RESUMEN

Insulin-like growth factor binding protein-5 (IGFBP-5) induces production of the extracellular matrix (ECM) components collagen and fibronectin both in vitro and in vivo and is overexpressed in patients with fibrosing lung diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). However, the mechanism by which IGFBP-5 exerts its fibrotic effect is incompletely understood. Recent reports have shown a substantial role of reactive oxygen species (ROS) in fibrosis; thus we hypothesized that IGFBP-5 induces production of ROS to mediate the profibrotic process. In vitro analyses revealed that ROS production was induced by recombinant and adenoviral vector-mediated IGFBP-5 (AdBP5) in a dose- and time-dependent manner, regulated through MEK/ERK and JNK signaling, and primarily mediated by NADPH oxidase (Nox). Silencing IGFBP-5 in SSc and IPF fibroblasts reduced ROS production. The antioxidants diphenyleneiodonium and N-acetylcysteine blocked IGFBP-5-stimulated ECM production in normal, SSc, and IPF human primary lung fibroblasts. In murine fibroblasts lacking critical components of the Nox machinery, AdBP5-stimulated ROS production and fibronectin expression were reduced compared with wild-type fibroblasts. IGFBP-5 stimulated transcriptional expression of Nox3 in human fibroblasts while selective knockdown of Nox3 reduced ROS production by IGFBP-5. Thus IGFBP-5 mediates fibrosis through production of ROS in a Nox-dependent manner.

Asunto(s)

Matriz Extracelular/metabolismo , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Pulmón/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/etiología , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/metabolismo , Estrés Oxidativo , ARN Interferente Pequeño/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismo

RESUMEN

Protein delivery is often used in tissue engineering applications to control differentiation processes, but is limited by protein instability and cost. An alternative approach is to control the cellular microenvironment through biomaterial-mediated sequestration of cell-secreted proteins important to differentiation. Thus, we utilized heparin-based microparticles to modulate cellular differentiation via protein sequestration in an in vitro model system of endochondral ossification. Heparin and poly(ethylene-glycol) (PEG; a low-binding material control)-based microparticles were incorporated into ATDC5 cell spheroids or incubated with ATDC5 cells in transwell culture. Reduced differentiation was observed in the heparin microparticle group as compared to PEG and no microparticle-containing groups. To determine if observed changes were due to sequestration of cell-secreted protein, the proteins sequestered by heparin microparticles were analyzed using SDS-PAGE and mass spectrometry. It was found that heparin microparticles bound insulin-like growth factor binding proteins (IGFBP)-3 and 5. When incubated with a small-molecule inhibitor of IGFBPs, NBI 31772, a similar delay in differentiation of ATDC5 cells was observed. These results indicate that heparin microparticles modulated chondrocytic differentiation in this system via sequestration of cell-secreted protein, a technique that could be beneficial in the future as a means to control cellular differentiation processes. STATEMENT OF SIGNIFICANCE: In this work, we present a proof-of-principle set of experiments in which heparin-based microparticles are shown to modulate cellular differentiation through binding of cell-secreted protein. Unlike existing systems that rely on expensive protein with limited half-lives to elicit changes in cellular behavior, this technique focuses on temporal modulation of cell-generated proteins. This technique also provides a biomaterials-based method that can be used to further identify sequestered proteins of interest. Thus, this work indicates that glycosaminoglycan-based biomaterial approaches could be used as substitutes or additions to traditional methods for modulating and identifying the cell-secreted proteins involved in directing cellular behavior.

Asunto(s)

Diferenciación Celular , Micropartículas Derivadas de Células/metabolismo , Condrocitos/citología , Proteínas/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Condrocitos/metabolismo , Condrogénesis , Regulación de la Expresión Génica , Heparina/química , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Ratones , Polietilenglicoles/química , Esferoides Celulares/citología , Coloración y Etiquetado

