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1.
Mol Metab ; 19: 97-106, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30409703

RESUMEN

OBJECTIVE: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications. METHODS: Whole body ablation of Lumican (Lum-/-) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling. RESULTS: Lumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance. CONCLUSIONS: These data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome.


Asunto(s)
Glucosa/metabolismo , Lumican/metabolismo , Obesidad/metabolismo , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Adulto , Animales , Dieta Alta en Grasa , Matriz Extracelular/metabolismo , Femenino , Homeostasis , Humanos , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Hígado/metabolismo , Lumican/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteoglicanos/metabolismo
2.
Cell Death Dis ; 7(6): e2250, 2016 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-27253414

RESUMEN

An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor.


Asunto(s)
Apoptosis , Citoprotección , Hepatocitos/metabolismo , Hepatocitos/patología , Inflamación/patología , Neoplasias Hepáticas/patología , Hígado/patología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Enfermedad Crónica , Citocinas/metabolismo , Citoprotección/efectos de los fármacos , Dieta Alta en Grasa , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Eliminación de Gen , Hepatitis/metabolismo , Hepatitis/patología , Hepatocitos/efectos de los fármacos , Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Hígado/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Fenotipo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/farmacología
3.
Leukemia ; 30(7): 1520-30, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27055871

RESUMEN

T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Apoptosis , Linfoma de Células T/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/análisis , Animales , Proteínas Reguladoras de la Apoptosis/análisis , Supervivencia Celular , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Humanos , Linfoma de Células T/patología , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/genética
4.
Oncogene ; 35(24): 3125-38, 2016 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-26500060

RESUMEN

Activation of hypoxia-inducible factor (HIF) is due to loss of von Hippel-Lindau protein (pVHL) function in most clear cell renal cell carcinomas (ccRCCs). Here we describe a novel pVHL-independent mechanism of HIF regulation and identify nuclear factor (NF)-κB essential modulator (NEMO) as a hitherto unknown oncogenic factor influencing human ccRCC progression. Over 60% of human ccRCCs (n=157) have negative or weak NEMO protein expression by immunohistochemistry. Moderate/strong NEMO protein expression is more frequent in VHL wild-type ccRCCs. We show that NEMO stabilizes HIFα via direct interaction and independently of NF-κB signaling in vitro. NEMO prolongs tumor cell survival via regulation of apoptosis and activation of epithelial-to-mesenchymal transition, facilitating tumor metastasis. Our findings suggest that NEMO-driven HIF activation is involved in progression of ccRCC. Therefore, NEMO may represent a clinically relevant link between NF-κB and the VHL/HIF pathways. Targeting NEMO with specific inhibitors in patients with metastatic ccRCC could be a novel treatment approach in patients with ccRCC expressing functional pVHL.


Asunto(s)
Carcinoma de Células Renales/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Quinasa I-kappa B/metabolismo , Neoplasias Renales/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Carcinoma de Células Renales/patología , Muerte Celular/fisiología , Movimiento Celular/fisiología , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Neoplasias Renales/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , FN-kappa B/metabolismo , Transducción de Señal , Regulación hacia Arriba
5.
Cell Death Differ ; 22(12): 2020-33, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26045047

RESUMEN

NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTßR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex. In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTßR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 8/química , Caspasa 8/metabolismo , Línea Celular , Proteína de Dominio de Muerte Asociada a Fas/química , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Proteínas Activadoras de GTPasa/química , Células HEK293 , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Receptor beta de Linfotoxina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/efectos de los fármacos , Timo/metabolismo , Timo/patología , Factor de Necrosis Tumoral alfa/farmacología , Quinasa de Factor Nuclear kappa B
6.
Mucosal Immunol ; 7(6): 1452-66, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24850428

