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Dual Function Molecules and Processes in Cell Fate Decision
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Dual Function Molecules and Processes in Cell Fate Decision

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 (30 June 2020) | Viewed by 55512

Special Issue Editors

Prof. Dr. Michela Giuliano

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Guest Editor
Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
Interests: cell death pathways; oncobiology; cancer; nutraceuticals; oxidative stress studies
Special Issues, Collections and Topics in MDPI journals
Dr. Sonia Emanuele

E-Mail Website
Guest Editor
Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
Interests: apoptosis; cancer; autophagy; epigenetics; HDAC inhibitors; cell stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent molecular discoveries in cell biology have highlighted a number of molecules  playing opposite roles in different processes, including cell death, survival, proliferation, and differentiation. This unusual behavior can be dependent on cell environment, post-translational modifications, epigenetic regulation, and complex network interactions. In some cases, hormetic responses can occur, as is the case with molecules, such as reactive oxygen species (ROS), which are active as bio-modulators at low doses and destructive at high concentrations. In addition, many cellular proteins exert a dual role in regulating cell fate determination, although the regulation mechanisms are not well known. Therefore, elucidating the molecular switches regulating this behavior remains an intriguing tool to investigate. The “Janus” role is not restricted to molecules but also involves cellular processes such as autophagy, a well characterized form of degradation of intracellular material that can be triggered as a pro-survival response or can culminate in cell death. The proposal for this Issue is to focus on these double-faced molecules/processes in the regulation of cell fate to provide a critical analysis of different situations and the regulative mechanisms involved in opposite cell responses.  

Prof. Michela Giuliano
Dr. Sonia Emanuele
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.

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Published Papers (11 papers)

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Editorial

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4 pages, 182 KiB  
Editorial
Dual Function Molecules and Processes in Cell Fate Decision: A Preface to the Special Issue
by Sonia Emanuele and Michela Giuliano
Int. J. Mol. Sci. 2020, 21(24), 9601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249601 - 16 Dec 2020
Viewed by 1086
Abstract
A lot of water has passed under the bridge since 1999, when C [...] Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)

Research

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14 pages, 1909 KiB  
Article
The Janus Role of Adhesion in Chondrogenesis
by Ignasi Casanellas, Anna Lagunas, Yolanda Vida, Ezequiel Pérez-Inestrosa, José A. Andrades, José Becerra and Josep Samitier
Int. J. Mol. Sci. 2020, 21(15), 5269; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155269 - 24 Jul 2020
Cited by 8 | Viewed by 4391
Abstract
Tackling the first stages of the chondrogenic commitment is essential to drive chondrogenic differentiation to healthy hyaline cartilage and minimize hypertrophy. During chondrogenesis, the extracellular matrix continuously evolves, adapting to the tissue adhesive requirements at each stage. Here, we take advantage of previously [...] Read more.
Tackling the first stages of the chondrogenic commitment is essential to drive chondrogenic differentiation to healthy hyaline cartilage and minimize hypertrophy. During chondrogenesis, the extracellular matrix continuously evolves, adapting to the tissue adhesive requirements at each stage. Here, we take advantage of previously developed nanopatterns, in which local surface adhesiveness can be precisely tuned, to investigate its effects on prechondrogenic condensation. Fluorescence live cell imaging, immunostaining, confocal microscopy and PCR analysis are used to follow the condensation process on the nanopatterns. Cell tracking parameters, condensate morphology, cell–cell interactions, mechanotransduction and chondrogenic commitment are evaluated in response to local surface adhesiveness. Results show that only condensates on the nanopatterns of high local surface adhesiveness are stable in culture and able to enter the chondrogenic pathway, thus highlighting the importance of controlling cell–substrate adhesion in the tissue engineering strategies for cartilage repair. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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42 pages, 16295 KiB  
Article
Cell-Fate Determination from Embryo to Cancer Development: Genomic Mechanism Elucidated
by Masa Tsuchiya, Alessandro Giuliani and Kenichi Yoshikawa
Int. J. Mol. Sci. 2020, 21(13), 4581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134581 - 27 Jun 2020
Cited by 8 | Viewed by 3515
Abstract
Elucidation of the genomic mechanism that guides the cell-fate change is one of the fundamental issues of biology. We previously demonstrated that whole genome expression is coordinated by the emergence of a critical point at both the cell-population and single-cell levels through the [...] Read more.
Elucidation of the genomic mechanism that guides the cell-fate change is one of the fundamental issues of biology. We previously demonstrated that whole genome expression is coordinated by the emergence of a critical point at both the cell-population and single-cell levels through the physical principle of self-organized criticality. In this paper, we further examine the genomic mechanism that determines the cell-fate changes from embryo to cancer development. The state of the critical point, acting as the organizing center of the cell fate, determines whether the genome resides in a super- or sub-critical state. In the super-critical state, a specific stochastic perturbation can spread over the entire system through the “genome engine”, an autonomous critical-control genomic system, whereas in the sub-critical state, the perturbation remains at a local level. The cell-fate changes when the genome becomes super-critical. We provide a consistent framework to develop a time-evolutional transition theory for the biological regulation of the cell-fate change. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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Review

