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3.
Elife ; 102021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33779546

RESUMO

While the mechanisms by which chemical signals control cell fate have been well studied, the impact of mechanical inputs on cell fate decisions is not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through linker of nucleoskeleton and cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.


Assuntos
Epiderme/fisiologia , Mecanotransdução Celular/fisiologia , Lâmina Nuclear/fisiologia , Plaquinas/genética , Animais , Diferenciação Celular , Feminino , Integrinas/metabolismo , Lamina Tipo A/metabolismo , Camundongos , Plaquinas/metabolismo
4.
Parasitol Res ; 120(3): 1067-1076, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33515065

RESUMO

Giardia intestinalis is a human parasite that causes a diarrheal disease in developing countries. G. intestinalis has a cytoskeleton (CSK) composed of microtubules and microfilaments, and the Giardia genome does not code for the canonical CSK-binding proteins described in other eukaryotic cells. To identify candidate actin and tubulin cross-linking proteins, we performed a BLAST analysis of the Giardia genome using a spectraplakins consensus sequence as a query. Based on the highest BLAST score, we selected a 259-kDa sequence designated as a cytoskeleton linker protein (CLP259). The sequence was cloned in three fragments and characterized by immunoprecipitation, confocal microscopy, and mass spectrometry (MS). CLP259 was located in the cytoplasm in the form of clusters of thick rods and colocalized with actin at numerous sites and with tubulin in the median body. Immunoprecipitation followed by mass spectrometry revealed that CLP259 interacts with structural proteins such as giardins, SALP-1, axonemal, and eight coiled-coils. The vesicular traffic proteins detected were Mu adaptin, Vacuolar ATP synthase subunit B, Bip, Sec61 alpha, NSF, AP complex subunit beta, and dynamin. These results indicate that CLP259 in trophozoites is a CSK linker protein for actin and tubulin and could act as a scaffold protein driving vesicular traffic.


Assuntos
Actinas/metabolismo , Giardia lamblia/metabolismo , Plaquinas/metabolismo , Tubulina (Proteína)/metabolismo , Actinas/química , Sequência de Aminoácidos , Animais , Anquirinas/química , Sequência de Bases , Western Blotting , Biologia Computacional , Sequência Consenso , Citoplasma/química , Citoesqueleto/química , Citoesqueleto/fisiologia , Citoesqueleto/ultraestrutura , Dinaminas/análise , Feminino , Imunofluorescência , Giardia lamblia/química , Giardia lamblia/ultraestrutura , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Plaquinas/química , Alinhamento de Sequência , Tubulina (Proteína)/química
5.
Int J Mol Sci ; 21(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066346

RESUMO

Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients.


Assuntos
Inibidores de Calcineurina/farmacologia , Vesículas Extracelulares/metabolismo , Nefropatias/prevenção & controle , Transplante de Rim/efeitos adversos , Proteoma/metabolismo , Adulto , Idoso , Biomarcadores/urina , Inibidores de Calcineurina/uso terapêutico , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Feminino , Fibrose , Sobrevivência de Enxerto , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/etiologia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Plaquinas/urina , Proteoma/genética , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Uroplaquinas/urina
6.
Elife ; 92020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894222

RESUMO

Actin filaments and microtubules create diverse cellular protrusions, but intermediate filaments, the strongest and most stable cytoskeletal elements, are not known to directly participate in the formation of protrusions. Here we show that keratin intermediate filaments directly regulate the morphogenesis of microridges, elongated protrusions arranged in elaborate maze-like patterns on the surface of mucosal epithelial cells. We found that microridges on zebrafish skin cells contained both actin and keratin filaments. Keratin filaments stabilized microridges, and overexpressing keratins lengthened them. Envoplakin and periplakin, plakin family cytolinkers that bind F-actin and keratins, localized to microridges, and were required for their morphogenesis. Strikingly, plakin protein levels directly dictate microridge length. An actin-binding domain of periplakin was required to initiate microridge morphogenesis, whereas periplakin-keratin binding was required to elongate microridges. These findings separate microridge morphogenesis into distinct steps, expand our understanding of intermediate filament functions, and identify microridges as protrusions that integrate actin and intermediate filaments.