RESUMEN

Loss of intestinal epithelial cell (IEC) homeostasis and apoptosis negatively affect intestinal barrier function. Uncontrolled activation of the unfolded protein response (UPR) in IEC contributes to an impaired barrier and is implicated in the pathogenesis of inflammatory bowel diseases. However, the contribution of the UPR target gene C/EBP homologous protein (CHOP), an apoptosis-associated transcription factor, to inflammation-related disease susceptibility remains unclear. Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis. To elucidate the molecular mechanisms of IEC-specific CHOP expression, we generated a conditional transgenic mouse model (Chop(IEC Tg/Tg)). Chop overexpression increased the susceptibility toward dextran sodium sulfate (DSS)-induced intestinal inflammation and mucosal tissue injury. Furthermore, a delayed recovery from DSS-induced colitis and impaired closure of mechanically induced mucosal wounds was observed. Interestingly, these findings seemed to be independent of CHOP-mediated apoptosis. In vitro and in vivo cell cycle analyses rather indicated a role for CHOP in epithelial cell proliferation. In conclusion, these data show that IEC-specific overexpression impairs epithelial cell proliferation and mucosal tissue regeneration, suggesting an important role for CHOP beyond mediating apoptosis.


Asunto(s)
Apoptosis/inmunología , Ciclo Celular/inmunología , Colitis Ulcerosa/inmunología , Mucosa Intestinal/fisiología , Regeneración/inmunología , Factor de Transcripción CHOP/inmunología , Animales , Apoptosis/genética , Ciclo Celular/genética , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Regeneración/genética , Factor de Transcripción CHOP/genética , Respuesta de Proteína Desplegada/genética , Respuesta de Proteína Desplegada/inmunología
7.
Br J Cancer ; 110(3): 686-94, 2014 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-24327013

RESUMEN

BACKGROUND: The mechanisms of brain metastasis in renal cell cancer (RCC) patients are poorly understood. Chemokine and chemokine receptor expression may contribute to the predilection of RCC for brain metastasis by recruitment of monocytes/macrophages and by control or induction of vascular permeability of the blood-brain barrier. METHODS: Frequency and patterns of brain metastasis were determined in 246 patients with metastatic RCC at autopsy. Expression of CXCR4, CCL7 (MCP-3), CCR2 and CD68(+) tumour-associated macrophages (TAMs) were analysed in a separate series of 333 primary RCC and in 48 brain metastases using immunohistochemistry. RESULTS: Fifteen percent of 246 patients with metastasising RCC had brain metastasis. High CXCR4 expression levels were found in primary RCC and brain metastases (85.7% and 91.7%, respectively). CCR2 (52.1%) and CCL7 expression (75%) in cancer cells of brain metastases was more frequent compared with primary tumours (15.5% and 16.7%, respectively; P<0.0001 each). The density of CD68(+) TAMs was similar in primary RCC and brain metastases. However, TAMs were more frequently CCR2-positive in brain metastases than in primary RCC (P<0.001). CONCLUSION: Our data demonstrate that the monocyte-specific chemokine CCL7 and its receptor CCR2 are expressed in tumour cells of RCC. We conclude that monocyte recruitment by CCR2 contributes to brain metastasis of RCC.


Asunto(s)
Neoplasias Encefálicas/genética , Quimiocina CCL7/biosíntesis , Neoplasias Renales/genética , Receptores CCR2/biosíntesis , Anciano , Anciano de 80 o más Años , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Autopsia , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Receptores CXCR4/biosíntesis
8.
Oncogene ; 33(25): 3217-24, 2014 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-23851506

RESUMEN

The tumor microenvironment consists of stromal cells and leukocytes that contribute to cancer progression. Cross-talk between tumor cells and their microenvironment is facilitated by a variety of soluble factors, including growth factors and cytokines such as chemokines. Due to a wide expression of chemokine receptors on cells in the tumor microenvironment, including tumor cells, chemokines affect various processes such as leukocyte recruitment, angiogenesis, tumor cell survival, tumor cell adhesion, proliferation, vascular permeability, immune suppression, invasion and metastasis. Inflammatory chemokines are instrumental players in cancer-related inflammation and significantly contribute to numerous steps during metastasis. Recruitment of myeloid-derived cells to metastatic sites is mainly mediated by the inflammatory chemokines CCL2 and CCL5. Tumor cell homing and extravasation from the circulation to distant organs are also regulated by inflammatory chemokines. Recent experimental evidence demonstrated that besides leukocyte recruitment, tumor cell-derived CCL2 directly activated endothelial cells and together with monocytes facilitated tumor cell extravasation, in a CCL2- and CCL5-dependent manner. Furthermore, CX3CL1 expression in the bone facilitated metastasis of CX3CR1 expressing tumor cells to this site. Current findings in preclinical models strongly suggest that inflammatory chemokines have an important role during metastasis and targeting of the chemokine axis might have a therapeutic potential.


