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1.
Mol Neurobiol ; 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38421469

RESUMO

Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair.

2.
Cancers (Basel) ; 15(24)2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38136392

RESUMO

Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial-mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications.

3.
Tissue Cell ; 85: 102240, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37879288

RESUMO

Development, growth, and remodeling of blood vessels occur through an intricate process involving cell differentiation, proliferation, and rearrangement by cell migration under the direction of various signaling pathways. Recent reports highlight that resident and exogenous mesenchymal stromal cells (MSCs) have the potential to regulate the neovascularization process through paracrine secretion of proangiogenic factors. Recent research has established that the vasculogenic potential of MSCs is regulated by several signaling pathways, including the Wnt signaling pathway, and their interplay. These findings emphasize the complex nature of the vasculogenic process and underscore the importance of understanding the underlying molecular mechanisms for the development of effective cell-based therapies in regenerative medicine. This review provides an updated briefing on the canonical and non-canonical Wnt signaling pathways and summarizes the recent reports of both in vitro and in vivo studies with the involvement of MSCs of various sources in the vasculogenic process mediated by Wnt signaling pathways. Here we outline the current understanding of the plausible role of the Wnt signaling pathway, specifically in MSC-regulated angiogenesis.


Assuntos
Células-Tronco Mesenquimais , Via de Sinalização Wnt , Diferenciação Celular , Movimento Celular
4.
Int J Biochem Cell Biol ; 145: 106191, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35272015

RESUMO

Ovarian cancer is a fatal malignancy in women with a low survival rate that demands new therapeutic paradigms. Cancer cells acquire various exclusive alterations to proliferate, invade, metastasize, and escape cell death, acting independently of growth-inducing or growth-inhibiting signals. The nature of cellular signaling in tumorigenesis is interwoven. Wnt signaling is an evolutionarily conserved signaling cascade that has been shown to regulate ovarian cancer pathogenesis. The molecular mechanism of Wnt signaling underlying the development of ovarian cancer, drug resistance, and relapse is not completely understood. Extracellularly secreted Wnt signaling inhibitors are crucial regulators of ovarian cancer tumorigenesis and malignant properties of cancer stem cells. Wnt inhibitors arbitrated modifications affecting Wnt pathway proteins on the cell membranes, in the cytoplasm, and in the nucleus have been shown to span essential contributions in the initiation, progression, and chemoresistance of ovarian cancer. Although many extrinsic inhibitors developed targeting the downstream components of the Wnt signaling pathway, investigating the molecular mechanisms of endogenous secreted inhibitors might substantiate prognostic or therapeutic biomarkers development. Given the importance of Wnt signaling in ovarian cancer, more systematic studies combined with clinical studies are requisite to probe the precise mechanistic interactions of Wnt antagonists in ovarian cancer. This review outlines the latest progress on the Wnt antagonists and ovarian cancer-specific regulators such as micro-RNAs, small molecules, and drugs regulating these Wnt antagonists in ovarian tumourigenesis.


Assuntos
Recidiva Local de Neoplasia , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Transformação Celular Neoplásica , Feminino , Humanos , Neoplasias Ovarianas/patologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
5.
ACS Cent Sci ; 8(2): 282-293, 2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35233459

RESUMO

The functioning of proteins is intimately tied to their fluctuations in the native ensemble. The structural-energetic features that determine fluctuation amplitudes and hence the shape of the underlying landscape, which in turn determine the magnitude of the functional output, are often confounded by multiple variables. Here, we employ the FF1 domain from human p190A RhoGAP protein as a model system to uncover the molecular basis for phosphorylation of a buried tyrosine, which is crucial to the transcriptional activity associated with transcription factor TFII-I. Combining spectroscopy, calorimetry, statistical-mechanical modeling, molecular simulations, and in vitro phosphorylation assays, we show that the FF1 domain samples a diverse array of conformations in its native ensemble, some of which are phosphorylation-competent. Upon eliminating unfavorable charge-charge interactions through a single charge-reversal (K53E) or charge-neutralizing (K53Q) mutation, we observe proportionately lower phosphorylation extents due to the altered structural coupling, damped equilibrium fluctuations, and a more compact native ensemble. We thus establish a conformational selection mechanism for phosphorylation in the FF1 domain with K53 acting as a "gatekeeper", modulating the solvent exposure of the buried tyrosine. Our work demonstrates the role of unfavorable charge-charge interactions in governing functional events through the modulation of native ensemble characteristics, a feature that could be prevalent in ordered protein domains.

