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1.
Am J Pathol ; 176(1): 122-33, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19959815

RESUMEN

In the present study, we assessed the role of Smad4, a component of the transforming growth factor-beta signaling pathway, in cutaneous wound repair. Interestingly, when Smad4 was deleted in the epidermis, several defects in wound healing were observed in non-keratinocyte compartments. In comparison with wounded wild-type mouse skin, Smad4-deficient wounds had delayed wound closure and remodeling. Increased angiogenesis and inflammation were found in Smad4-deficient skin; these effects were exacerbated throughout the entire wound healing process. In addition, increased numbers of myofibroblasts but reduced collagen levels were found in Smad4-deficient wounds in comparison with wild-type wounds. Since Smad4 is not a secreted protein, we assessed if the above non-cell autonomous alterations were the result of molecular alterations in Smad4-deficient keratinocytes, which exert paracrine effects on wound stroma. Smad4-deficient skin and wounds had elevated levels of transforming growth factor-beta1, which have been shown to induce similar phenotypes, as well as of several transforming growth factor-beta1 target genes, such as matrix metalloproteinases, vascular endothelial growth factor-A, and chemokine (C-C motif) ligand 5. Furthermore, the above pathological and molecular alterations were exacerbated in skin cancer lesions that spontaneously developed from Smad4-deficient skin. Therefore, loss of Smad4 in the epidermis appears to significantly affect the microenvironment during wound healing and carcinogenesis.


Asunto(s)
Epidermis/patología , Eliminación de Gen , Proteína Smad4/deficiencia , Cicatrización de Heridas , Anomalías Múltiples/patología , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Movimiento Celular , Epidermis/anomalías , Epidermis/enzimología , Regulación Neoplásica de la Expresión Génica , Queratinocitos/metabolismo , Queratinocitos/patología , Macrófagos/patología , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Noqueados , Monocitos/patología , Neovascularización Patológica/metabolismo , Especificidad de Órganos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteína Smad4/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
2.
Dev Biol ; 322(1): 156-66, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18692037

RESUMEN

We have previously shown that keratinocyte-specific deletion of Smad4, a TGFbeta/Activin/BMP signaling mediator, results in a progressive alopecia. To further assess the molecular mechanisms of Smad4 loss-mediated alopecia, we examined expression levels of key molecules associated with hair follicle differentiation in Smad4-deleted skin. Among them, Desmoglein 4 (Dsg4) was down-regulated in Smad4-deleted skin prior to the onset of hair follicle abnormalities with gradual depletion coinciding with hair follicle degeneration. Chromatin immunoprecipitation (ChIP) assay showed that Smad4, together with the BMP mediators Smad1 and Smad5, but not the TGFbeta/Activin mediators Smad2 or Smad3, bound to the Smad Binding Element (SBE) of the Dsg4 promoter. A Dsg4 reporter assay revealed that Smad4 was required for the maximal transactivation of Dsg4 in cooperation with Smad1 and Smad5. Mutating the SBE of the Dsg4 promoter abrogated Smad4 transactivation of Dsg4. Furthermore, BMP ligands, but not ligands of TGFbeta and Activin, induced endogenous Dsg4 expression. Our data demonstrate that in the presence of Smad4, BMP signaling participated in transcriptional regulation of Dsg4. Thus, Smad4 loss-associated Dsg4 depletion contributed, at least in part, to hair follicles degeneration in Smad4 deficient skin.


Asunto(s)
Alopecia/genética , Desmogleínas/metabolismo , Folículo Piloso/metabolismo , Proteína Smad4/deficiencia , Alopecia/metabolismo , Alopecia/patología , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Desmogleínas/genética , Regulación hacia Abajo/genética , Folículo Piloso/patología , Queratinocitos/metabolismo , Queratinocitos/patología , Ligandos , Ratones , Ratones Noqueados , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transducción de Señal/genética , Piel/patología , Proteína Smad1/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad5/metabolismo , Activación Transcripcional/genética
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