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1.
Elife ; 52016 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-27431613

RESUMEN

The RAS pathway is central to epidermal homeostasis, and its activation in tumors or in Rasopathies correlates with hyperproliferation. Downstream of RAS, RAF kinases are actionable targets regulating keratinocyte turnover; however, chemical RAF inhibitors paradoxically activate the pathway, promoting epidermal proliferation. We generated mice with compound epidermis-restricted BRAF/RAF1 ablation. In these animals, transient barrier defects and production of chemokines and Th2-type cytokines by keratinocytes cause a disease akin to human atopic dermatitis, characterized by IgE responses and local and systemic inflammation. Mechanistically, BRAF and RAF1 operate independently to balance MAPK signaling: BRAF promotes ERK activation, while RAF1 dims stress kinase activation. In vivo, JNK inhibition prevents disease onset, while MEK/ERK inhibition in mice lacking epidermal RAF1 phenocopies it. These results support a primary role of keratinocytes in the pathogenesis of atopic dermatitis, and the animals lacking BRAF and RAF1 in the epidermis represent a useful model for this disease.


Asunto(s)
Dermatitis Atópica/patología , Dermatitis Atópica/prevención & control , Queratinocitos/fisiología , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Animales , Ratones , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-raf/genética
2.
J Exp Med ; 208(11): 2263-77, 2011 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-21967767

RESUMEN

Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection.


Asunto(s)
Cadherinas/metabolismo , Células Caliciformes/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Listeria monocytogenes/metabolismo , Transcitosis/fisiología , Animales , Biomarcadores/metabolismo , Polaridad Celular , Exocitosis/fisiología , Células Caliciformes/citología , Humanos , Listeria monocytogenes/patogenicidad , Listeriosis/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Membrana Mucosa/microbiología , Membrana Mucosa/fisiología , Membrana Mucosa/ultraestructura
3.
Carcinogenesis ; 31(7): 1165-74, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20047953

RESUMEN

Some 25 years ago, Raf was discovered as the transforming principle shared by a murine sarcoma and an avian carcinoma virus. Thus, Raf and tumorigenesis have been connected from the very beginning. Ten years later, the work of many groups instated Raf as the link between Ras, the oncogene most frequently mutated in human cancers, and the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK/ERK) module, which with its manifold substrates can contribute to different aspects of carcinogenesis. Finally, the discovery of activating B-Raf mutations in a subset of human cancers, notably melanomas, conclusively established Raf as a major player in tumor development. Recent studies in animal models now show that endogenous C-Raf is essential for the development and maintenance of Ras-induced epidermal tumors. Surprisingly, the role of C-Raf in this case is not that of an mitogen-activated protein kinase activator, but rather that of an endogenous inhibitor of Rho signaling, expanding the range of tumor-related Raf targets. This review focuses on old and new targets of Raf in tumorigenesis.


Asunto(s)
Neoplasias/etiología , Quinasas raf/fisiología , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Genes ras , Humanos , MAP Quinasa Quinasa Quinasa 5/fisiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Proteínas Proto-Oncogénicas B-raf/fisiología , Proteínas Proto-Oncogénicas c-raf/fisiología , Transducción de Señal
4.
J Cell Biol ; 187(3): 335-42, 2009 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-19948477

RESUMEN

The activity of Raf-1 and Rok-alpha kinases is regulated by intramolecular binding of the regulatory region to the kinase domain. Autoinhibition is relieved upon binding to the small guanosine triphosphatases Ras and Rho. Downstream of Ras, Raf-1 promotes migration and tumorigenesis by antagonizing Rok-alpha, but the underlying mechanism is unknown. In this study, we show that Rok-alpha inhibition by Raf-1 relies on an intermolecular interaction between the Rok-alpha kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-alpha's own autoinhibitory region. Thus, Raf-1 mediates Rok-alpha inhibition in trans, which is a new concept in kinase regulation. This mechanism is physiologically relevant because Raf-1reg is sufficient to rescue all Rok-alpha-dependent defects of Raf-1-deficient cells. Downstream of Ras and Rho, the Raf-1-Rok-alpha interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility.