6.
Sci Signal ; 10(473)2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28377411

RESUMO

The ability to tune cellular functions in response to nutrient availability has important consequences for immune homeostasis. The activity of the receptor Notch in regulatory T (Treg) cells, which suppress the functions of effector T cells, is indispensable for Treg cell survival under conditions of diminished nutrient supply. Anti-apoptotic signaling induced by the Notch1 intracellular domain (NIC) originates from the cytoplasm and is spatially decoupled from the nuclear, largely transcriptional functions of NIC. We showed that Sirtuin 1 (Sirt1), which is an NAD+ (nicotinamide adenine dinucleotide)-dependent lysine deacetylase that inhibits NIC-dependent gene transcription, stabilized NIC proximal to the plasma membrane to promote the survival and function of activated Treg cells. Sirt1 was required for NIC-dependent protection from apoptosis in cell lines but not for the activity of the anti-apoptotic protein Bcl-xL. In addition, a variant NIC protein in which four lysines were mutated to arginines (NIC4KR) retained anti-apoptotic activity, but was not regulated by Sirt1, and reconstituted the functions of nonnuclear NIC in Notch1-deficient Treg cells. Loss of Sirt1 compromised Treg cell survival, resulting in antigen-induced T cell proliferation and inflammation in two mouse models. Thus, the Sirt1-Notch interaction may constitute an important checkpoint that tunes noncanonical Notch1 signaling.


Assuntos
Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Sirtuína 1/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Arginina/genética , Arginina/imunologia , Arginina/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Immunoblotting , Lisina/genética , Lisina/imunologia , Lisina/metabolismo , Camundongos , Microscopia de Fluorescência , Mutação de Sentido Incorreto , Interferência de RNA , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Linfócitos T Reguladores/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/imunologia , Proteína bcl-X/metabolismo
7.
Int J Cell Biol ; 2014: 674753, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24688545

RESUMO

Tissue homeostasis is a dynamic process involving proliferation and the removal of redundant or damaged cells. This is exemplified in the coordinated deletion-triggered by limiting trophic factors/cytokines in the extracellular milieu-of differentiated T cells overproduced during the mammalian immune response. However, mechanisms by which extracellular cues are perceived and transduced as apoptotic triggers remain incompletely understood. T-effectors are dependent on cytokines for survival and undergo apoptosis following cytokine withdrawal. Here we report that leptomycin B (LMB), an inhibitor of nuclear export machinery, protected T-effectors from apoptosis implicating a nuclear intermediate in the apoptotic pathway. Evidence is presented that the linker histone H1.2 localizes to the cytoplasm, by a mechanism sensitive to regulation by LMB, to activate apoptotic signaling culminating in nuclear and mitochondrial damage in T-effectors in response to cytokine deprivation. H1.2 is detected in a complex with the proapoptotic mitochondrial resident Bak and its subcellular localization regulated by Jun-N-terminal kinase (JNK), an intermediate in the apoptotic cascade in T-effectors. These data suggest that metabolic stressors may impinge on H1.2 dynamics favoring its activity at the mitochondrion, thereby functioning as a molecular switch for T-effector apoptosis.

8.
PLoS One ; 7(9): e43718, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22957031

RESUMO

Cellular differentiation programs are accompanied by large-scale changes in nuclear organization and gene expression. In this context, accompanying transitions in chromatin assembly that facilitates changes in gene expression and cell behavior in a developmental system are poorly understood. Here, we address this gap and map structural changes in chromatin organization during murine T-cell development, to describe an unusual heterogeneity in chromatin organization and associated functional correlates in T-cell lineage. Confocal imaging of DNA assembly in cells isolated from bone marrow, thymus and spleen reveal the emergence of heterogeneous patterns in DNA organization in mature T-cells following their exit from the thymus. The central DNA pattern dominated in immature precursor cells in the thymus whereas both central and peripheral DNA patterns were observed in naïve and memory cells in circulation. Naïve T-cells with central DNA patterns exhibited higher mechanical pliability in response to compressive loads in vitro and transmigration assays in vivo, and demonstrated accelerated expression of activation-induced marker CD69. T-cell activation was characterized by marked redistribution of DNA assembly to a central DNA pattern and increased nuclear size. Notably, heterogeneity in DNA patterns recovered in cells induced into quiescence in culture, suggesting an internal regulatory mechanism for chromatin reorganization. Taken together, our results uncover an important component of plasticity in nuclear organization, reflected in chromatin assembly, during T-cell development, differentiation and transmigration.


Assuntos
Movimento Celular , DNA/metabolismo , Ativação Linfocitária , Linfócitos T/imunologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células da Medula Óssea/citologia , Linhagem da Célula , Núcleo Celular/metabolismo , Cromatina/metabolismo , Células-Tronco Hematopoéticas/citologia , Lectinas Tipo C/metabolismo , Camundongos , Microscopia Confocal/métodos , Modelos Biológicos , Modelos Estatísticos , Análise de Sequência de DNA , Baço/citologia , Linfócitos T/citologia
9.
Sci Signal ; 5(234): ra53, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22827997

RESUMO

Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor-dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (T(regs)) in vitro and in vivo and was compromised by T cell-specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1(-/-) T(regs) from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin complex 2 (mTORC2) for this cell survival function. Biochemical and imaging approaches revealed a membrane-proximal complex containing NICD and the mTORC2 component Rictor, and this complex was stabilized by specific interactions with the Notch ligand Delta-like-1 and mediated the survival of T(regs). Together, our evidence for the spatial control of Notch and the crosstalk of Notch signaling with other pathways reveals coupling between the localization of Notch and diverse intracellular signaling pathways.


