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2.
Gastroenterology ; 138(3): 1166-77, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20026066

RESUMO

BACKGROUND & AIMS: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. METHODS: The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. RESULTS: Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. CONCLUSIONS: PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia.


Assuntos
Carcinoma in Situ/metabolismo , Células Epiteliais/metabolismo , Proteínas Hedgehog/metabolismo , Ductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/metabolismo , Lesões Pré-Cancerosas/metabolismo , Animais , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Células Cultivadas , Ceruletídeo , Molde por Corrosão , Modelos Animais de Doenças , Células Epiteliais/ultraestrutura , Mucinas Gástricas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Humanos , Imuno-Histoquímica , Metaplasia , Camundongos , Camundongos Transgênicos , Ductos Pancreáticos/ultraestrutura , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fatores de Tempo
3.
J Clin Endocrinol Metab ; 88(1): 501-4, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12519896

RESUMO

Compared to Old World primates, including man, New World primates display target-tissue resistance to gonadal steroid hormones. In female New World primates this resistant phenotype is characterized by elevated concentrations of plasma estradiol and progesterone. Here we describe the discovery of an intracellular estrogen binding protein (IEBP) that acts to concentrate 17 beta-estradiol (E2) in the cytoplasm of New World primate target cells. IEBP was purified by E2-affinity chromatography from postnuclear extracts of the B95-8 cells established from an E2-resistant New World primate. Compared with unpurified extract, affinity-purified IEBP demonstrated a 300-fold enrichment in specific E2 binding activity; half-maximal displacement of [3H]E2 from affinity-purified IEBP was observed with 0.1 nM E2. Affinity-purified extracts were subjected to SDS-PAGE with isolation of a dominant 27-28 kDa protein. N-terminal sequencing of tryptic peptides of the protein showed sequence homology with human heat shock protein-27 (hsp27). By immunoblot and E2 binding capacity, IEBP was 1] 2-3-fold greater in New World than in Old World primate tissues and cell lines, 2] heat-inducible and 3] up-regulated in vivo in the presence of the functioning female gonad. In conclusion, IEBP is a specific E2-interacting heat shock protein in the hsp-27 family that is relatively overexpressed in estrogen-resistant cells.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/isolamento & purificação , Estradiol/metabolismo , Estrogênios/farmacologia , Sequência de Aminoácidos/genética , Animais , Ligação Competitiva , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Citoplasma/metabolismo , Resistência a Medicamentos , Membranas Intracelulares/metabolismo , Dados de Sequência Molecular , Família Multigênica , Proteínas de Neoplasias/genética , Primatas , Homologia de Sequência de Aminoácidos
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