Assuntos
Extensões da Superfície Celular , Queratinas , Plaquinas , Animais , Extensões da Superfície Celular/química , Extensões da Superfície Celular/metabolismo , Células Epiteliais/química , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Filamentos Intermediários/química , Filamentos Intermediários/metabolismo , Queratinas/química , Queratinas/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Plaquinas/química , Plaquinas/metabolismo , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Pele/citologia , Peixe-Zebra , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismo
7.
Eur J Dermatol ; 30(4): 338-344, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32969793

RESUMO

BACKGROUND: Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid diagnosis of AIBDs. OBJECTIVES: To evaluate the diagnostic accuracy based on BIOCHIP mosaic (FA1501-1005-60) in Chinese patients with AIBDs. MATERIALS AND METHODS: Seventy-seven patients with AIBDs and 20 controls were enrolled. The BIOCHIP mosaic was performed using both serum and plasma samples. RESULTS: Based on BIOCHIP mosaic, the data from paired plasma and serum samples demonstrated a high degree of concordance (Cohen's kappa = 0.896-1.000) for autoantibodies against Dsg1, Dsg3, BP180-NC16A-4X, BP230gC, prickle-cell desmosomes, and pemphigoid antigens. Moreover, BIOCHIP mosaic also demonstrated a high degree of consistency for the detection rate of anti-Dsg1, Dsg3, plakins, BP180-NC16A-4X and non-collagenous domain of type VII collagen autoantibodies for the diagnosis of pemphigus foliaceus (77.3%), pemphigus vulgaris (88.6%), paraneoplastic pemphigus (100.0%), bullous pemphigoid (92.8%) and epidermolysis bullosa acquisita (99.0%), respectively. CONCLUSION: Using BIOCHIP mosaic, serum and plasma samples may be used interchangeably at 1/10 dilution. Overall, the BIOCHIP mosaic was shown to be a useful and accurate tool for the diagnosis of AIBDs.


Assuntos
Doenças Autoimunes/diagnóstico , Técnica Indireta de Fluorescência para Anticorpo/métodos , Dermatopatias Vesiculobolhosas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Distonina/imunologia , Humanos , Proteínas com Domínio LIM/imunologia , Pessoa de Meia-Idade , Colágenos não Fibrilares/imunologia , Plaquinas/imunologia , Valor Preditivo dos Testes , Dermatopatias Vesiculobolhosas/imunologia , Proteínas Supressoras de Tumor/imunologia , Adulto Jovem
8.
Biochim Biophys Acta Mol Cell Res ; 1867(11): 118801, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32712070

RESUMO

The plakin family of cytolinkers interacts with intermediate filaments (IFs) through plakin repeat domain (PRD) and linker modules. Recent structure/function studies have established the molecular basis of envoplakin-PRD and periplakin-linker interactions with vimentin. Both plakin modules share a broad basic groove which recognizes acidic rod elements on IFs, a mechanism that is applicable to other plakin family members. This review postulates a universal IF engagement mechanism that illuminates the specific effects of pathogenic mutations associated with diseases including arrhythmogenic right ventricular cardiomyopathy, and reveals how diverse plakin proteins offer tailored IF tethering to ensure stable, dynamic and regulated cellular structures.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Filamentos Intermediários/genética , Plaquinas/genética , Sequência de Aminoácidos/genética , Displasia Arritmogênica Ventricular Direita/patologia , Humanos , Mutação/genética , Plaquinas/classificação , Ligação Proteica/genética , Domínios Proteicos/genética , Vimentina/genética
9.
Medicine (Baltimore) ; 99(22): e20419, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481437

RESUMO

We explored the potential of combining carcinoembryonic antigen (CEA) and salivary mRNAs for gastric cancer (GC) detection.This study included 2 phases of study: a biomarker discovery phase and an independent validation phase. In the discovery phase, we measured CEA levels in blood samples and expression level of messenger RNAs (SPINK7, PPL, SEMA4B, SMAD4) in saliva samples of 140 GC patients and 140 healthy controls. We evaluated the clinical performance of each biomarker and developed a predictive model using machine-learning algorithm to differentiate GC patients and healthy controls.Our biomarker panel successfully discriminated GC patients from healthy controls with both high sensitivity (0.94) and high specificity (0.91). We next applied our biomarker panel in the independent validation phase, in which we recruited a new patient cohort of 60 GC patients and 60 healthy controls. Using our biomarker panel, the GC patients were discriminated from healthy controls in the validation phase, with sensitivity of 0.92 and specificity of 0.87.A combination of blood CEA and salivary messenger RNA could be a promising approach to detect GC.


