous studies on the changes in the transcriptome following exposure to IR in diverse systems can be found in the scientific literature. The limitation of this knowledge is illustrated by the fact that the number of transcripts that show changes after IR exposure is about an order of magnitude lower than the number of transcripts that re-localize to or from ribosomes under similar conditions. Furthermore, changes in the post-translational modification on proteins such as phosphorylation, acetylation and degradation, are profoundly important for proper response to IR. These considerations make proteomics a highly suitable tool for mechanistic studies of the effect of IR. Yet such studies remain outnumbered by the use of proteomics for diagnostic purposes such as the identification of biomarkers for the outcome of radiation therapy. Here, we will discuss the role of the ribosome and translational regulation in the survival and preservation of cells and tissues after exposure to ionizing radiation. In doing so, we hope to provide a strong incentive for the study of proteome-wide changes after IR exposure.
Type of Paper: Review
Title: Ursolic Acid-Regulated Energy Metabolism— Reliever or Propeller of Ultraviolet-Induced Oxidative Stress and DNA Damage?
Authors: Yuan-Hao Lee1,* and Randolph D. Glickman2
1 Dept. of Oncologic Sciences, University of South Alabama, Mobile, AL, USA
2 Dept. of Ophthalmology, and Center for Biomedical Neuroscience, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA * Author to whom correspondence should be addressed; E-Mail: firstname.lastname@example.org; Tel: +1-251-623-1944.
Abstract: Ultraviolet (UV) exposure is one leading cause of diseases such as skin cancers and cataract. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS). Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers) and result in double-stranded breaks through homologous recombination repair. In addition, ROS also promote phosphorylation of tyrosine kinase-coupled hormone receptors and alter the downstream energy metabolism. One important question in the field is what determines differential sensitivity of various types of cells to UV. Several molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK family members, which include DNA-PKcs, ATM and mTOR, whose signaling can be affected by energy metabolism. However, it remains unclear to what extent that the activation of hormone receptors regulates PIKKs and whether this crosstalk is causal to all kinds of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of insulin/insulin-like growth receptor. It covered the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interacting with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin receptor agonist, ursolic acid (UA), which resulted in metabolic adaptation of normal cells against UV-induced ROS and metabolic switch of tumor cells subject to UV-induced damage.
Keywords: ultraviolet; phosphatidylinositol 3-kinase-related kinases; hormone receptors