Asunto(s)
Quimiocinas/inmunología , Inflamación/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología , Animales , Humanos , Inflamación/patología , Metástasis de la Neoplasia
9.
Oncogene ; 29(36): 5006-18, 2010 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-20603617

RESUMEN

The cytokines lymphotoxin (LT) alpha, beta and their receptor (LTbetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTbetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTbetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTbetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTbetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.


Asunto(s)
Carcinoma/etiología , Neoplasias Hepáticas/etiología , Tejido Linfoide/fisiología , Receptor beta de Linfotoxina/fisiología , Neoplasias de la Próstata/etiología , Animales , Carcinoma/genética , Carcinoma/patología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Transformación Celular Neoplásica/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Receptor beta de Linfotoxina/genética , Masculino , Modelos Biológicos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología
10.
J Gen Virol ; 89(Pt 6): 1545-1550, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18474572

RESUMEN

Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-kappaB (NF-kappaB) activity in the brain parallels the first pathological changes. The NF-kappaB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IkappaB kinase (IKK) signalosome is crucial for NF-kappaB signalling, consisting of the catalytic IKKalpha/IKKbeta subunits and the regulatory IKKgamma subunit. This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-kappaB signalling in the CNS impacts on prion pathogenesis.


Asunto(s)
FN-kappa B/metabolismo , Proteínas PrPSc/metabolismo , Scrapie/metabolismo , Animales , Encéfalo/patología , Quinasa I-kappa B/genética , Ratones , Ratones Transgénicos , FN-kappa B/genética , Proteínas PrPSc/patogenicidad , Scrapie/patología , Transducción de Señal , Virulencia
11.
Gene ; 273(1): 131-9, 2001 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-11483369

RESUMEN

The tubby-like protein 1 (tulp1) gene is a member of the tubby multigene family which includes tub, tulp1, tulp2 and tulp3. Human and mouse tulp1 genes were cloned and mutations in tulp1 have been implicated in retinitis pigmentosa in man. Here we report on the cDNA cloning of the chicken tulp1 homologue and its protein product deduced from the nucleotide sequence. The chicken Tulp1 protein comprises 358 amino acids with a calculated molecular mass of 40 kDa. The overall structure of Tub and Tulp proteins, exemplified by the highly conserved C-terminal domain of 255 amino acids and the signature motif KLACE, is also preserved in chicken Tulp1. Phylogenetic analysis demonstrates that chicken tulp1 cDNA and protein are closely related to human and mouse tulp1. In addition, chicken tulp1 mRNA is abundantly expressed in retina similar to tulp1 expression in human and mouse. Two tulp1-specific transcripts of 2 and 3 kb in size were identified that showed differential regulation during embryonic and postnatal development. Finally, tulp1 mRNA was found to be expressed in chicken erythroid cells and upregulated by ligand-activated thyroid hormone receptor (TR alpha/c-erbA).


Asunto(s)
Pollos/genética , Proteínas del Ojo/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Regulación de la Expresión Génica , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Hormonas Tiroideas/farmacología
12.
EMBO Rep ; 2(6): 499-504, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11415982

RESUMEN

Thyroid hormone T3/T4 is a major regulator of energy metabolism in vertebrates, and defects in thyroid status are frequently associated with changes in body weight. It is demonstrated here that thyroid hormone regulates in vivo and in vitro the tub gene, which when mutated in tubby mice causes obesity, insulin resistance and sensory deficits. Hypothyroidism in rats altered tub mRNA and protein in discrete brain areas. These changes could be attributed to thyroid hormone deficiency since T3/T4 treatment restored normal tub expression. T3 also upregulated tub mRNA within 4-6 h in neuronal cells in culture, suggesting that T3 is a positive regulator of tub gene expression. Thus, these results establish a novel pathway of T3 action and provide an important molecular link between thyroid status and the tubby-associated syndrome.


Asunto(s)
Regulación de la Expresión Génica , Proteínas/metabolismo , Hormonas Tiroideas/fisiología , Proteínas Adaptadoras Transductoras de Señales , Animales , Northern Blotting , Peso Corporal , Encéfalo/metabolismo , Línea Celular , Perfilación de la Expresión Génica , Hipotiroidismo/metabolismo , