2024

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18 pages, 4074 KiB

Open AccessArticle

Phosphodiesterases 4B and 4D Differentially Regulate cAMP Signaling in Calcium Handling Microdomains of Mouse Hearts

by Axel E. Kraft, Nadja I. Bork, Hariharan Subramanian, Nikoleta Pavlaki, Antonio V. Failla, Bernd Zobiak, Marco Conti and Viacheslav O. Nikolaev

Cells 2024, 13(6), 476; https://doi.org/10.3390/cells13060476 - 08 Mar 2024

Viewed by 721

Abstract

The ubiquitous second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) regulates cardiac excitation-contraction coupling (ECC) by signaling in discrete subcellular microdomains. Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations of PDE4 activity in human hearts [...] Read more.

The ubiquitous second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) regulates cardiac excitation-contraction coupling (ECC) by signaling in discrete subcellular microdomains. Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations of PDE4 activity in human hearts has been shown to result in arrhythmias and heart failure. Here, we sought to systematically investigate specific roles of PDE4B and PDE4D in the regulation of cAMP dynamics in three distinct subcellular microdomains, one of them located at the caveolin-rich plasma membrane which harbors the L-type calcium channels (LTCCs), as well as at two sarco/endoplasmic reticulum (SR) microdomains centered around SR Ca²⁺-ATPase (SERCA2a) and cardiac ryanodine receptor type 2 (RyR2). Transgenic mice expressing Förster Resonance Energy Transfer (FRET)-based cAMP-specific biosensors targeted to caveolin-rich plasma membrane, SERCA2a and RyR2 microdomains were crossed to PDE4B-KO and PDE4D-KO mice. Direct analysis of the specific effects of both PDE4 subfamilies on local cAMP dynamics was performed using FRET imaging. Our data demonstrate that all three microdomains are differentially regulated by these PDE4 subfamilies. Whereas both are involved in cAMP regulation at the caveolin-rich plasma membrane, there are clearly two distinct cAMP microdomains at the SR formed around RyR2 and SERCA2a, which are preferentially controlled by PDE4B and PDE4D, respectively. This correlates with local cAMP-dependent protein kinase (PKA) substrate phosphorylation and arrhythmia susceptibility. Immunoprecipitation assays confirmed that PDE4B is associated with RyR2 along with PDE4D. Stimulated Emission Depletion (STED) microscopy of immunostained cardiomyocytes suggested possible co-localization of PDE4B with both sarcolemmal and RyR2 microdomains. In conclusion, our functional approach could show that both PDE4B and PDE4D can differentially regulate cardiac cAMP microdomains associated with calcium homeostasis. PDE4B controls cAMP dynamics in both caveolin-rich plasma membrane and RyR2 vicinity. Interestingly, PDE4B is the major regulator of the RyR2 microdomain, as opposed to SERCA2a vicinity, which is predominantly under PDE4D control, suggesting a more complex regulatory pattern than previously thought, with multiple PDEs acting at the same location. Full article

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2023

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13 pages, 2185 KiB

Open AccessArticle

CRISPR/Cas9 Knock-Out in Primary Neonatal and Adult Cardiomyocytes Reveals Distinct cAMP Dynamics Regulation by Various PDE2A and PDE3A Isoforms

by Egor B. Skryabin, Kirstie A. De Jong, Hariharan Subramanian, Nadja I. Bork, Alexander Froese, Boris V. Skryabin and Viacheslav O. Nikolaev

Cells 2023, 12(11), 1543; https://doi.org/10.3390/cells12111543 - 04 Jun 2023

Viewed by 1522

Abstract

Cyclic nucleotide phosphodiesterases 2A (PDE2A) and PDE3A play an important role in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-to-cAMP crosstalk. Each of these PDEs has up to three distinct isoforms. However, their specific contributions to cAMP dynamics are [...] Read more.

Cyclic nucleotide phosphodiesterases 2A (PDE2A) and PDE3A play an important role in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-to-cAMP crosstalk. Each of these PDEs has up to three distinct isoforms. However, their specific contributions to cAMP dynamics are difficult to explore because it has been challenging to generate isoform-specific knock-out mice or cells using conventional methods. Here, we studied whether the CRISPR/Cas9 approach for precise genome editing can be used to knock out Pde2a and Pde3a genes and their distinct isoforms using adenoviral gene transfer in neonatal and adult rat cardiomyocytes. Cas9 and several specific gRNA constructs were cloned and introduced into adenoviral vectors. Primary adult and neonatal rat ventricular cardiomyocytes were transduced with different amounts of Cas9 adenovirus in combination with PDE2A or PDE3A gRNA constructs and cultured for up to 6 (adult) or 14 (neonatal) days to analyze PDE expression and live cell cAMP dynamics. A decline in mRNA expression for PDE2A (~80%) and PDE3A (~45%) was detected as soon as 3 days post transduction, with both PDEs being reduced at the protein level by >50–60% in neonatal cardiomyocytes (after 14 days) and >95% in adult cardiomyocytes (after 6 days). This correlated with the abrogated effects of selective PDE inhibitors in the live cell imaging experiments based on using cAMP biosensor measurements. Reverse transcription PCR analysis revealed that only the PDE2A2 isoform was expressed in neonatal myocytes, while adult cardiomyocytes expressed all three PDE2A isoforms (A1, A2, and A3) which contributed to the regulation of cAMP dynamics as detected by live cell imaging. In conclusion, CRISPR/Cas9 is an effective tool for the in vitro knock-out of PDEs and their specific isoforms in primary somatic cells. This novel approach suggests distinct regulation of live cell cAMP dynamics by various PDE2A and PDE3A isoforms in neonatal vs. adult cardiomyocytes. Full article

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19 pages, 2700 KiB

Open AccessArticle

cAMP Compartmentalisation in Human Myometrial Cells

by Alice Varley, Andreas Koschinski, Mark R. Johnson and Manuela Zaccolo

Cells 2023, 12(5), 718; https://doi.org/10.3390/cells12050718 - 24 Feb 2023

Viewed by 1462

Abstract

Preterm birth is the leading cause of childhood mortality and morbidity. A better understanding of the processes that drive the onset of human labour is essential to reduce the adverse perinatal outcomes associated with dysfunctional labour. Beta-mimetics, which activate the myometrial cyclic adenosine [...] Read more.

Preterm birth is the leading cause of childhood mortality and morbidity. A better understanding of the processes that drive the onset of human labour is essential to reduce the adverse perinatal outcomes associated with dysfunctional labour. Beta-mimetics, which activate the myometrial cyclic adenosine monophosphate (cAMP) system, successfully delay preterm labour, suggesting a key role for cAMP in the control of myometrial contractility; however, the mechanisms underpinning this regulation are incompletely understood. Here we used genetically encoded cAMP reporters to investigate cAMP signalling in human myometrial smooth muscle cells at the subcellular level. We found significant differences in the dynamics of the cAMP response in the cytosol and at the plasmalemma upon stimulation with catecholamines or prostaglandins, indicating compartment-specific handling of cAMP signals. Our analysis uncovered significant disparities in the amplitude, kinetics, and regulation of cAMP signals in primary myometrial cells obtained from pregnant donors compared with a myometrial cell line and found marked response variability between donors. We also found that in vitro passaging of primary myometrial cells had a profound impact on cAMP signalling. Our findings highlight the importance of cell model choice and culture conditions when studying cAMP signalling in myometrial cells and we provide new insights into the spatial and temporal dynamics of cAMP in the human myometrium. Full article

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2022

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17 pages, 4422 KiB

Open AccessArticle

Compartmentation of cGMP Signaling in Induced Pluripotent Stem Cell Derived Cardiomyocytes during Prolonged Culture

by Maria Faleeva, Ivan Diakonov, Prashant Srivastava, Masoud Ramuz, Gaia Calamera, Kjetil Wessel Andressen, Nadja Bork, Lorenza Tsansizi, Marie-Victoire Cosson, Andreia Sofia Bernardo, Viacheslav Nikolaev and Julia Gorelik

Cells 2022, 11(20), 3257; https://doi.org/10.3390/cells11203257 - 17 Oct 2022

Cited by 1 | Viewed by 1854

Abstract

The therapeutic benefit of stimulating the cGMP pathway as a form of treatment to combat heart failure, as well as other fibrotic pathologies, has become well established. However, the development and signal compartmentation of this crucial pathway has so far been overlooked. We [...] Read more.