Assuntos
Apoptose/imunologia , Sobrevivência Celular/imunologia , Receptor Notch1/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Western Blotting , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Citometria de Fluxo , Técnicas de Inativação de Genes , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina , Receptor Cross-Talk/imunologia , Receptor Notch1/genética , Receptor Notch1/imunologia , Transativadores/metabolismo , Fatores de Transcrição
10.
Proc Natl Acad Sci U S A ; 107(15): 6882-7, 2010 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-20339081

RESUMO

Survival of differentiated cells is one of several processes regulated by Notch activity, although the general principles underlying this function remain to be characterized. Here, we probe the mechanism underlying Notch-mediated survival, building on emerging evidence that apoptotic responses coordinated by specialized intermediates converge on mitochondria, identifying a core event in death pathways. The Bcl-2 family protein Bax is one such intermediate, which in a unifying response to diverse apoptotic stimuli nucleates multiprotein assemblies on mitochondria, committing cells to irrevocable damage. Using Bax as the prototype stimulus, we analyze Notch signaling for potential interactions with mitochondria, probe intrinsic properties of the Notch receptor, and describe key intermediates in the Notch-activated signaling cascade. Ligand-dependent processing was necessary to generate the Notch intracellular domain (NIC) although signaling was independent of canonical interactions with nuclear factors. Notably, antiapoptotic activity was recapitulated by NIC recombinants, localized outside the nucleus, and compromised by enforced nuclear sequestration. NIC signaled via the kinase Akt to prevent the loss of mitochondrial function, contiguity, and consequent nuclear damage, outcomes critically depend on mitochondrial remodeling proteins Mitofusins-(Mfn)-1 and 2. Thus, the NIC-Akt-Mfn signaling cascade identifies a pathway regulating cell-survival, independent of canonical functions associated with NIC activity.


Assuntos
Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Receptores Notch/metabolismo , Animais , Apoptose , Células COS , Sobrevivência Celular , Chlorocebus aethiops , GTP Fosfo-Hidrolases/química , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Proteínas de Membrana Transportadoras/química , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/metabolismo
11.
BMC Cell Biol ; 8: 16, 2007 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-17519046

RESUMO

BACKGROUND: Bcl-2 family proteins are key regulators of mitochondrial integrity and comprise both pro- and anti-apoptotic proteins. Bax a pro-apoptotic member localizes as monomers in the cytosol of healthy cells and accumulates as oligomers in mitochondria of apoptotic cells. The Bcl-2 homology-3 (BH3) domain regulates interactions within the family, but regions other than BH3 are also critical for Bax function. Thus, the N-terminus has been variously implicated in targeting to mitochondria, interactions with BH3-only proteins as well as conformational changes linked to Bax activation. The transmembrane (TM) domains (alpha5-alpha6 helices in the core and alpha9 helix in the C-terminus) in Bax are implicated in localization to mitochondria and triggering cytotoxicity. Here we have investigated N-terminus modulation of TM function in the context of regulation by the anti-apoptotic protein Bcl-xL. RESULTS: Deletion of 29 amino acids in the Bax N-terminus (Bax 30-192) caused constitutive accumulation at mitochondria and triggered high levels of cytotoxicity, not inhibited by Bcl-xL. Removal of the TM domains (Bax 30-105) abrogated mitochondrial localization but resulted in Bcl-xL regulated activation of endogenous Bax and Bax-Bak dependent apoptosis. Inclusion of the alpha5-alpha6 helices/TMI domain (Bax 30-146) phenocopied Bax 30-192 as it restored mitochondrial localization, Bcl-xL independent cytotoxicity and was not dependent on endogenous Bax-Bak. Inhibition of function and localization by Bcl-xL was restored in Bax 1-146, which included the TM1 domain. Regardless of regulation by Bcl-xL, all N-terminal deleted constructs immunoprecipitated Bcl-xLand converged on caspase-9 dependent apoptosis consistent with mitochondrial involvement in the apoptotic cascade. Sub-optimal sequence alignments of Bax and Bcl-xL indicated a sequence similarity between the alpha5-alpha6 helices of Bax and Bcl-xL. Alanine substitutions of three residues (T14A-S15A-S16A) in the N-terminus (Bax-Ala3) attenuated regulation by the serine-threonine kinase Akt/PKB but not by Bcl-xL indicative of distinct regulatory mechanisms. CONCLUSION: Collectively, the analysis of Bax deletion constructs indicates that the N-terminus drives conformational changes facilitating inhibition of cytotoxicity by Bcl-xL. We speculate that the TM1 helices may serve as 'structural antagonists' for BH3-Bcl-xL interactions, with this function being regulated by the N-terminus in the intact protein.


Assuntos
Apoptose/genética , Análise Mutacional de DNA , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Motivos de Aminoácidos , Animais , Células Cultivadas , Clonagem Molecular , Humanos , Camundongos , Mitocôndrias/metabolismo , Ligação Proteica , Conformação Proteica , Subunidades Proteicas/metabolismo , Alinhamento de Sequência , Deleção de Sequência/genética , Proteína X Associada a bcl-2/química , Proteína X Associada a bcl-2/genética , Proteína bcl-X/química , Proteína bcl-X/genética
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