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31 pages, 503 KiB  
Review
Dual Effects of Non-Coding RNAs (ncRNAs) in Cancer Stem Cell Biology
by Athina A. Kyriazi, Efstathios Papiris, Konstantinos Kitsos Kalyvianakis, George Sakellaris and Stavroula Baritaki
Int. J. Mol. Sci. 2020, 21(18), 6658; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186658 - 11 Sep 2020
Cited by 18 | Viewed by 3194
Abstract
The identification of cancer stem cells (CSCs) as initiators of carcinogenesis has revolutionized the era of cancer research and our perception for the disease treatment options. Additional CSC features, including self-renewal and migratory and invasive capabilities, have further justified these cells as putative [...] Read more.
The identification of cancer stem cells (CSCs) as initiators of carcinogenesis has revolutionized the era of cancer research and our perception for the disease treatment options. Additional CSC features, including self-renewal and migratory and invasive capabilities, have further justified these cells as putative diagnostic, prognostic, and therapeutic targets. Given the CSC plasticity, the identification of CSC-related biomarkers has been a serious burden in CSC characterization and therapeutic targeting. Over the past decades, a compelling amount of evidence has demonstrated critical regulatory functions of non-coding RNAs (ncRNAs) on the exclusive features of CSCs. We now know that ncRNAs may interfere with signaling pathways, vital for CSC phenotype maintenance, such as Notch, Wnt, and Hedgehog. Here, we discuss the multifaceted contribution of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as representative ncRNA classes, in sustaining the CSC-like traits, as well as the underlying molecular mechanisms of their action in various CSC types. We further discuss the use of CSC-related ncRNAs as putative biomarkers of high diagnostic, prognostic, and therapeutic value. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
17 pages, 271 KiB  
Review
Hypoxia and HIF Signaling: One Axis with Divergent Effects
by Chiara Corrado and Simona Fontana
Int. J. Mol. Sci. 2020, 21(16), 5611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165611 - 05 Aug 2020
Cited by 95 | Viewed by 4858
Abstract
The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation [...] Read more.
The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation of multiple genes involved in many biological processes. Among them, hypoxia-inducible factor (HIF) represents the master regulator of the hypoxia response. The active heterodimeric complex HIF α/β, binding to hypoxia-responsive elements (HREs), determines the induction of at least 100 target genes to restore tissue homeostasis. A growing body of evidence demonstrates that hypoxia signaling can act by generating contrasting responses in cells and tissues. Here, this dual and controversial role of hypoxia and the HIF signaling pathway is discussed, with particular reference to the effects induced on the complex activities of the immune system and on mechanisms determining cell and tissue responses after an injury in both acute and chronic human diseases related to the heart, lung, liver, and kidney. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
13 pages, 602 KiB  
Review
Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity
by Stefan Tukaj
Int. J. Mol. Sci. 2020, 21(15), 5298; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155298 - 26 Jul 2020
Cited by 59 | Viewed by 7185
Abstract
Heat shock proteins (Hsp) are a diverse group of constitutive and/or stress-induced molecules that are categorized into several classes on the basis of their molecular weight. Mammalian Hsp have been mostly regarded as intracellular chaperones that mediate a range of essential cellular functions, [...] Read more.
Heat shock proteins (Hsp) are a diverse group of constitutive and/or stress-induced molecules that are categorized into several classes on the basis of their molecular weight. Mammalian Hsp have been mostly regarded as intracellular chaperones that mediate a range of essential cellular functions, including proper folding of newly synthesized polypeptides, refolding of denatured proteins, protein transport, and stabilization of native proteins’ structures. The well-characterized and highly evolutionarily conserved, stress-inducible 70-kDa heat shock protein (Hsp70), is a key molecular chaperone that is overexpressed in the cell in response to stress of various origin. Hsp70 exhibits an immunosuppressive