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies in the world. microRNA-140-5p (miR-140) has been shown to be involved in cartilage development and osteoarthritis (OA) pathogenesis. Some contradictions still exist concerning the role of miR-140 in tumor progression and metastasis, and the underlying mechanism is uncertain. METHODS: Immunohistochemistry was performed to determine the expressions of ADAMTS5 and IGFBP5 in CRC tissues. Human CRC cell lines HCT116 and RKO were transfected with miR-140 mimic, inhibitor, or small interfering RNA (siRNA) against ADAMTS5 or IGFBP5, respectively, using oligofectamine or lipofectamine 2000. Scratch-wound assay and transwell migration and invasion assays were used to evaluate the effects of miR-140 on the capabilities of migration and invasion. The levels of miR-140 and ADAMTS5 and IGFBP5 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of ADAMTS5 and IGFBP5 proteins. RESULTS: miR-140 was significantly reduced, whereas ADAMTS5 and IGFBP5 were upregulated, in the human CRC tissues compared to the corresponding normal colorectal mucosa. miR-140 downregulation and ADAMTS5 or IGFBP5 overexpression were associated with the advanced TNM stage and distant metastasis of CRC. There was a reverse correlation between miR-140 levels and ADAMTS5 and IGFBP5 expression in CRC tissues. ADAMTS5 and IGFBP5 were downregulated by miR-140 at both the protein and mRNA levels in the CRC cell lines. The gain-of- and loss-of-function studies showed that miR-140 inhibited CRC cell migratory and invasive capacities at least partially via downregulating the expression of ADAMTS5 and IGFBP5. CONCLUSIONS: These findings suggest that miR-140 suppresses CRC progression and metastasis, possibly through downregulating ADAMTS5 and IGFBP5. miR-140 might be a potential therapeutic candidate for the treatment of CRC.

Asunto(s)

Proteína ADAMTS5/genética , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , MicroARNs/genética , Proteína ADAMTS5/antagonistas & inhibidores , Proteína ADAMTS5/metabolismo , Anciano , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Células HCT116 , Humanos , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Masculino , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Oligorribonucleótidos Antisentido/genética , Oligorribonucleótidos Antisentido/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal

RESUMEN

Colon cancer is one of the most common malignancies, causes considerable morbidity and mortality. The current treatment for colon cancer is more modest than had been hoped. There is an urgent clinical need to explore new agents or adjuvants for colon cancer treatment. Natural products and their derivates act as one of the major source for anticancer agent. In the present study, we investigated the anti-proliferation and chemoprevention effects of tetrandrine (Tet) on colon cancer cells to uncover the possible molecular basis of this effect. We found that Tet can inhibit proliferation and induce apoptosis in LoVo cells. With dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) induced colon cancer model, we found that Tet can prevent or inhibit DMH plus DSS induced aberrant crypt foci (ACF) and colon cancer formation, as well as suppress tumor growth in the xenograft colon cancer model. Tet can downregulate the expression of IGFBP-5 in LoVo cells. Exogenous expression of IGFBP-5 can attenuate the anti-cancer activity of Tet, while IGFBP-5 knockdown potentiates this effect of Tet on LoVo cells. Tet can inhibit Wnt/ß-catenin signaling transduction, which can be partly reversed by exogenous expression of IGFBP-5, but is enhanced by IGFBP-5 knockdown. Our results demonstrated that the anticancer activity of Tet in colon cancer cells may be mediated partly by downregulating the expression of IGFBP-5, thus inactivating Wnt/ß-catenin signaling transduction.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Bencilisoquinolinas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Animales , Proliferación Celular/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Femenino , Humanos , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Masculino , Ratones , Ratones Desnudos , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell-autonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.

Asunto(s)

Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Transducción de Señal/genética , Somatomedinas/fisiología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/metabolismo , Animales , Ataxina-1 , Ataxina-7 , Ataxinas , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Regulación de la Expresión Génica/fisiología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Transducción de Señal/fisiología , Somatomedinas/metabolismo , Ataxias Espinocerebelosas/etiología

RESUMEN

IGF-I has been shown to play a role in the progression of atherosclerosis in experimental animal models. IGF-binding protein-4 (IGFBP-4) binds to IGF-I and prevents its association with receptors. Overexpression of a protease-resistant form of IGFBP-4 has been shown to inhibit the ability of IGF-I to stimulate normal smooth muscle cell growth in mice. Based on these observations, we prepared a protease-resistant form of IGFBP-4 and infused it into hypercholesterolemic pigs. Infusion of the protease-resistant mutant inhibited lesion development by 53.3 +/- 6.1% (n = 6; P < 0.01). Control vessels that received an equimolar concentration of IGF-I and the protease-resistant IGFBP-4 showed no reduction in lesion size compared with control lesions that were infused with vehicle. Infusion of a nonmutated form of IGFBP-4 did not significantly inhibit lesion development. Proliferating cell nuclear antigen analysis showed that the mutant IGFBP-4 appeared to inhibit cell proliferation. The area occupied by extracellular matrix was also reduced proportionally compared with total lesion area. Immunoblotting revealed that the mutant IGFBP-4 remained intact, whereas the wild-type IGFBP-4 that was infused was proteolytically cleaved. Further analysis of the lesions revealed that a marker protein, IGFBP-5, whose synthesis is stimulated by IGF-I, was decreased in the lesions that received the protease-resistant, IGFBP-4 mutant, whereas there was no change in lesions that received wild-type IGFBP-4 or the mutant protein plus IGF-I. These findings clearly illustrate that infusion of protease-resistant IGFBP-4 into the perilesion environment results in inhibition of cell proliferation and attenuation of the development of neointima. The findings support the hypothesis that inhibiting IGFBP-4 proteolysis in the lesion microenvironment could be an effective means for regulating neointimal expansion.