Assuntos
Antígeno Carcinoembrionário/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/diagnóstico , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Diagnóstico por Computador , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Plaquinas/metabolismo , Estudo de Prova de Conceito , Saliva/metabolismo , Semaforinas/metabolismo , Sensibilidade e Especificidade , Inibidores de Serinopeptidase do Tipo Kazal/metabolismo , Proteína Smad4/metabolismo , Neoplasias Gástricas/metabolismo
10.
Med Microbiol Immunol ; 209(4): 447-459, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535702

RESUMO

Tetraspanins are master organizers of the cell membrane. Recent evidence suggests that tetraspanins themselves may become crowded by virus particles and that these crowds/aggregates co-internalize with the viral particles. Using microscopy, we studied human papillomavirus (HPV) type 16-dependent aggregates on the cell surface of tetraspanin overexpressing keratinocytes. We find that aggregates are (1) rich in at least two different tetraspanins, (2) three-dimensional architectures extending up to several micrometers into the cell, and (3) decorated intracellularly by filamentous actin. Moreover, in cells not overexpressing tetraspanins, we note that obscurin-like protein 1 (OBSL1), which is thought to be a cytoskeletal adaptor, associates with filamentous actin. We speculate that HPV contact with the cell membrane could trigger the formation of a large tetraspanin web. This web may couple the virus contact site to the intracellular endocytic actin machinery, possibly involving the cytoskeletal adaptor protein OBSL1. Functionally, such a tetraspanin web could serve as a virus entry platform, which is co-internalized with the virus particle.


Assuntos
Actinas/fisiologia , Proteínas do Citoesqueleto/fisiologia , Papillomavirus Humano 16/fisiologia , Tetraspanina 24/fisiologia , Tetraspanina 30/fisiologia , Endocitose , Células HaCaT/virologia , Células HeLa/ultraestrutura , Células HeLa/virologia , Células Hep G2/virologia , Humanos , Microscopia Confocal , Microscopia Eletrônica , Infecções por Papillomavirus/virologia , Plaquinas/fisiologia , Vírion/fisiologia , Vírion/ultraestrutura , Internalização do Vírus
11.
Commun Biol ; 3(1): 83, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081916

RESUMO

Plakin proteins form connections that link the cell membrane to the intermediate filament cytoskeleton. Their interactions are mediated by a highly conserved linker domain through an unresolved mechanism. Here analysis of the human periplakin linker domain structure reveals a bi-lobed module transected by an electropositive groove. Key basic residues within the periplakin groove are vital for co-localization with vimentin in human cells and compromise direct binding which also requires acidic residues D176 and E187 in vimentin. We propose a model whereby basic periplakin linker domain residues recognize acidic vimentin side chains and form a complementary binding groove. The model is shared amongst diverse linker domains and can be used to investigate the effects of pathogenic mutations in the desmoplakin linker associated with arrhythmogenic right ventricular cardiomyopathy. Linker modules either act solely or collaborate with adjacent plakin repeat domains to create strong and adaptable tethering within epithelia and cardiac muscle.


