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Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 34425

Special Issue Editors

Dr. Giulia Piaggio

E-Mail Website
Guest Editor
Department of Research, Diagnosis and Innovative Technologies, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
Interests: molecular oncology; transcription; gene expression; proliferation; in vivo imaging; animal models of cancer; apoptosis and cell cycle
Dr. Cristina Mazzoni

E-Mail Website
Co-Guest Editor
Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Interests: yeast models; ageing; cell death; oxidative stress; mRNA metabolism
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Massimo Gulisano

E-Mail Website
Co-Guest Editor
Director of the Molecular Preclinical and Translational Imaging Research Centre, IMPRonTE, Department of Drug Sciences, University of Catania, via S. Sofia 64, 95125 Catania, Italy
Interests: regenerative medicine; mouse models; molecular and preclinical imaging; organoids; neurodegeneration
Dr. Barbara Belletti

E-Mail Website
Co-Guest Editor
Unit of Molecular Oncology, OMMPPT, Department of Cancer Research and Advanced Diagnostics, Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS, National Cancer Institute, Via Gallini 2, 33081 Aviano, Italy
Interests: cancer; breast cancer; mouse models; cell cycle; signal transduction; oncogene; oncosuppressor
Dr. Carmen Valente

E-Mail Website
Co-Guest Editor
Istituto Di Biochimica Delle Proteine, Naples, Italy
Interests: cell biology; protein; biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue deals with cutting-edge aspects of cell biology. It aims at detailed emerging concepts in the field of cell stress response, including oncogenic insults. It will focus on recent advances on signal transduction and protein trafficking molecular mechanisms as well as on mechanisms of development, differentiation, and aging that control cell/tissue plasticity and repair/regenerative processes both in normal and transformed cells. It will include the following topics: tissue repair and regenerative medicine, molecular pathways of cell stress response, molecular mechanisms of differentiation, signal transduction, and organelle biogenesis and function.

