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1.
EMBO J ; 31(5): 1147-59, 2012 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-22227519

RESUMO

RASSF2 belongs to the Ras-association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2(-/-) BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co-culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2(-/-) osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2(-/-) mice. Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)-κB during both osteoclast and osteoblast differentiation. RASSF2 associated with IκB kinase (IKK) α and ß forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant-negative form of IKK into Rassf2(-/-) osteoclast or osteoblast precursors inhibited NF-κB hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF-κB signalling.


Assuntos
Hematopoese , Quinase I-kappa B/metabolismo , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Reabsorção Óssea , Diferenciação Celular , Proliferação de Células , Quinase I-kappa B/antagonistas & inibidores , Camundongos , Camundongos Knockout , NF-kappa B/biossíntese , Osteogênese , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Supressoras de Tumor/deficiência
2.
Proc Natl Acad Sci U S A ; 110(19): 7732-7, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23620511

RESUMO

Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Células Epiteliais Alveolares/citologia , Animais , Apoptose , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Cruzamentos Genéticos , Via de Sinalização Hippo , Homeostase , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Proteínas Serina-Treonina Quinases/fisiologia , Serina-Treonina Quinase 3 , Transdução de Sinais , Fatores de Tempo
3.
J Immunol ; 190(4): 1623-30, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23303667

RESUMO

Bone mineralization is a normal physiological process, whereas ectopic calcification of soft tissues is a pathological process that leads to irreversible tissue damage. We have established a coxsackievirus B3 (CVB3)-infected mouse model that manifests both osteoporosis and ectopic calcification specifically in heart, pancreas, and lung. The CVB3-infected mice showed increased serum concentrations of both cytokines including IL-1ß, TNF-α, and the receptor activator of NF-κB ligand (RANKL) that stimulate osteoclast formation and of the osteoclast-derived protein tartrate-resistant acid phosphatase 5b. They exhibited more osteoclasts in bone, with no change in the number of osteoblasts, and a decrease in bone formation and the serum concentration of osteoblast-produced osteocalcin. These results indicate that CVB3-induced osteoporosis is likely due to upregulation of osteoclast formation and function, in addition to decreased osteoblast activity. In addition, the serum in the CVB3-infected mice contained a high inorganic phosphate content, which causes ectopic calcification. RANKL treatment induced an increase in the in vitro cardiac fibroblast calcification by inorganic phosphate via the upregulation of osteogenic BMP2, SPARC, Runx2, Fra-1, and NF-κB signaling. We finally observed that i.p. administration of RANK-Fc, a recombinant antagonist of RANKL, prevented bone loss as well as ectopic calcification in CVB3-infected mice. Thus, our results indicate that RANKL may contribute to both abnormal calcium deposition in soft tissues and calcium depletion in bone. In addition, our animal model should provide a tool for the development of new therapeutic agents for calcium disturbance in soft and hard tissues.


Assuntos
Calcinose/prevenção & controle , Infecções por Coxsackievirus/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Osteoporose/prevenção & controle , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Calcinose/patologia , Calcinose/virologia , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia , Ossificação Heterotópica/virologia , Osteoblastos/patologia , Osteoblastos/virologia , Osteoclastos/patologia , Osteoclastos/virologia , Osteoporose/virologia , Ligante RANK/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética
4.
J Clin Invest ; 134(11)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38652549

RESUMO

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.


Assuntos
Linfócitos T CD8-Positivos , Matriz Extracelular , Sarcoma , Microambiente Tumoral , Proteínas de Sinalização YAP , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Animais , Microambiente Tumoral/imunologia , Camundongos , Proteínas de Sinalização YAP/imunologia , Proteínas de Sinalização YAP/genética , Humanos , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Sarcoma/imunologia , Sarcoma/patologia , Sarcoma/genética , Sarcoma/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/imunologia , Colágeno Tipo VI/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/imunologia , Oncogenes , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia
5.
JCI Insight ; 8(20)2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37870957