activity via, e.g., downregulation of the nuclear factor-kappa B (NF-κB) activation, and pharmacological induction of Hsp70 can ameliorate the autoimmune arthritis development in animal models. Moreover, Hsp70 might be passively or actively released from the necrotic or stressed cells, respectively. Highly immunogenic extracellular Hsp70 has been reported to impact both the innate and adaptive immune responses, and to be implicated in the autoimmune reaction. In addition, preclinical studies revealed that immunization with highly conserved Hsp70 peptides could be regarded as a potential treatment target for autoimmune arthritis, such as the rheumatoid arthritis, via induction of antigen-specific regulatory T helper cells (also called Treg). Here, a dual role of the intra- and extracellular Hsp70 is presented in the context of the autoimmune reaction. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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20 pages, 1784 KiB  
Review
p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles
by Sonia Emanuele, Marianna Lauricella, Antonella D’Anneo, Daniela Carlisi, Anna De Blasio, Diana Di Liberto and Michela Giuliano
Int. J. Mol. Sci. 2020, 21(14), 5029; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145029 - 16 Jul 2020
Cited by 39 | Viewed by 5378
Abstract
p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, [...] Read more.
p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, thereby targeting the selected cargo to the autophagosome with consequent autophagic degradation. Beside this function, p62 behaves as an interactive hub in multiple signalling including those mediated by Nrf2, NF-κB, caspase-8, and mTORC1. The protein is thus crucial for the control of oxidative stress, inflammation and cell survival, apoptosis, and metabolic reprogramming, respectively. As a multifunctional protein, p62 falls into the category of those factors that can exert opposite roles in the cells. Chronic p62 accumulation was found in many types of tumors as well as in stress granules present in different forms of neurodegenerative diseases. However, the protein seems to have a Janus behaviour since it may also serve protective functions against tumorigenesis or neurodegeneration. This review describes the diversified roles of p62 through its multiple domains and interactors and specifically focuses on its oncoJanus and neuroJanus roles. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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16 pages, 3014 KiB  
Review
Targeting Wnt/β-Catenin Pathway for Developing Therapies for Hair Loss
by Bu Young Choi
Int. J. Mol. Sci. 2020, 21(14), 4915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144915 - 12 Jul 2020
Cited by 98 | Viewed by 14078
Abstract
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for [...] Read more.
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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15 pages, 733 KiB  
Review
TRANSPARENT TESTA GLABRA1, a Key Regulator in Plants with Multiple Roles and Multiple Function Mechanisms
by Hainan Tian and Shucai Wang
Int. J. Mol. Sci. 2020, 21(14), 4881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144881 - 10 Jul 2020
Cited by 22 | Viewed by 3924
Abstract
TRANSPARENT TESTA GLABRA1 (TTG1) is a WD40 repeat protein. The phenotypes caused by loss-of-function of TTG1 were observed about half a century ago, but the TTG1 gene was identified only about twenty years ago. Since then, TTG1 has been found to be a [...] Read more.
TRANSPARENT TESTA GLABRA1 (TTG1) is a WD40 repeat protein. The phenotypes caused by loss-of-function of TTG1 were observed about half a century ago, but the TTG1 gene was identified only about twenty years ago. Since then, TTG1 has been found to be a plant-specific regulator with multiple roles and multiple functional mechanisms. TTG1 is involved in the regulation of cell fate determination, secondary metabolisms, accumulation of seed storage reserves, plant responses to biotic and abiotic stresses, and flowering time in plants. In some processes, TTG1 may directly or indirectly regulate the expression of downstream target genes via forming transcription activator complexes with R2R3 MYB and bHLH transcription factors. Whereas in other processes, TTG1 may function alone or interact with other proteins to regulate downstream target genes. On the other hand, the studies on the regulation of TTG1 are very limited. So far, only the B3-domain family transcription factor FUSCA3 (FUS3) has been found to regulate the expression of TTG1, phosphorylation of TTG1 affects its interaction with bHLH transcription factor TT2, and TTG1 proteins can be targeted for degradation by the 26S proteasome. Here, we provide an overview of TTG1, including the identification of TTG1, the functions of TTG1, the possible function mechanisms of TTG1, and the regulation of TTG1. We also proposed potential research directions that may shed new light on the regulation and functional mechanisms of TTG1 in plants. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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18 pages, 493 KiB  