Dr. Giulia Piaggio
Dr. Mazzoni Cristina
Dr. Massimo Gulisano
Dr. Barbara Belletti
Dr. Carmen Valente
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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15 pages, 2066 KiB  
Article
The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments
by Marina Maria Bellet, Claudia Stincardini, Claudio Costantini, Marco Gargaro, Stefania Pieroni, Marilena Castelli, Danilo Piobbico, Paolo Sassone-Corsi, Maria Agnese Della-Fazia, Luigina Romani and Giuseppe Servillo
Int. J. Mol. Sci. 2021, 22(6), 2974; https://doi.org/10.3390/ijms22062974 - 15 Mar 2021
Cited by 14 | Viewed by 2943
Abstract
The circadian clock driven by the daily light–dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian [...] Read more.
The circadian clock driven by the daily light–dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other’s expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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13 pages, 1225 KiB  
Article
Lung Surfactant Decreases Biochemical Alterations and Oxidative Stress Induced by a Sub-Toxic Concentration of Carbon Nanoparticles in Alveolar Epithelial and Microglial Cells
by Giuseppe Caruso, Claudia G. Fresta, Angelita Costantino, Giacomo Lazzarino, Angela M. Amorini, Giuseppe Lazzarino, Barbara Tavazzi, Susan M. Lunte, Prajnaparamita Dhar, Massimo Gulisano and Filippo Caraci
Int. J. Mol. Sci. 2021, 22(5), 2694; https://doi.org/10.3390/ijms22052694 - 07 Mar 2021
Cited by 3 | Viewed by 2504
Abstract
Carbon-based nanomaterials are nowadays attracting lots of attention, in particular in the biomedical field, where they find a wide spectrum of applications, including, just to name a few, the drug delivery to specific tumor cells and the improvement of non-invasive imaging methods. Nanoparticles [...] Read more.
Carbon-based nanomaterials are nowadays attracting lots of attention, in particular in the biomedical field, where they find a wide spectrum of applications, including, just to name a few, the drug delivery to specific tumor cells and the improvement of non-invasive imaging methods. Nanoparticles inhaled during breathing accumulate in the lung alveoli, where they interact and are covered with lung surfactants. We recently demonstrated that an apparently non-toxic concentration of engineered carbon nanodiamonds (ECNs) is able to induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells. Therefore, the complete understanding of their “real” biosafety, along with their possible combination with other molecules mimicking the in vivo milieu, possibly allowing the modulation of their side effects becomes of utmost importance. Based on the above, the focus of the present work was to investigate whether the cellular alterations induced by an apparently non-toxic concentration of ECNs could be counteracted by their incorporation into a synthetic lung surfactant (DPPC:POPG in 7:3 molar ratio). By using two different cell lines (alveolar (A549) and microglial (BV-2)), we were able to show that the presence of lung surfactant decreased the production of ECNs-induced nitric oxide, total reactive oxygen species, and malondialdehyde, as well as counteracted reduced glutathione depletion (A549 cells only), ameliorated cell energy status (ATP and total pool of nicotinic coenzymes), and improved mitochondrial phosphorylating capacity. Overall, our results on alveolar basal epithelial and microglial cell lines clearly depict the benefits coming from the incorporation of carbon nanoparticles into a lung surfactant (mimicking its in vivo lipid composition), creating the basis for the investigation of this combination in vivo. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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20 pages, 2831 KiB  
Article
Heat Shock Affects Mitotic Segregation of Human Chromosomes Bound to Stress-Induced Satellite III RNAs
by Manuela Giordano, Lucia Infantino, Marco Biggiogera, Alessandra Montecucco and Giuseppe Biamonti
Int. J. Mol. Sci. 2020, 21(8), 2812; https://doi.org/10.3390/ijms21082812 - 17 Apr 2020
Cited by 12 | Viewed by 3364
Abstract
Heat shock activates the transcription of arrays of Satellite III (SatIII) DNA repeats in the pericentromeric heterochromatic domains of specific human chromosomes, the longest of which is on chromosome 9. Long non-coding SatIII RNAs remain associated with transcription sites where they form nuclear [...] Read more.
Heat shock activates the transcription of arrays of Satellite III (SatIII) DNA repeats in the pericentromeric heterochromatic domains of specific human chromosomes, the longest of which is on chromosome 9. Long non-coding SatIII RNAs remain associated with transcription sites where they form nuclear stress bodies or nSBs. The biology of SatIII RNAs is still poorly understood. Here, we show that SatIII RNAs and nSBs are detectable up to four days after thermal stress and are linked to defects in chromosome behavior during mitosis. Heat shock perturbs the execution of mitosis. Cells reaching mitosis during the first 3 h of recovery accumulate in pro-metaphase. During the ensuing 48 h, this block is no longer detectable; however, a significant fraction of mitoses shows chromosome segregation defects. Notably, most of lagging chromosomes and chromosomal bridges are bound to nSBs and contain arrays of SatIII DNA. Disappearance of mitotic defects at the end of day 2 coincides with the processing of long non-coding SatIII RNAs into a ladder of small RNAs associated with chromatin and ranging in size from 25 to 75 nt. The production of these molecules does not rely on DICER and Argonaute 2 components of the RNA interference apparatus. Thus, massive transcription of SatIII DNA may contribute to chromosomal instability. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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13 pages, 3059 KiB  
Article
ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α
by Duckgue Lee, Daniel Hokinson, Soyoung Park, Rosalie Elvira, Fedho Kusuma, Ji-Min Lee, Miyong Yun, Seok-Geun Lee and Jaeseok Han
Int. J. Mol. Sci. 2019, 20(24), 6309; https://doi.org/10.3390/ijms20246309 - 13 Dec 2019
Cited by 53 | Viewed by 7962
Abstract
Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest [...] Read more.
Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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Review