RESUMO

The histone demethylase JMJD2A/KDM4A facilitates prostate cancer development, yet how JMJD2A function is regulated has remained elusive. Here, we demonstrate that SET7/9-mediated methylation on 6 lysine residues modulated JMJD2A. Joint mutation of these lysine residues suppressed JMJD2A's ability to stimulate the MMP1 matrix metallopeptidase promoter upon recruitment by the ETV1 transcription factor. Mutation of just 3 methylation sites (K505, K506, and K507) to arginine residues (3xR mutation) was sufficient to maximally reduce JMJD2A transcriptional activity and also decreased its binding to ETV1. Introduction of the 3xR mutation into DU145 prostate cancer cells reduced in vitro growth and invasion and also severely compromised tumorigenesis. Consistently, the 3xR genotype caused transcriptome changes related to cell proliferation and invasion pathways, including downregulation of MMP1 and the NPM3 nucleophosmin/nucleoplasmin gene. NPM3 downregulation phenocopied and its overexpression rescued, to a large degree, the 3xR mutation in DU145 cells, suggesting that NPM3 was a seminal downstream effector of methylated JMJD2A. Moreover, we found that NPM3 was overexpressed in prostate cancer and might be indicative of disease aggressiveness. SET7/9-mediated lysine methylation of JMJD2A may aggravate prostate tumorigenesis in a manner dependent on NPM3, implying that the SET7/9→JMJD2A→NPM3 axis could be targeted for therapy.


Assuntos
Histona Desmetilases , Histona Desmetilases com o Domínio Jumonji , Neoplasias da Próstata , Humanos , Masculino , Carcinogênese , Transformação Celular Neoplásica , Histona Desmetilases/genética , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metilação , Neoplasias da Próstata/genética
6.
Biochem Biophys Res Commun ; 391(1): 969-73, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19962960

RESUMO

The tumor suppressor, RASSF2 (Ras association domain family 2), is frequently downregulated in a number of cancers. Although exogenously expressed RASSF2 induces apoptotic cell death, the precise roles of RASSF2 under pro-apoptotic conditions remain largely unknown. Here, we demonstrate that MST1 (mammalian sterile 20-like kinase 1) regulates RASSF2 protein stability. Knockdown of MST1 in cancer cells markedly destabilizes RASSF2, and Mst1-deficient mice show reduced Rassf2 protein levels in several organs. Conversely, RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex, which inhibits the MST-FOXO3 signaling pathway. RASSF2 also engages the JNK pathway and induces apoptosis in an MST1-independent manner. Collectively, these findings indicate that MST1 is a major determinant of RASSF2 protein stability, and suggest that RASSF2 acts in a complex manner that extends beyond simple protein-protein association to play an important role in MST1 regulation.


Assuntos
Neoplasias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Linhagem Celular , Ativação Enzimática , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Estabilidade Proteica , Transdução de Sinais , Proteínas Supressoras de Tumor/genética
7.
Int J Oncol ; 57(6): 1319-1332, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33174020

RESUMO

ETS variant 1 (ETV1) is an oncogenic transcription factor. However, its role in colorectal cancer has remained understudied. The present study demonstrated that ETV1 downregulation led to reduced HCT116 colorectal cancer cell growth and clonogenic activity. Furthermore, the ETV1 mRNA levels were enhanced in colorectal tumors and were associated with disease severity. In addition, ETV1 directly bound to Jumonji C domain­containing (JMJD) 1A, a histone demethylase known to promote colon cancer. ETV1 and JMJD1A, but not a catalytically inactive mutant thereof, cooperated in inducing the matrix metalloproteinase (MMP)1 gene promoter that was similar to the cooperation between ETV1 and another histone demethylase, JMJD2A. RNA­sequencing revealed multiple potential ETV1 target genes in HCT116 cells, including the FOXQ1 and TBX6 transcription factor genes. Moreover, JMJD1A co­regulated FOXQ1 and other ETV1 target genes, but not TBX6, whereas JMJD2A downregulation had no impact on FOXQ1 as well as TBX6 transcription. Accordingly, the FOXQ1 gene promoter was stimulated by ETV1 and JMJD1A in a cooperative manner, and both ETV1 and JMJD1A bound to the FOXQ1 promoter. Notably, the overexpression of FOXQ1 partially reversed the growth inhibitory effects of ETV1 ablation on HCT116 cells, whereas TBX6 impaired HCT116 cell growth and may thereby dampen the oncogenic activity of ETV1. The latter also revealed for the first time, to the best of our knowledge, a potential tumor suppressive function of TBX6. Taken together, the present study uncovered a ETV1/JMJD1A­FOXQ1 axis that may drive colorectal tumorigenesis.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição/metabolismo , Carcinogênese/genética , Proliferação de Células/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição Forkhead/genética , Células HCT116 , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Metaloproteinase 1 da Matriz/genética , Mutagênese Sítio-Dirigida , Mutação , Regiões Promotoras Genéticas , Análise de Sobrevida , Proteínas com Domínio T/genética , Fatores de Tempo , Fatores de Transcrição/genética
8.
Sci Rep ; 9(1): 8186, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160676

