Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome.

Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transforming growth factor-ß (TGF-ß)- and angiotensin II-dependent pathways, alterations in the vascular extracellular matrix (ECM) may also play a role in the onset and progression of the aortic disease. Lysyl oxidases (LOX) are extracellular enzymes, which initiates the formation of covalent cross-linking of collagens and elastin, thereby contributing to the maturation of the ECM. Here we have explored the role of LOX in the formation of aortic aneurysms in MFS. We show that aortic tissue from MFS patients and MFS mouse model (Fbn1(C1039G/+)) displayed enhanced expression of the members of the LOX family, LOX and LOX-like 1 (LOXL1), and this is associated with the formation of mature collagen fibers. Administration of a LOX inhibitor for 8weeks blocked collagen accumulation and aggravated elastic fiber impairment, and these effects correlated with the induction of a strong and rapidly progressing aortic dilatation, and with premature death in the more severe MFS mouse model, Fbn1(mgR/mgR), without any significant effect on wild type animals. This detrimental effect occurred preferentially in the ascending portion of the aorta, with little or no involvement of the aortic root, and was associated to an overactivation of both canonical and non-canonical TGF-ß signaling pathways. The blockade of angiotensin II type I receptor with losartan restored TGF-ß signaling activation, normalized elastic fiber impairment and prevented the aortic dilatation induced by LOX inhibition in Fbn1(C1039G/+) mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS.

The role of the transcription factor AP-1 in colitis-associated and beta-catenin-dependent intestinal tumorigenesis in mice.

Chronic inflammation is an important cancer risk factor but the molecular pathways linking inflammation and cancer are incompletely understood. The transcription factor c-Jun/AP-1 (activator protein 1) is involved in inflammatory responses and tumorigenesis and has been proposed as an essential mediator of oncogenic beta-catenin signaling in the intestine. Here, we examined the functions of c-Jun in two distinct mouse models of conditional and intestine-specific activation of beta-catenin. c-Jun is strongly expressed in the small intestine of mutant mice. However, beta-catenin-dependent cell proliferation is surprisingly not affected in mice lacking c-jun in intestinal epithelium, suggesting that c-Jun is not an essential immediate target of beta-catenin signaling in the small intestine. To examine the functions of Jun and Fos proteins during inflammation and cancer in the colon, colitis-associated tumors were induced chemically in the respective knockout mice. Tumors were characterized by activated beta-catenin and strongly expressed c-Jun and JunB. However, tumorigenesis was not affected by inactivation of c-Jun in either intestinal epithelium or myeloid cells. Moreover, tumorigenesis was not altered in mice lacking junB, junD, c-fos, fra-1 or fra-2, suggesting that inhibition of c-Jun or other single AP-1 proteins is not a determining factor in colitis-associated cancer in mice.

PKB/Akt media la radio sensibilidad asociada a Ataxia Telangiectasia / PKB/Akt mediates radiosensitivity associated to ataxia telangiectasia

El gen mutado en el síndrome de Ataxia Telangiectasia está implicado en múltiples funciones celulares queabarcan desde la respuesta al daño genotóxico causado por la radiación ionizante hasta la respuesta a insulina.Curiosamente la ruta de señalización mediada por Akt esta relacionada con los mismos estímulos. En el presenteestudio demostramos como el gen mutado en Ataxia Telangiectasia (ATM) controla la fosforilación deAkt, en respuesta a estímulos como la radiación ionizante o la insulina. Estos datos han sido obtenidos usandomodelos experimentales como células derivadas de enfermos de Ataxia o de ratones nulos para la expresión deATM. Nuestro estudio propone nuevas explicaciones para entender la radio sensibilidad característica de estosenfermos y destaca el papel primordial de Akt en la respuesta a la radiación ionizante

The gene mutated in ataxia telangiectasia (ATM) has been implicated in several functions such as cell cycle, response to DNA damage, and insulin. Curiously, the PKB/Akt-mediated signaling route is related to the same cellular responses. We show in this work that ATM is a major determinant of full PKB/Akt activation in response to insulin or gamma-radiation. This conclusion was inferred from the results obtained in transient transfection assays using exogenous PKB/Akt and ATM in Cos cells, and also in cell lines derived from ataxia telangiectasia patients or KO mice. Our study proposes new clues to understand the radiosensitivity associated to ataxia telangiectasia and supports a critical role for PKB/Akt in the cellular response to ionizing radiation

In vivo radiosensitizing effect of the adenovirus E1A gene in murine and human malignant tumors.

The adenovirus E1A gene is a potent inducer of chemosensitivity and radiosensitivity through p53-dependent and independent mechanisms. We have studied the sensitivity of murine (MSC11A5, a sarcomatoid epidermoid carcinoma) and human (HeLa, human cervix carcinoma) E1A-expressing tumors, in vivo, after treatment with cisplatin or gamma-irradiation. In athymic mice, half-body irradiation was performed in an AECL Cobalt unit, at an SSD of 80 cm. Daily fractions of 300 cGy over 3 days, up to a total dose of 9 Gy. Cisplatin was injected intraperitoneally at a dose of 9 mg per kg of body weight. After gamma-irradiation or intraperitoneal injection of cisplatin, about 30% of the E1A-expressing tumors regressed completely or were associated with a marked decrease in tumorigenicity over the following weeks. We conclude that malignant tumors, when expressing adenovirus E1A, are very sensitive to treatment with DNA-damaging agents, in vivo, regardless of the p53 status of the tumors.