Asunto(s)

Hipercolesterolemia/patología , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/química , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Péptido Hidrolasas/metabolismo , Túnica Íntima/patología , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Medicamentos , Femenino , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Arteria Femoral/patología , Hipercolesterolemia/metabolismo , Hiperplasia , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Masculino , Mutación , Porcinos , Transfección , Túnica Íntima/efectos de los fármacos , Túnica Íntima/metabolismo

RESUMEN

Signal transduction through the IGF axis is implicated in proliferation, differentiation and survival during development and adult life. The IGF axis includes the IGF binding proteins (IGFBPs) that bind IGFs with high affinity and modulate their activity. In neuroblastoma (NB), a malignant childhood tumor, we found that IGFBP-5 is frequently expressed. Since NB is an IGF2-sensitive tumor, we investigated the relevance and the function of endogenous IGFBP-5 in LAN-5 and in SY5Y(N) cell lines transfected with micro and small interfering RNAs directed to IGFBP-5 mRNA. Cells in which IGFBP-5 expression was suppressed were growth-inhibited and more prone to apoptosis than the parental cell line and controls. Apoptosis was further enhanced by X-ray irradiation. The ability of these cells to undergo neuronal differentiation was impaired after IGFBP-5 inhibition but the effect was reversed by exposure to recombinant IGFBP-5. Together, these data demonstrate the importance of IGFBP-5 for NB cell functions and suggest that IGFBP-5 might serve as a novel therapeutic target in NB.

Asunto(s)

Apoptosis/fisiología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , MicroARNs/genética , Neuroblastoma/metabolismo , Interferencia de ARN , Apoptosis/efectos de la radiación , Diferenciación Celular , Proliferación Celular , Humanos , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/farmacología , Neuroblastoma/patología , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Proteínas Recombinantes/farmacología , Somatomedinas/fisiología , Transfección , Células Tumorales Cultivadas , Rayos X

RESUMEN

Recently we have determined the crystal structure of the insulin-like growth factor-I (IGF-I) in complex with the N-terminal domain of the IGF-binding protein-5 (IGFBP-5). Here we report results of computer screening for potential inhibitors of this interaction using the crystal coordinates. From the compounds suggested by in silico screens, successful binders were identified by NMR spectroscopic methods. NMR was also used to map their binding sites and calculate their binding affinities. Small molecular weight compounds (FMOC derivatives) bind to the IGF-I binding site on the IGFBP-5 with micromolar affinities and thus serve as potential starting compounds for the design of more potent inhibitors and therapeutic agents for diseases that are associated with abnormal IGF-I regulation.

Asunto(s)

Aminoácidos/química , Fluorenos/química , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/química , Factor I del Crecimiento Similar a la Insulina/química , Sitios de Unión , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad Cuantitativa

RESUMEN

Transforming growth factor-beta (TGF-beta) and insulin-like growth factors (IGFs) play critical roles in the control of myogenesis. Insulin-like growth factor-binding protein-5 (IGFBP-5), by regulating the bioavailability of IGFs, is involved in controlling IGF-dependent differentiation. We investigated the effects of TGF-beta on the IGFBP-5 production induced by IGFs in mouse myoblasts. TGF-beta leads to a decrease in IGFBP-5 synthesis at both transcript and protein levels, and blocked muscle differentiation. The Smad proteins and the c-Jun N-terminal kinase (JNK) have been shown to be involved in TGF-beta signaling pathways. We provide evidence that the JNK pathway, rather than Smad proteins, is involved in the response of muscle cells to TGF-beta. This factor failed to stimulate the GAL4-Smad 2/3 transcriptional activities of the constructs used to transfect myoblasts. Moreover, stable expression of the antagonistic Smad7 did not abolish the inhibitory effect of TGF-beta on IGFBP-5 production whereas expression of a dominant-negative version of MKK4, an upstream activator of JNK, did. We also showed, using a specific inhibitor, that the p38 mitogen-activated protein kinase (p38 MAPK) was not involved in the inhibition of IGFBP-5 production. Thus, TGF-beta-mediated IGFBP-5 inhibition is independent of Smads and requires activation of the JNK signaling pathway.