The therapeutic benefit of stimulating the cGMP pathway as a form of treatment to combat heart failure, as well as other fibrotic pathologies, has become well established. However, the development and signal compartmentation of this crucial pathway has so far been overlooked. We studied how the three main cGMP pathways, namely, nitric oxide (NO)-cGMP, natriuretic peptide (NP)-cGMP, and β₃-adrenoreceptor (AR)-cGMP, mature over time in culture during cardiomyocyte differentiation from human pluripotent stem cells (hPSC-CMs). After introducing a cGMP sensor for Förster Resonance Energy Transfer (FRET) microscopy, we used selective phosphodiesterase (PDE) inhibition to reveal cGMP signal compartmentation in hPSC-CMs at various times of culture. Methyl-β-cyclodextrin was employed to remove cholesterol and thus to destroy caveolae in these cells, where physical cGMP signaling compartmentalization is known to occur in adult cardiomyocytes. We identified PDE3 as regulator of both the NO-cGMP and NP-cGMP pathway in the early stages of culture. At the late stage, the role of the NO-cGMP pathway diminished, and it was predominantly regulated by PDE1, PDE2, and PDE5. The NP-cGMP pathway shows unrestricted locally and unregulated cGMP signaling. Lastly, we observed that maturation of the β₃-AR-cGMP pathway in prolonged cultures of hPSC-CMs depends on the accumulation of caveolae. Overall, this study highlighted the importance of structural development for the necessary compartmentation of the cGMP pathway in maturing hPSC-CMs. Full article

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2021

Jump to: 2024, 2023, 2022, 2020

14 pages, 2959 KiB

Open AccessArticle

Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis

by Zhuofu Ni and Xiaodong Cheng

Cells 2021, 10(10), 2750; https://doi.org/10.3390/cells10102750 - 14 Oct 2021

Cited by 2 | Viewed by 2006

Abstract

Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are one of the several families of cellular effectors of the prototypical second messenger cAMP. To understand the origin and molecular evolution of EPAC proteins, we performed a comprehensive phylogenetic analysis of EPAC1 and [...] Read more.

Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are one of the several families of cellular effectors of the prototypical second messenger cAMP. To understand the origin and molecular evolution of EPAC proteins, we performed a comprehensive phylogenetic analysis of EPAC1 and EPAC2. Our study demonstrates that unlike its cousin PKA, EPAC proteins are only present in multicellular Metazoa. Within the EPAC family, EPAC1 is only associated with chordates, while EPAC2 spans the entire animal kingdom. Despite a much more contemporary origin, EPAC1 proteins show much more sequence diversity among species, suggesting that EPAC1 has undergone more selection and evolved faster than EPAC2. Phylogenetic analyses of the individual cAMP binding domain (CBD) and guanine nucleotide exchange (GEF) domain of EPACs, two most conserved regions between the two isoforms, further reveal that EPAC1 and EPAC2 are closely clustered together within both the larger cyclic nucleotide receptor and RAPGEF families. These results support the notion that EPAC1 and EPAC2 share a common ancestor resulting from a fusion between the CBD of PKA and the GEF from RAPGEF1. On the other hand, the two terminal extremities and the RAS-association (RA) domains show the most sequence diversity between the two isoforms. Sequence diversities within these regions contribute significantly to the isoform-specific functions of EPACs. Importantly, unique isoform-specific sequence motifs within the RA domain have been identified. Full article

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23 pages, 2148 KiB

Open AccessReview

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

by Dolores Viña, Nuria Seoane, Elisardo C. Vasquez and Manuel Campos-Toimil

Cells 2021, 10(8), 1951; https://doi.org/10.3390/cells10081951 - 31 Jul 2021

Cited by 17 | Viewed by 4343

Abstract

The vascular hypothesis used to explain the pathophysiology of Alzheimer’s disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood–brain barrier (BBB) permeability plays [...] Read more.

The vascular hypothesis used to explain the pathophysiology of Alzheimer’s disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood–brain barrier (BBB) permeability plays a prominent role in this process. It is generally accepted that, in physiological conditions, cyclic AMP (cAMP) plays a key role in maintaining BBB permeability by regulating the formation of tight junctions between endothelial cells of the brain microvasculature. It is also known that intracellular cAMP signaling is highly compartmentalized into small nanodomains and localized cAMP changes are sufficient at modifying the permeability of the endothelial barrier. This spatial and temporal distribution is maintained by the enzymes involved in cAMP synthesis and degradation, by the location of its effectors, and by the existence of anchor proteins, as well as by buffers or different cytoplasm viscosities and intracellular structures limiting its diffusion. This review compiles current knowledge on the influence of cAMP compartmentalization on the endothelial barrier and, more specifically, on the BBB, laying the foundation for a new therapeutic approach in the treatment of AD. Full article

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19 pages, 4440 KiB

Open AccessReview

Ca²⁺ Microdomains, Calcineurin and the Regulation of Gene Transcription

by Gerald Thiel, Tobias Schmidt and Oliver G. Rössler

Cells 2021, 10(4), 875; https://doi.org/10.3390/cells10040875 - 12 Apr 2021

Cited by 21 | Viewed by 2876

Abstract

Ca²⁺ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca²⁺ [...] Read more.

