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1.
Am J Physiol Lung Cell Mol Physiol ; 299(5): L607-20, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20656893

RESUMO

Integration of cell adhesive, survival, and proliferative processes is essential for capillary morphogenesis of endothelial cells (EC) in vitro and vascular development and function in vivo. Unfortunately, the molecular and cellular mechanisms that impact these processes are poorly defined. Here we examined how lack of bim and/or bcl-2 expression impact lung EC function. The absence of bcl-2 or bim had a significant impact on EC adhesion and migration. Lack of bcl-2 expression decreased lung EC migration, whereas lack of bim expression increased migration compared with their wild-type counterparts. Decreased adhesion to fibronectin and vitronectin was observed in both bcl-2-/- and bim-/- lung EC, with bcl-2-/- EC having very little adhesion to either matrix protein. Capillary morphogenesis was greatly diminished in bcl-2-/- EC, which correlated with decreased lung alveolarization in vivo, an angiogenesis-dependent process. We also observed aberrant production of extracellular matrix proteins, eNOS expression, and nitric oxide production in bcl-2-/- lung EC, which could contribute to inability to undergo capillary morphogenesis. The changes in cell adhesion and migration noted in the absence of bim or bcl-2 were independent of their impact on apoptosis. We observed no significant affect on the steady-state rate of apoptosis of lung EC in the absence of bim or bcl-2. Thus, bcl-2 family members, bim and bcl-2, play a central role in modulation of EC proangiogenic properties, which goes beyond their role as simple mediators of mitochondrial homeostasis and apoptosis.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Movimento Celular/fisiologia , Células Endoteliais/fisiologia , Pulmão/citologia , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Antimetabólitos/metabolismo , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Moléculas de Adesão Celular/metabolismo , Proliferação de Células , Células Endoteliais/citologia , Proteínas da Matriz Extracelular/metabolismo , Fluoruracila/metabolismo , Integrinas/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética
2.
Cancer Res ; 68(18): 7394-402, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18794127

RESUMO

Cytochrome P450 1B1 (Cyp1b1) metabolism contributes to physiologic functions during embryogenesis but also to carcinogenic activation of polycyclic aromatic hydrocarbons (PAH). We generated Cyp1b1-deficient mice carrying the Min allele of the adenomatous polyposis coli gene. These Cyp1b1-deficient Min mice developed twice as many tumors as Min controls, which, however, remained similar in size and histology. Tumors from older (130 days) Cyp1b1-deficient Min mice selectively exhibited focal areas of nuclear atypia associated with less organized epithelia. The metabolism of endogenous substrates by Cyp1b1, therefore, suppresses tumor initiation but also affects progression. Treatment of Min mice with 7,12-dimethylbenzanthracene (DMBA) doubled both tumor multiplicity and size within 20 days but not when mice lacked Cyp1b1. This was paralleled by an abnormal staining of crypts with beta-catenin, phospho-IkappaB kinase, and RelA, which may represent an early stage of tumorigenesis similar to aberrant crypt formation. Cyp1b1 deletion did not affect circulating DMBA and metabolites. Cyp1b1 expression was higher in the tumors compared with normal small intestines. Increased tumorigenesis may, therefore, arise from generation of DMBA metabolites by Cyp1b1 in the developing tumors. Benzo(a)pyrene (BP), which is similarly activated by Cyp1b1 in vitro, did not affect tumorigenesis in Min mice. By contrast, BP and DMBA each suppressed tumor multiplicity in the absence of Cyp1b1. Cyp1b1 metabolism of DMBA and endogenous oxygenation products may each affect a tumor-promoting nuclear factor-kappaB activation, whereas Ah receptor activation by PAH affects suppression. Tumorigenesis may, therefore, depend on activation of PAH by Cyp1b1 and on offsetting suppression by Cyp1b1 of endogenous tumor-enhancing substrates.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Carcinógenos/farmacocinética , Neoplasias Intestinais/enzimologia , 9,10-Dimetil-1,2-benzantraceno/farmacocinética , Animais , Hidrocarboneto de Aril Hidroxilases/deficiência , Benzo(a)pireno/farmacocinética , Citocromo P-450 CYP1B1 , Feminino , Quinase I-kappa B/metabolismo , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Azeite de Oliva , Fosforilação , Óleos de Plantas/farmacocinética , Fator de Transcrição RelA/metabolismo , beta Catenina/metabolismo
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