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1.
Immunity ; 33(5): 671-84, 2010 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21093323

RESUMO

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Homeodomínio/genética , Ativação Linfocitária/genética , Receptores Notch/genética , Animais , Linfócitos B/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Linfócitos T/imunologia , Timo/imunologia , Fatores de Transcrição HES-1
2.
Breast Cancer Res ; 16(5): 433, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25212966

RESUMO

INTRODUCTION: Interleukin-like epithelial-to-mesenchymal transition inducer (ILEI) is an essential cytokine in tumor progression that is upregulated in several cancers, and its altered subcellular localization is a predictor of poor survival in human breast cancer. However, the regulation of ILEI activity and the molecular meaning of its altered localization remain elusive. METHODS: The influence of serum withdrawal, broad-specificity protease inhibitors, different serine proteases and plasminogen depletion on the size and amount of the secreted ILEI protein was investigated by Western blot analysis of EpRas cells. Proteases with ILEI-processing capacity were identified by carrying out an in vitro cleavage assay. Murine mammary tumor and metastasis models of EpC40 and 4T1 cells overexpressing different mutant forms of ILEI were used-extended with in vivo aprotinin treatment for the inhibition of ILEI-processing proteases-to test the in vivo relevance of proteolytic cleavage. Stable knockdown of urokinase plasminogen activator receptor (uPAR) in EpRas cells was performed to investigate the involvement of uPAR in ILEI secretion. The subcellular localization of the ILEI protein in tumor cell lines was analyzed by immunofluorescence. Immunohistochemistry for ILEI localization and uPAR expression was performed on two human breast cancer arrays, and ILEI and uPAR scores were correlated with the metastasis-free survival of patients. RESULTS: We demonstrate that secreted ILEI requires site-specific proteolytic maturation into its short form for its tumor-promoting function, which is executed by serine proteases, most efficiently by plasmin. Noncleaved ILEI is tethered to fibronectin-containing fibers of the extracellular matrix through a propeptide-dependent interaction. In addition to ILEI processing, plasmin rapidly increases ILEI secretion by mobilizing its intracellular protein pool in a uPAR-dependent manner. Elevated ILEI secretion correlates with an altered subcellular localization of the protein, most likely representing a shift into secretory vesicles. Moreover, altered subcellular ILEI localization strongly correlates with high tumor cell-associated uPAR protein expression, as well as with poor survival, in human breast cancer. CONCLUSIONS: Our findings point out extracellular serine proteases, in particular plasmin, and uPAR as valuable therapeutic targets against ILEI-driven tumor progression and emphasize the prognostic relevance of ILEI localization and a combined ILEI-uPAR marker analysis in human breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Citocinas/fisiologia , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/fisiologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Fibrinolisina/metabolismo , Humanos , Estimativa de Kaplan-Meier , Elastase de Leucócito/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Camundongos Nus , Transplante de Neoplasias , Calicreína Plasmática/metabolismo , Processamento de Proteína Pós-Traducional , Transporte Proteico , Proteólise
3.
Cell Rep ; 4(3): 437-44, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23933255

RESUMO

The transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell-mediated tumor surveillance.


Assuntos
Quinase 8 Dependente de Ciclina/metabolismo , Células Matadoras Naturais/imunologia , Leucemia Experimental/imunologia , Neoplasias Mamárias Experimentais/imunologia , Melanoma Experimental/imunologia , Fator de Transcrição STAT1/metabolismo , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Vigilância Imunológica , Células Matadoras Naturais/metabolismo , Leucemia Experimental/metabolismo , Leucemia Experimental/patologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais
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