Asunto(s)
Proteínas Proto-Oncogénicas c-raf/fisiología , Quinasas Asociadas a rho/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Activación Enzimática , Retroalimentación Fisiológica , Ratones , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-raf/química , Proteínas Proto-Oncogénicas c-raf/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores
5.
PLoS One ; 2(11): e1165, 2007 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-18043727

RESUMEN

The spindle assembly checkpoint (SAC) ensures correct separation of sister chromatids in somatic cells and provokes a cell cycle arrest in metaphase if one chromatid is not correctly attached to the bipolar spindle. Prolonged metaphase arrest due to overexpression of Mad2 has been shown to be deleterious to the ensuing anaphase, leading to the generation of aneuploidies and tumorigenesis. Additionally, some SAC components are essential for correct timing of prometaphase. In meiosis, we and others have shown previously that the Mad2-dependent SAC is functional during the first meiotic division in mouse oocytes. Expression of a dominant-negative form of Mad2 interferes with the SAC in metaphase I, and a knock-down approach using RNA interference accelerates anaphase onset in meiosis I. To prove unambigiously the importance of SAC control for mammalian female meiosis I we analyzed oocyte maturation in Mad2 heterozygote mice, and in oocytes overexpressing a GFP-tagged version of Mad2. In this study we show for the first time that loss of one Mad2 allele, as well as overexpression of Mad2 lead to chromosome missegregation events in meiosis I, and therefore the generation of aneuploid metaphase II oocytes. Furthermore, SAC control is impaired in mad2+/- oocytes, also leading to the generation of aneuploidies in meiosis I.


Asunto(s)
Proteínas de Ciclo Celular/fisiología , Cromosomas , Meiosis , Huso Acromático , Animales , Femenino , Proteínas Mad2 , Ratones
6.
Curr Biol ; 13(18): 1596-608, 2003 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-13678590

RESUMEN

BACKGROUND: The importance of mitotic spindle checkpoint control has been well established during somatic cell divisions. The metaphase-to-anaphase transition takes place only when all sister chromatids have been properly attached to the bipolar spindle and are aligned at the metaphase plate. Failure of this checkpoint may lead to unequal separation of sister chromatids. On the contrary, the existence of such a checkpoint during the first meiotic division in mammalian oocytes when homologous chromosomes are segregated has remained controversial. RESULTS: Here, we show that mouse oocytes respond to spindle damage by a transient and reversible cell cycle arrest in metaphase I with high Maturation Promoting Factor (MPF) activity. Furthermore, the mitotic checkpoint protein Mad2 is present throughout meiotic maturation and is recruited to unattached kinetochores. Overexpression of Mad2 in meiosis I leads to a cell cycle arrest in metaphase I. Expression of a dominant-negative Mad2 protein interferes with proper spindle checkpoint arrest. CONCLUSIONS: Errors in meiosis I cause missegregation of chromosomes and can result in the generation of aneuploid embryos with severe birth defects. In human oocytes, failures in spindle checkpoint control may be responsible for the generation of trisomies (e.g., Down Syndrome) due to chromosome missegregation in meiosis I. Up to now, the mechanisms ensuring correct separation of chromosomes in meiosis I remained unknown. Our study shows for the first time that a functional Mad2-dependent spindle checkpoint exists during the first meiotic division in mammalian oocytes.


Asunto(s)
Proteínas Portadoras/metabolismo , Metafase/fisiología , Oocitos/citología , Oocitos/metabolismo , Huso Acromático/metabolismo , Animales , Proteínas de Ciclo Celular , Cromosomas de los Mamíferos/efectos de los fármacos , Cromosomas de los Mamíferos/metabolismo , Femenino , Proteínas Mad2 , Mesotelina , Metafase/efectos de los fármacos , Ratones , Nocodazol/farmacología , Proteínas Nucleares , Oocitos/efectos de los fármacos , Huso Acromático/efectos de los fármacos
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