Assuntos
Plaquinas/química , Plaquinas/metabolismo , Vimentina/química , Vimentina/metabolismo , Sequência de Aminoácidos , Aminoácidos Acídicos/química , Aminoácidos Acídicos/genética , Aminoácidos Acídicos/metabolismo , Ácido Aspártico/metabolismo , Ácido Glutâmico/metabolismo , Células HeLa , Humanos , Filamentos Intermediários/química , Filamentos Intermediários/metabolismo , Modelos Moleculares , Mutação de Sentido Incorreto , Plaquinas/genética , Ligação Proteica/genética , Domínios e Motivos de Interação entre Proteínas/genética , Estrutura Quaternária de Proteína , Vimentina/genética
12.
Mol Biol Cell ; 30(18): 2422-2434, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31268833

RESUMO

Planar cell polarity (PCP) regulates coordinated cellular polarity among neighboring cells to establish a polarity axis parallel to the plane of the tissue. Disruption in PCP results in a range of developmental anomalies and diseases. A key feature of PCP is the polarized and asymmetric localization of several membrane PCP proteins, which is essential to establish the polarity axis to orient cells coordinately. However, the machinery that regulates the asymmetric partition of PCP proteins remains largely unknown. In the present study, we show Van gogh-like 2 (Vangl2) in early and recycling endosomes as made evident by colocalization with diverse endosomal Rab proteins. Vangl2 biochemically interacts with adaptor protein-3 complex (AP-3). Using short hairpin RNA knockdown, we found that Vangl2 subcellular localization was modified in AP-3-depleted cells. Moreover, Vangl2 membrane localization within the cochlea is greatly reduced in AP-3-deficient mocha mice, which exhibit profound hearing loss. In inner ears from AP-3-deficient mocha mice, we observed PCP-dependent phenotypes, such as misorientation and deformation of hair cell stereociliary bundles and disorganization of hair cells characteristic of defects in convergent extension that is driven by PCP. These findings demonstrate a novel role of AP-3-mediated sorting mechanisms in regulating PCP proteins.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Complexo 3 de Proteínas Adaptadoras/metabolismo , Animais , Movimento Celular/fisiologia , Polaridade Celular/fisiologia , Orelha Interna/citologia , Orelha Interna/metabolismo , Endossomos/genética , Endossomos/metabolismo , Células Ciliadas Auditivas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Plaquinas/metabolismo , Transporte Proteico , Fatores de Transcrição/metabolismo
13.
J Comput Biol ; 26(10): 1130-1139, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31180245

RESUMO

This study aimed to identify stromal molecular signatures associated with breast and prostate cancer. The microarray data GSE26910 was downloaded from Gene Expression Omnibus database, including six invasive breast tumor stroma, six matched normal controls, six invasive prostate tumor stroma, and six matched controls. The differentially expressed genes (DEGs) in invasive breast and prostate tumors stroma were, respectively, identified. Then common stromal genes (B_P.DEGs) were further screened. Protein-protein interaction (PPI) network was constructed and Gene Ontology analysis was performed. Besides, gene-chemical interactions were mapped in Comparative Toxicogenomics Database to screen the chemicals related to feature genes. The results showed that, in total, 16 B_P.DEGs were identified. Thereinto, only seven B_P.DEGs were mapped into PPI, and only four functional modules (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I (ADCYAP1R1) module, aspartoacylase (ASPA) module, glutathione S-transferase mu 5 (GSTM5) module, and periplakin (PPL) module) were involved in important biological processes associated with cancer progression. In addition, the chemicals, such as dihydrotestosterone, apocarotenal, testosterone, and progesterone, were screened for the roles of feature genes in the progression of breast and prostate cancer. In conclusion, ADCYAP1R1, GSTM5, and PPL were stromal molecular signatures and might play a key role in the progression of breast and prostate cancer.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Genômica , Glutationa Transferase/genética , Humanos , Masculino , Invasividade Neoplásica/genética , Plaquinas/genética , Neoplasias da Próstata/metabolismo , Mapas de Interação de Proteínas , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética
14.
Sci Rep ; 9(1): 2357, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787334

RESUMO

The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted.