Asunto(s)

Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , MAP Quinasa Quinasa 4 , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Esquelético/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Northern Blotting , Diferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Genes Dominantes , Insulina/metabolismo , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteínas Quinasas JNK Activadas por Mitógenos , Luciferasas/metabolismo , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Mutación , Plásmidos/metabolismo , Unión Proteica , ARN Mensajero/metabolismo , Transducción de Señal , Proteína Smad2 , Proteína smad3 , Proteína smad7 , Transactivadores/metabolismo , Transcripción Genética , Activación Transcripcional , Transfección , Troponina T/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos

RESUMEN

Insulin-like growth factor-I (IGF-I)-mediated growth of cells can be modulated by specific IGF binding proteins (IGFBPs) that inhibit or augment IGF-I ligand-receptor interaction. IGFBP expression and production by human intestinal muscle cells in culture was characterized in rapidly growing cells (day 3 of culture), in confluent cells (day 7), and in postconfluent cells (day 14). RT-PCR analysis identified IGFBP-3, IGFBP-4, and IGFBP-5 mRNA during all three phases of growth. The production of IGFBP-3 and IGFBP-5 was regulated in reciprocal fashion. IGFBP-5 production was high on day 3 and decreased two- to fivefold by day 14, and IGFBP-3 production was low on day 3 and increased five- to eightfold by day 14. IGFBP-4 production remained constant. IGFBP-3 inhibited and IGFBP-5 augmented IGF-I-induced proliferation. IGFBP-3 and IGFBP-5 production was regulated in reciprocal fashion by transforming growth factor-beta1 (TGF-beta1). Immunoneutralization of endogenous TGF-beta1 decreased the production of IGFBP-3 and increased the production of IGFBP-5. Addition of exogenous recombinant human TGF-beta1 had the opposite effect. We conclude that the expression and time-dependent production of IGFBP-3, IGFBP-4, and IGFBP-5 and their regulation by endogenous TGF-beta1 represent mechanisms by which human intestinal muscle cells regulate autocrine IGF-I-mediated growth.

Asunto(s)

Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Mucosa Intestinal/metabolismo , Músculo Liso/metabolismo , Factor de Crecimiento Transformador beta/fisiología , Western Blotting , División Celular/fisiología , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/química , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/química , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/química , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/farmacología , Intestinos/citología , Músculo Liso/citología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Insulin-like growth factor I (IGF-I) is an important mediator of estradiol-induced uterine growth in vivo. Insulin-like growth factor binding proteins (IGFBPs) are known to regulate access of insulin-like growth factors to IGF receptors. In this report we demonstrate that the positive uterotrophic agent estradiol, suppresses expression of the IGFBP-5 gene in the uterus to less than 15% of control values, while oophorectomy results in uterine involution and is associated with a greater than 3-fold stimulation of uterine IGFBP-5 gene expression. Immunohistochemical studies show that in intact rat uterus, the luminal epithelial cells are weakly stained with IGFBP-5 antibodies. Following ovariectomy, IGFBP-5 is confined in the luminal epithelial layer and longidinal smooth muscle cells. Administration of estradiol to ovariectomized rats increases uterine weight and uterine IGF-I gene expression, while immunostaining of IGFBP-5 in the luminal epithelial cells and longidinal smooth muscle cells is almost extinguished. In vitro studies using primary uterine cells reveal that IGF-I increases thymidine incorporation and inhibits IGFBP-5 gene expression, whereas estradiol has no effect suggesting that in vivo estradiol-induced IGFBP-5 suppression is mediated through increased IGF-I production. Our results suggest that in vivo, the uterotrophic effects of estradiol are mediated at least in part by estradiol-stimulated uterine IGF-I expression which in turn inhibits IGFBP-5 expression, an action which would be expected to increase IGF bioactivity.

Asunto(s)

Estradiol/farmacología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/fisiología , Útero/efectos de los fármacos , Animales , Western Blotting , Células Cultivadas , Estradiol/fisiología , Femenino , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/antagonistas & inhibidores , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ovariectomía , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Timidina/metabolismo , Útero/metabolismo