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23 pages, 1927 KiB  
Review
Differential Co-Expression Analyses Allow the Identification of Critical Signalling Pathways Altered during Tumour Transformation and Progression
by Aurora Savino, Paolo Provero and Valeria Poli
Int. J. Mol. Sci. 2020, 21(24), 9461; https://doi.org/10.3390/ijms21249461 - 12 Dec 2020
Cited by 22 | Viewed by 4430
Abstract
Biological systems respond to perturbations through the rewiring of molecular interactions, organised in gene regulatory networks (GRNs). Among these, the increasingly high availability of transcriptomic data makes gene co-expression networks the most exploited ones. Differential co-expression networks are useful tools to identify changes [...] Read more.
Biological systems respond to perturbations through the rewiring of molecular interactions, organised in gene regulatory networks (GRNs). Among these, the increasingly high availability of transcriptomic data makes gene co-expression networks the most exploited ones. Differential co-expression networks are useful tools to identify changes in response to an external perturbation, such as mutations predisposing to cancer development, and leading to changes in the activity of gene expression regulators or signalling. They can help explain the robustness of cancer cells to perturbations and identify promising candidates for targeted therapy, moreover providing higher specificity with respect to standard co-expression methods. Here, we comprehensively review the literature about the methods developed to assess differential co-expression and their applications to cancer biology. Via the comparison of normal and diseased conditions and of different tumour stages, studies based on these methods led to the definition of pathways involved in gene network reorganisation upon oncogenes’ mutations and tumour progression, often converging on immune system signalling. A relevant implementation still lagging behind is the integration of different data types, which would greatly improve network interpretability. Most importantly, performance and predictivity evaluation of the large variety of mathematical models proposed would urgently require experimental validations and systematic comparisons. We believe that future work on differential gene co-expression networks, complemented with additional omics data and experimentally tested, will considerably improve our insights into the biology of tumours. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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27 pages, 1711 KiB  
Review
Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1
by Erica Buoso, Mirco Masi, Marco Racchi and Emanuela Corsini
Int. J. Mol. Sci. 2020, 21(23), 9229; https://doi.org/10.3390/ijms21239229 - 03 Dec 2020
Cited by 27 | Viewed by 8072
Abstract
Endocrine disruptors (EDCs) can display estrogenic and androgenic effects, and their exposure has been linked to increased cancer risk. EDCs have been shown to directly affect cancer cell regulation and progression, but their influence on tumour microenvironment is still not completely elucidated. In [...] Read more.
Endocrine disruptors (EDCs) can display estrogenic and androgenic effects, and their exposure has been linked to increased cancer risk. EDCs have been shown to directly affect cancer cell regulation and progression, but their influence on tumour microenvironment is still not completely elucidated. In this context, the signalling hub protein RACK1 (Receptor for Activated C Kinase 1) could represent a nexus between cancer and the immune system due to its roles in cancer progression and innate immune activation. Since RACK1 is a relevant EDCs target that responds to steroid-active compounds, it could be considered a molecular bridge between the endocrine-regulated tumour microenvironment and the innate immune system. We provide an analysis of immunomodulatory and cancer-promoting effects of different EDCs in shaping tumour microenvironment, with a final focus on the scaffold protein RACK1 as a pivotal molecular player due to its dual role in immune and cancer contexts. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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27 pages, 1779 KiB  
Review
Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe
by Cristina Panuzzo, Aleksandar Jovanovski, Barbara Pergolizzi, Lucrezia Pironi, Serena Stanga, Carmen Fava and Daniela Cilloni
Int. J. Mol. Sci. 2020, 21(11), 3928; https://doi.org/10.3390/ijms21113928 - 30 May 2020
Cited by 17 | Viewed by 4378
Abstract
Mitochondria are the main fascinating energetic source into the cells. Their number, shape, and dynamism are controlled by the cell’s type and current behavior. The perturbation of the mitochondrial inward system via stress response and/or oncogenic insults could activate several trafficking molecular mechanisms [...] Read more.
Mitochondria are the main fascinating energetic source into the cells. Their number, shape, and dynamism are controlled by the cell’s type and current behavior. The perturbation of the mitochondrial inward system via stress response and/or oncogenic insults could activate several trafficking molecular mechanisms with the intention to solve the problem. In this review, we aimed to clarify the crucial pathways in the mitochondrial system, dissecting the different metabolic defects, with a special emphasis on hematological malignancies. We investigated the pivotal role of mitochondria in the maintenance of hematopoietic stem cells (HSCs) and their main alterations that could induce malignant transformation, culminating in the generation of leukemic stem cells (LSCs). In addition, we presented an overview of LSCs mitochondrial dysregulated mechanisms in terms of (1) increasing in oxidative phosphorylation program (OXPHOS), as a crucial process for survival and self-renewal of LSCs,(2) low levels of reactive oxygen species (ROS), and (3) aberrant expression of B-cell lymphoma 2 (Bcl-2) with sustained mitophagy. Furthermore, these peculiarities may represent attractive new “hot spots” for mitochondrial-targeted therapy. Finally, we remark the potential of the LCS metabolic effectors to be exploited as novel therapeutic targets. Full article
(This article belongs to the Special Issue Mechanisms of Cell Response to Stress and Oncogenic Insults: Role of Signalling, Trafficking and Organelles)
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