RESUMEN
Bighorn sheep sinus tumors are a recently described disease affecting the paranasal sinuses of Rocky Mountain bighorn sheep (Ovis canadensis canadensis). Several features of this disease suggest an infectious cause, although a specific etiologic agent has not been identified. To test the hypothesis that bighorn sheep sinus tumors are caused by an infectious agent, we inoculated 4 bighorn sheep lambs and 4 domestic sheep lambs intranasally with a cell-free filtrate derived from a naturally occurring bighorn sheep sinus tumor; we held 1 individual of each species as a control. Within 18 months after inoculation, all 4 inoculated domestic sheep (100%) and 1 of the 4 inoculated bighorn sheep (25%) developed tumors within the ethmoid sinuses or nasal conchae, with features similar to naturally occurring bighorn sheep sinus tumors. Neither of the uninoculated sheep developed tumors. Histologically, the experimentally transmitted tumors were composed of stellate to spindle cells embedded within a myxoid matrix, with marked bone production. Tumor cells stained positively with vimentin, S100, alpha smooth muscle actin, and osteocalcin, suggesting origin from a multipotent mesenchymal cell. A periosteal origin for these tumors is suspected. Immunohistochemical staining for the envelope protein of JSRV (with cross-reactivity to ENTV) was equivocal, and PCR assays specific for these agents were negative.
Asunto(s)
Neoplasias de los Senos Paranasales/veterinaria , Enfermedades de las Ovejas/transmisión , Animales , Femenino , Masculino , Neoplasias de los Senos Paranasales/diagnóstico por imagen , Neoplasias de los Senos Paranasales/etiología , Neoplasias de los Senos Paranasales/patología , Senos Paranasales/patología , Ovinos , Enfermedades de las Ovejas/diagnóstico por imagen , Enfermedades de las Ovejas/etiología , Enfermedades de las Ovejas/patología , Borrego Cimarrón , Oveja Doméstica , Tomografía Computarizada por Rayos X/veterinariaRESUMEN
Amphibian metamorphosis is marked by dramatic thyroid hormone (T(3))-induced changes including de novo morphogenesis, tissue remodeling and organ resorption through programmed cell death. These changes involve cascades of gene regulation initiated by thyroid hormone and its receptors. Previous studies suggest that chromatin remodeling involving changes in core histone acetylation plays a fundamental role in transcriptional regulation. A basic model has been suggested where targeted histone deacetylation is involved in transcriptional repression and histone acetylation is involved in transcriptional activation. On the other hand, the developmental roles of histone acetylation remain to be elucidated. Here we demonstrate that tadpole treatment with trichostatin A, a specific potent histone deacetylase inhibitor, blocks metamorphosis. Gene expression analyses show that trichostatin A induces the release of T(3)-response gene repression without affecting T(3)-induction of direct T(3)-response genes. However, the drug blocks the regulation of late T(3)-response genes, which may be responsible for its inhibitory effects on metamorphosis. These data support a role of deacetylases in transcriptional repression by unliganded T(3) receptor during premetamorphosis and another role at a downstream step of the gene regulation cascade induced by T(3) during metamorphosis.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica/fisiología , Histona Desacetilasas/metabolismo , Intestinos/crecimiento & desarrollo , Metamorfosis Biológica/fisiología , Animales , Apoptosis/fisiología , Cartilla de ADN , Activación Enzimática/fisiología , Inhibidores Enzimáticos/farmacología , Células Epiteliales/fisiología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/farmacología , Intestinos/citología , Metamorfosis Biológica/efectos de los fármacos , Receptores de Hormona Tiroidea/genética , Triyodotironina/farmacología , Triyodotironina/fisiología , Xenopus laevisRESUMEN
N-CoR (nuclear receptor corepressor) is a corepressor for multiple transcription factors including unliganded thyroid hormone receptors (TRs). In vitro, N-CoR can interact with the Sin3 corepressor, which in turn binds to the histone deacetylase Rpd3 (HDAC1), predicting the existence of a corepressor complex containing N-CoR, Sin3, and histone deacetylase. However, previous biochemical studies of endogenous Sin3 complexes have failed to find an N-CoR association. Xenopus laevis eggs and oocytes contain all of the necessary components for transcriptional repression by unliganded TRs. In this study, we report the biochemical fractionation of three novel macromolecular complexes containing N-CoR, two of which possess histone deacetylase activity, from Xenopus egg extract. One complex contains Sin3, Rpd3, and RbAp48; the second complex contains a Sin3-independent histone deacetylase; and the third complex lacks histone deacetylase activity. This study describes the first biochemical isolation of endogenous N-CoR-containing HDAC complexes and illustrates that N-CoR associates with distinct histone deacetylases that are both dependent and independent of Sin3. Immunoprecipitation studies show that N-CoR binds to unliganded TR expressed in the frog oocyte, confirming that N-CoR complexes are involved in repression by unliganded TR. These results suggest that N-CoR targets transcriptional repression of specific promoters through at least two distinct histone deacetylase pathways.