Ca²⁺ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca²⁺ concentration upon stimulation. The elevated Ca²⁺ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca²⁺ at different locations in the cell. Ca²⁺ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca²⁺ ions. A major function of the rise in intracellular Ca²⁺ is the change of the genetic expression pattern of the cell via the activation of Ca²⁺-responsive transcription factors. It has been proposed that Ca²⁺-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca²⁺. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca²⁺ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca²⁺ induces an intracellular signaling cascade, involving the activation of the Ca²⁺/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca²⁺/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca²⁺ concentration in the cytoplasm and the nucleus, the role of Ca²⁺ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca²⁺ signaling and gene expression. Full article

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15 pages, 3115 KiB

Open AccessArticle

Cardiac Hypertrophy Changes Compartmentation of cAMP in Non-Raft Membrane Microdomains

by Nikoleta Pavlaki, Kirstie A. De Jong, Birgit Geertz, Viacheslav O. Nikolaev and Alexander Froese

Cells 2021, 10(3), 535; https://doi.org/10.3390/cells10030535 - 03 Mar 2021

Cited by 3 | Viewed by 2240

Abstract

3′,5′-Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which plays critical roles in cardiac function and disease. In adult mouse ventricular myocytes (AMVMs), several distinct functionally relevant microdomains with tightly compartmentalized cAMP signaling have been described. At least two types of microdomains [...] Read more.

3′,5′-Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which plays critical roles in cardiac function and disease. In adult mouse ventricular myocytes (AMVMs), several distinct functionally relevant microdomains with tightly compartmentalized cAMP signaling have been described. At least two types of microdomains reside in AMVM plasma membrane which are associated with caveolin-rich raft and non-raft sarcolemma, each with distinct cAMP dynamics and their differential regulation by receptors and cAMP degrading enzymes phosphodiesterases (PDEs). However, it is still unclear how cardiac disease such as hypertrophy leading to heart failure affects cAMP signals specifically in the non-raft membrane microdomains. To answer this question, we generated a novel transgenic mouse line expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor E1-CAAX targeted to non-lipid raft membrane microdomains of AMVMs and subjected these mice to pressure overload induced cardiac hypertrophy. We could detect specific changes in PDE3-dependent compartmentation of β-adrenergic receptor induced cAMP in non-raft membrane microdomains which were clearly different from those occurring in caveolin-rich sarcolemma. This indicates differential regulation and distinct responses of these membrane microdomains to cardiac remodeling. Full article

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2020

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14 pages, 2307 KiB

Open AccessArticle

Age-Dependent Maturation of iPSC-CMs Leads to the Enhanced Compartmentation of β₂AR-cAMP Signalling

by Alveera Hasan, Neda Mohammadi, Aisha Nawaz, Thusharika Kodagoda, Ivan Diakonov, Sian E. Harding and Julia Gorelik

Cells 2020, 9(10), 2275; https://doi.org/10.3390/cells9102275 - 12 Oct 2020

Cited by 7 | Viewed by 3327

Abstract

The ability to differentiate induced-pluripotent stem cells into cardiomyocytes (iPSC-CMs) has opened up novel avenues for potential cardiac therapies. However, iPSC-CMs exhibit a range of somewhat immature functional properties. This study explored the development of the beta-adrenergic receptor (βAR) pathway, which is crucial [...] Read more.

The ability to differentiate induced-pluripotent stem cells into cardiomyocytes (iPSC-CMs) has opened up novel avenues for potential cardiac therapies. However, iPSC-CMs exhibit a range of somewhat immature functional properties. This study explored the development of the beta-adrenergic receptor (βAR) pathway, which is crucial in regulating contraction and signifying the health and maturity of myocytes. We explored the compartmentation of β₂AR-signalling and phosphodiesterases (PDEs) in caveolae, as functional nanodomains supporting the mature phenotype. Förster Resonance Energy Transfer (FRET) microscopy was used to study the cyclic adenosine monophosphate (cAMP) levels in iPSC-CMs at day 30, 60, and 90 following βAR subtype-specific stimulation. Subsequently, the PDE2, PDE3, and PDE4 activity was investigated using specific inhibitors. Cells were treated with methyl-β-cyclodextrin (MβCD) to remove cholesterol as a method of decompartmentalising β₂AR. As iPSC-CMs mature with a prolonged culture time, the caveolae density is increased, leading to a reduction in the overall cytoplasmic cAMP signal stimulated through β₂AR (but not β₁AR). Pan-phosphodiesterase inhibition or caveolae depletion leads to an increase in the β₂AR-stimulated cytoplasmic cAMP. Moreover, with time in culture, the increase in the βAR-dependent cytoplasmic cAMP becomes more sensitive to cholesterol removal. The regulation of the β₂AR response by PDE2 and 4 is similarly increased with the time in culture. We conclude that both the β₂AR and PDEs are restricted to the caveolae nanodomains, and thereby exhibit a tighter spatial restriction over the cAMP signal in late-stage compared to early iPSC-CMs. Full article