Assuntos
Cloridrato de Erlotinib/uso terapêutico , Plaquinas/genética , Biomarcadores Farmacológicos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Genótipo , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fosforilação , Polimorfismo de Nucleotídeo Único/genética , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
15.
Mol Biol Cell ; 30(3): 357-369, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30516430

RESUMO

The architecture of the cytoskeleton and its remodeling are tightly regulated by dynamic reorganization of keratin-rich intermediate filaments. Plakin family proteins associate with the network of intermediate filaments (IFs) and affect its reorganization during migration, differentiation, and response to stress. The smallest plakin, periplakin (PPL), interacts specifically with intermediate filament proteins K8, K18, and vimentin via its C-terminal linker domain. Here, we show that periplakin is SUMOylated at a conserved lysine in its linker domain (K1646) preferentially by small ubiquitin-like modifier 1 (SUMO1). Our data indicate that PPL SUMOylation is essential for the proper reorganization of the keratin IF network. Stresses perturbing intermediate-filament and cytoskeletal architecture induce hyper--SUMOylation of periplakin. Okadaic acid induced hyperphosphorylation-dependent collapse of the keratin IF network results in a similar hyper-SUMOylation of PPL. Strikingly, exogenous overexpression of a non-SUMOylatable periplakin mutant (K1646R) induced aberrant bundling and loose network interconnections of the keratin filaments. Time-lapse imaging of cells expressing the K1646R mutant showed the enhanced sensitivity of keratin filament collapse upon okadaic acid treatment. Our data identify an important regulatory role for periplakin SUMOylation in dynamic reorganization and stability of keratin IFs.


Assuntos
Filamentos Intermediários/metabolismo , Queratinas/metabolismo , Plaquinas/metabolismo , Sumoilação , Sequência de Aminoácidos , Sequência Conservada , Citoesqueleto/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Células HeLa , Humanos , Lisina/metabolismo , Modelos Biológicos , Plaquinas/química , Domínios Proteicos , Estresse Fisiológico
17.
JCI Insight ; 3(5)2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29515024

RESUMO

Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis development after bleomycin-induced injury. Notably, Ppl deletion promoted an antiinflammatory alveolar environment linked to profound changes in type 2 alveolar epithelial cells, including overexpression of antiinflammatory cytokines, decreased expression of profibrotic mediators, and altered cell signaling with a reduced response to TGF-ß1. These results identify periplakin as a previously unidentified regulator of the response to injury in the lung.


Assuntos
Células Epiteliais Alveolares/patologia , Fibrose Pulmonar Idiopática/patologia , Lesão Pulmonar/patologia , Plaquinas/metabolismo , Mucosa Respiratória/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/imunologia , Animais , Bleomicina/administração & dosagem , Bleomicina/toxicidade , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/imunologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plaquinas/genética , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Transdução de Sinais/imunologia
18.
Int J Mol Sci ; 19(4)2018 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-29587367

RESUMO

Cancer is a highly lethal disease that is characterized by aberrant cell proliferation, migration, and adhesion, which are closely related to the dynamic changes of cytoskeletons and cytoskeletal-adhesion. These will further result in cell invasion and metastasis. Plakins are a family of giant cytolinkers that connect cytoskeletal elements with each other and to junctional complexes. With various isoforms composed of different domain structures, mammalian plakins are broadly expressed in numerous tissues. They play critical roles in many cellular processes, including cell proliferation, migration, adhesion, and signaling transduction. As these cellular processes are key steps in cancer development, mammalian plakins have in recent years attracted more and more attention for their potential roles in cancer. Current evidence shows the importance of mammalian plakins in various human cancers and demonstrates mammalian plakins as potential biomarkers for cancer. Here, we introduce the basic characteristics of mammalian plakins, review the recent advances in understanding their biological functions, and highlight their roles in human cancers, based on studies performed by us and others. This will provide researchers with a comprehensive understanding of mammalian plakins, new insights into the development of cancer, and novel targets for cancer diagnosis and therapy.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Plaquinas/genética , Plaquinas/metabolismo , Animais , Movimento Celular , Proliferação de Células , Citoesqueleto/metabolismo , Humanos , Camundongos , Camundongos Knockout , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/patologia , Transdução de Sinais
19.
Int J Mol Sci ; 19(2)2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29373494

RESUMO

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents.


Assuntos
Antineoplásicos/farmacologia , Proteínas dos Microfilamentos/metabolismo , Plaquinas/metabolismo , Animais , Antineoplásicos/química , Sítios de Ligação , Humanos , Proteínas dos Microfilamentos/química , Moduladores de Mitose/química , Moduladores de Mitose/farmacologia , Plaquinas/química , Ligação Proteica
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