RESUMEN
Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.
Asunto(s)
Actinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Receptor de Endotelina A/fisiología , Receptor de Endotelina B/fisiología , Tenascina/biosíntesis , Neoplasias Encefálicas/metabolismo , Adhesión Celular , Proliferación Celular , Citoesqueleto/metabolismo , Adhesiones Focales , Glioma/metabolismo , Humanos , Cinética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Transducción de Señal , Fibras de Estrés/metabolismo , Tenascina/metabolismoRESUMEN
Runx2 is a master regulator of bone development and has also been described as an oncogene. Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα), both implicated in bone metabolism and breast cancer, have been shown to share common transcriptional targets. Here, we show that ERα is a positive regulator of Runx2-I transcription. Moreover, ERRα can act as a transcriptional activator of Runx2-I in presence of peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α). In contrast, ERRα behaves as a negative regulator of Runx2-I transcription in presence of PGC-1ß. ERα and ERRα cross-talk via a common estrogen receptor response element on the Runx2-I promoter. In addition, estrogen regulates PGC-1ß that in turn is able to modulate both ERα and ERRα transcriptional activity.
Asunto(s)
Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Receptor alfa de Estrógeno/fisiología , Receptores de Estrógenos/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Receptor alfa de Estrógeno/genética , Femenino , Regulación de la Expresión Génica , Células HeLa , Humanos , Células MCF-7 , Modelos Genéticos , Regiones Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Estrógenos/genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic ß-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.
Asunto(s)
Regulación hacia Abajo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Tenascina/metabolismo , Proteínas Wnt/metabolismo , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Transducción de Señal , Tenascina/deficiencia , Tenascina/genética , Proteínas Wnt/antagonistas & inhibidoresRESUMEN
The antiadhesive extracellular matrix molecule tenascin-C abrogates cell spreading on fibronectin through competitive inhibition of syndecan-4, thereby preventing focal adhesion kinase (FAK) activation and triggering enhanced proteolytic degradation of both RhoA and tropomyosin 1 (TM1). Here, we show that simultaneous signaling by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) initiates glioma cell spreading and migration through syndecan-4-independent activation of paxillin and FAK and by stabilizing expression of RhoA, TM1, TM2, and TM3. By using gene silencing methods, we show that paxillin, TM1, TM2, and TM3 are essential for LPA/PDGF-induced cell spreading on a fibronectin/tenascin-C (FN/TN) substratum. LPA/PDGF-induced cell spreading and migration on FN/TN depends on phosphatidylinositol 3-kinase, RhoKinase, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 but is independent of phospholipase C and Jun kinase. RNA microarray data reveal expression of tenascin-C, PDGFs, LPA, and the respective receptors in several types of cancer, suggesting that the TN/LPA/PDGF axis exists in malignant tumors. These findings may in turn be relevant for diagnostic or therapeutic applications targeting cancer.
Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Lisofosfolípidos/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Tenascina/fisiología , Animales , Western Blotting , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Fibronectinas/metabolismo , Técnica del Anticuerpo Fluorescente , Glioma/metabolismo , Humanos , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sindecano-4/metabolismo , Tropomiosina/metabolismoRESUMEN
Cell specification in the nervous system requires patterning genes dictating spatio-temporal coordinates as well as fate determinants. In the case of neurons, which are controlled by the family of proneural transcription factors, binding specificity and patterned expression trigger both differentiation and specification. In contrast, a single gene, glide cell deficient/glial cell missing (glide/gcm), is sufficient for all fly lateral glial differentiation. How can different types of cells develop in the presence of a single fate determinant, that is, how do differentiation and specification pathways integrate and produce distinct glial populations is not known. By following an identified lineage, we here show that glia specification is triggered by high glide/gcm expression levels, mediated by cell-specific protein-protein interactions. Huckebein (Hkb), a lineage-specific factor, provides a molecular link between glide/gcm and positional cues. Importantly, Hkb does not activate transcription; rather, it physically interacts with Glide/Gcm thereby triggering its autoregulation. These data emphasize the importance of fate determinant cell-specific quantitative regulation in the establishment of cell diversity.
Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriología , Neuroglía/citología , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Diferenciación Celular/genética , Linaje de la Célula , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/citología , Drosophila melanogaster/genética , Homeostasis , Datos de Secuencia Molecular , Factores de Transcripción/genética , Transcripción Genética , Regulación hacia ArribaRESUMEN
Neuronal differentiation relies on proneural factors that also integrate positional information and contribute to the specification of the neuronal type. The molecular pathway triggering glial specification is not understood yet. In Drosophila, all lateral glial precursors and glial-promoting activity have been identified, which provides us with a unique opportunity to dissect the regulatory pathways controlling glial differentiation and specification. Although glial lineages are very heterogeneous with respect to position, time of differentiation, and lineage tree, they all express and require two homologous genes, glial cell deficient/glial cell missing (glide/gcm) and glide2, that act in concert, with glide/gcm constituting the major glial-promoting factor. Here, we show that glial specification resides in glide/gcm transcriptional regulation. The glide/gcm promoter contains lineage-specific elements as well as quantitative and turmoil elements scattered throughout several kilobases. Interestingly, there is no correlation between a specific regulatory element and the type of glial lineage. Thus, the glial-promoting factor acts as a naive switch-on button that triggers gliogenesis in response to multiple pathways converging onto its promoter. Both negative and positive regulation are required to control glide/gcm expression, indicating that gliogenesis is actively repressed in some neural lineages.