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14 pages, 1150 KiB

Open AccessReview

Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?

by Karina Formoso, Frank Lezoualc’h and Jeanne Mialet-Perez

Cells 2020, 9(9), 1954; https://doi.org/10.3390/cells9091954 - 25 Aug 2020

Cited by 6 | Viewed by 2763

Abstract

The compartmentation of signaling processes is accomplished by the assembly of protein complexes called signalosomes. These signaling platforms colocalize enzymes, substrates, and anchoring proteins into specific subcellular compartments. Exchange protein directly activated by cAMP 1 (EPAC1) is an effector of the second messenger, [...] Read more.

The compartmentation of signaling processes is accomplished by the assembly of protein complexes called signalosomes. These signaling platforms colocalize enzymes, substrates, and anchoring proteins into specific subcellular compartments. Exchange protein directly activated by cAMP 1 (EPAC1) is an effector of the second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) that is associated with multiple roles in several pathologies including cardiac diseases. Both EPAC1 intracellular localization and molecular partners are key players in the regulation of cell fate, which may have important therapeutic potential. In this review, we summarize the recent findings on EPAC1 structure, regulation, and pharmacology. We describe the importance of EPAC1 subcellular distribution in its biological action, paying special attention to its nuclear localization and mechanism of action leading to cardiomyocyte hypertrophy. In addition, we discuss the role of mitochondrial EPAC1 in the regulation of cell death. Depending on the cell type and stress condition, we present evidence that supports either a protective or detrimental role of EPAC1 activation. Full article

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18 pages, 1465 KiB

Open AccessReview

Understanding Glioblastoma Biomarkers: Knocking a Mountain with a Hammer

by Malak Hassn Mesrati, Amir Barzegar Behrooz, Asmaa Y. Abuhamad and Amir Syahir

Cells 2020, 9(5), 1236; https://doi.org/10.3390/cells9051236 - 16 May 2020

Cited by 41 | Viewed by 5212

Abstract

Gliomas are the most frequent and deadly form of human primary brain tumors. Among them, the most common and aggressive type is the high-grade glioblastoma multiforme (GBM), which rapidly grows and renders patients a very poor prognosis. Meanwhile, cancer stem cells (CSCs) have [...] Read more.

Gliomas are the most frequent and deadly form of human primary brain tumors. Among them, the most common and aggressive type is the high-grade glioblastoma multiforme (GBM), which rapidly grows and renders patients a very poor prognosis. Meanwhile, cancer stem cells (CSCs) have been determined in gliomas and play vital roles in driving tumor growth due to their competency in self-renewal and proliferation. Studies of gliomas have recognized CSCs via specific markers. This review comprehensively examines the current knowledge of the most significant CSCs markers in gliomas in general and in glioblastoma in particular and specifically focuses on their outlook and importance in gliomas CSCs research. We suggest that CSCs should be the superior therapeutic approach by directly targeting the markers. In addition, we highlight the association of these markers with each other in relation to their cascading pathways, and interactions with functional miRNAs, providing the role of the networks axes in glioblastoma signaling pathways. Full article

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17 pages, 1360 KiB

Open AccessReview

Modulation of mTORC1 Signaling Pathway by HIV-1

by Burkitkan Akbay, Anna Shmakova, Yegor Vassetzky and Svetlana Dokudovskaya

Cells 2020, 9(5), 1090; https://doi.org/10.3390/cells9051090 - 28 Apr 2020

Cited by 20 | Viewed by 4505

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host [...] Read more.

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication. Full article

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25 pages, 6202 KiB

Open AccessFeature PaperArticle

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

by Damiano Cosimo Rigiracciolo, Nijiro Nohata, Rosamaria Lappano, Francesca Cirillo, Marianna Talia, Domenica Scordamaglia, J. Silvio Gutkind and Marcello Maggiolini

Cells 2020, 9(4), 1010; https://doi.org/10.3390/cells9041010 - 18 Apr 2020

Cited by 59 | Viewed by 6600 | Correction

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype. Full article

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28 pages, 2458 KiB

Open AccessReview

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

by Jasmina Dimitrova-Shumkovska, Ljupcho Krstanoski and Leo Veenman

Cells 2020, 9(4), 870; https://doi.org/10.3390/cells9040870 - 02 Apr 2020

Cited by 46 | Viewed by 5945

Abstract

Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, [...] Read more.

Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders. Full article

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