RESUMO

The ETS transcription factor ETV1 is frequently overexpressed in aggressive prostate cancer, which is one underlying cause of this disease. Accordingly, transgenic mice that prostate-specifically overexpress ETV1 develop prostatic intraepithelial neoplasia. However, progression to the adenocarcinoma stage is stifled in these mice, suggesting that inhibitory pathways possibly preclude ETV1 from exerting its full oncogenic potential. Here we provide evidence that TGF-ß/SMAD signaling represents such an inhibitory pathway. First, we discovered that ETV1 forms complexes with SMAD4. Second, SMAD2, SMAD3 and SMAD4 overexpression impaired ETV1's ability to stimulate gene transcription. Third, TGF-ß1 inhibited ETV1-induced invasion by benign RWPE-1 prostate cells. Fourth, increased expression of SMAD3 and SMAD4 was observable in prostates of ETV1 transgenic mice. Conversely, we found that ETV1 may enhance TGF-ß signaling in PC3 prostate cancer cells, revealing a different facet of the ETV1/TGF-ß interplay. Altogether, these data provide more insights into the regulation and action of ETV1 and additionally suggest that TGF-ß/SMAD signaling exerts its tumor suppressive activity, at least in part, by curtailing the oncogenic potential of ETV1 in prostatic lesions.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/metabolismo , Proteínas Smad/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasia Prostática Intraepitelial/metabolismo , Transdução de Sinais
9.
Oncol Lett ; 16(5): 6652-6662, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30405805

RESUMO

Jumonji C domain-containing 1A (JMJD1A) is a histone demethylase and epigenetic regulator that has been implicated in cancer development. In the current study, its mRNA and protein expression was analyzed in human colorectal tumors. It was demonstrated that JMJD1A levels were increased and correlated with a more aggressive phenotype. Downregulation of JMJD1A in human HCT116 colorectal cancer cells caused negligible growth defects, but robustly decreased clonogenic activity. Transcriptome analysis revealed that JMJD1A downregulation led to multiple changes in HCT116 cells, including inhibition of MYC- and MYCN-regulated pathways and stimulation of the TP53 tumor suppressor response. One gene identified to be stimulated by JMJD1A was α-thalassemia/mental retardation syndrome X-linked (ATRX), which encodes for a chromatin remodeler. The JMJD1A protein, but not a catalytically inactive mutant, activated the ATRX gene promoter and JMJD1A also affected levels of dimethylation on lysine 9 of histone H3. Similar to JMJD1A, ATRX was significantly overexpressed in human colorectal tumors and correlated with increased disease recurrence and lethality. Furthermore, ATRX downregulation in HCT116 cells reduced their growth and clonogenic activity. Accordingly, upregulation of ATRX may represent one mechanism by which JMJD1A promotes colorectal cancer. In addition, the data presented in this study suggest that the current notion of ATRX as a tumor suppressor is incomplete and that ATRX might context dependently also function as a tumor promoter.

10.
Nat Commun ; 6: 6380, 2015 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-25871009

RESUMO

Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, the involvement of epsins in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signalling effector, dishevelled (Dvl2), and impairing Wnt signalling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signalling in colon cancer cells to ensure robust colon cancer progression. The pro-carcinogenic role of Epsins suggests that they are potential therapeutic targets to combat colon cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Adenocarcinoma/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Fosfoproteínas/genética , Via de Sinalização Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Azoximetano , Sítios de Ligação , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Proteínas Desgrenhadas , Células HT29 , Humanos , Camundongos , Camundongos Knockout , Fosfoproteínas/metabolismo , Cultura Primária de Células , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Dodecilsulfato de Sódio , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Clin Invest ; 125(12): 4349-64, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26571402

RESUMO

Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium-targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin-interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium-specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/farmacologia , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peptídeos/farmacologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Motivos de Aminoácidos , Animais , Camundongos , Camundongos Knockout , Metástase Neoplásica , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptídeos/genética , Peptídeos/metabolismo , Estrutura Terciária de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Sci Signal ; 7(347): ra97, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25314967

RESUMO

Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin-deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Sistema Linfático/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Alelos , Animais , Proliferação de Células , Separação Celular , Cruzamentos Genéticos , Endocitose , Células Endoteliais/citologia , Feminino , Citometria de Fluxo , Proteínas de Fluorescência Verde/química , Indóis/química , Ligantes , Linfonodos/patologia , Linfedema/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naftalenos/química , Plasmídeos/metabolismo , Transdução de Sinais , Fatores de Tempo
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