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1.
Appl Immunohistochem Mol Morphol ; 30(2): 119-125, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34545848

RESUMO

Psoriasis is a chronic, immune-mediated inflammatory disease which pathogenesis is closely linked to γδ T cells. Recently, a critical role for butyrophilin 3A1 (BTN3A1) in mediating the activation of Vγ9Vδ2 T cells, which are reported to redistribute from blood to the perturbed skin lesions in psoriasis, has been proposed. Additional molecular partners, including RhoB and periplakin, have also been speculated to interact with BTN3A1 in modulating Vγ9Vδ2 T-cell activation. Immunohistochemical staining was performed to examine the expressions of BTN3A1, RhoB, and the plakin family members, including periplakin, epiplakin, and envoplakin in the psoriasis vulgaris lesions as compared with the normal control. The expressions of BTN3A1 and RhoB were found significantly upregulated in the psoriatic lesions. Besides, a downregulation of periplakin and an upregulation of epiplakin were noticed in the psoriasis vulgaris lesions. Our data suggest that BTN3A1 and RhoB might participate in the pathogenesis of psoriasis through Vγ9Vδ2 T-cell responses. In addition, a potential involvement of the plakin protein family, especially periplakin and epiplakin, in psoriasis pathology was proposed.


Assuntos
Psoríase , Receptores de Antígenos de Linfócitos T gama-delta , Antígenos CD/metabolismo , Butirofilinas/química , Butirofilinas/metabolismo , Humanos , Plaquinas , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
2.
Nat Commun ; 12(1): 6795, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34815391

RESUMO

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14-mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.


Assuntos
Desmoplaquinas/genética , Esofagite Eosinofílica/genética , Mucosa Esofágica/patologia , Plaquinas/genética , Adolescente , Biópsia , Calpaína/metabolismo , Estudos de Casos e Controles , Criança , Análise Mutacional de DNA , Desmoplaquinas/metabolismo , Desmossomos/patologia , Esofagite Eosinofílica/patologia , Mucosa Esofágica/citologia , Feminino , Células HEK293 , Células HaCaT , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Plaquinas/metabolismo , Proteólise , RNA-Seq , Análise de Célula Única , Sequenciamento Completo do Exoma
4.
Cell Commun Signal ; 19(1): 55, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001250

RESUMO

The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer. Video Abstract.


Assuntos
Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Plaquinas/metabolismo , Animais , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Plaquinas/química
6.
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
8.
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
9.
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
10.
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 , 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
11.
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.


Cells adopt a wide array of irregular and bumpy shapes, which are scaffolded by an internal structure called the cytoskeleton. This network of filaments can deform the cell membrane the way tent poles frame a canvas. Cells contain three types of cytoskeleton elements (actin filaments, intermediate filaments, and microtubules), each with unique chemical and mechanical properties. One of the main roles of the cytoskeleton is to create protrusions, a range of structures that 'stick out' of a cell to allow movement and interactions with the environment. Both actin filaments and microtubules help form protrusions, but the role of intermediate filaments remains unclear. Microridges are a type of protrusion found on cells covered by mucus, for instance on the surface of the eye, inside the mouth, or on fish skin. These small bumps are organised on the membrane of a cell in fingerprint-like arrangements. Scientists know that actin networks are necessary for microridges to form; yet, many structures supported by actin filaments are not stable over time, suggesting that another component of the cytoskeleton might be lending support. Intermediate filaments are the strongest, most stable type of cytoskeleton element, and they can connect to actin filaments via linker proteins. However, research has yet to show that this kind of cooperation happens in any membrane protrusion. Here, Inaba et al. used high-resolution microscopy to monitor microridge development in the skin of live fish. In particular, they focused on a type of intermediate filaments known as keratin filaments. This revealed that, inside microridges, the keratin and actin networks form alongside each other, with linker proteins called Envoplakin and Periplakin connecting the two structures together. Genetic experiments revealed that Envoplakin and Periplakin must attach to actin for microridges to start forming. However, the two proteins bind to keratin for protrusions to grow. This work therefore highlights how intermediate filaments and linker proteins contribute to the formation of these structures. Many tissues must be covered in mucus to remain moist and healthy. As microridges likely contribute to mucus retention, the findings by Inaba et al. may help to better understand how disorders linked to problems in mucus emerge.


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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
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