Review
The “Janus” Role of C/EBPs Family Members in Cancer Progression
by Manlio Tolomeo and Stefania Grimaudo
Int. J. Mol. Sci. 2020, 21(12), 4308; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124308 - 17 Jun 2020
Cited by 24 | Viewed by 4897
Abstract
CCAAT/enhancer-binding proteins (C/EBPs) constitute a family of transcription factors composed of six members that are critical for normal cellular differentiation in a variety of tissues. They promote the expression of genes through interaction with their promoters. Moreover, they have a key role in [...] Read more.
CCAAT/enhancer-binding proteins (C/EBPs) constitute a family of transcription factors composed of six members that are critical for normal cellular differentiation in a variety of tissues. They promote the expression of genes through interaction with their promoters. Moreover, they have a key role in regulating cellular proliferation through interaction with cell cycle proteins. C/EBPs are considered to be tumor suppressor factors due to their ability to arrest cell growth (contributing to the terminal differentiation of several cell types) and for their role in cellular response to DNA damage, nutrient deprivation, hypoxia, and genotoxic agents. However, C/EBPs can elicit completely opposite effects on cell proliferation and cancer development and they have been described as both tumor promoters and tumor suppressors. This “Janus” role of C/EBPs depends on different factors, such as the type of tumor, the isoform/s expressed in cells, the type of dimerization (homo- or heterodimerization), the presence of inhibitory elements, and the ability to inhibit the expression of other tumor suppressors. In this review, we discuss the implication of the C/EBPs family in cancer, focusing on the molecular aspects that make these transcription factors tumor promoters or tumor suppressors. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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9 pages, 482 KiB  
Perspective
Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity
by Tam Duong, Neal R. Rasmussen and David J. Reiner
Int. J. Mol. Sci. 2020, 21(20), 7610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207610 - 15 Oct 2020
Cited by 2 | Viewed by 2186
Abstract
The C. elegans vulva is an excellent model for the study of developmental biology and cell–cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During C. elegans vulval development, an [...] Read more.
The C. elegans vulva is an excellent model for the study of developmental biology and cell–cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During C. elegans vulval development, an EGF signal from the anchor cell initiates the activation of RasLET-60 > RafLIN-45 > MEKMEK-2 > ERKMPK-1 signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via NotchLIN-12 to develop 2° cells. In addition, RasLET-60 switches effectors to RalGEFRGL-1 > RalRAL-1 to promote 2° fate. Shin et al. (2019) showed that RalGEFRGL-1 is a dual-function protein in VPCs fate patterning. RalGEFRGL-1 functions as a scaffold for PDKPDK-1 > AktAKT-1/2 modulatory signaling to promote 1° fate in addition to propagating the RasLET-60 modulatory signal through RalRAL-1 to promote 2° fate. The deletion of RalGEFRGL-1 increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEFRGL-1 represents an “insulated switch”, whereby the promotion of one signaling activity curtails the promotion of the opposing activity. This property might increase the impact of the switch on fidelity more than two separately encoded proteins could. Understanding how developmental fidelity is controlled will help us to better understand the origins of cancer and birth defects, which occur in part due to the misspecification of cell fates. Full article
(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision)
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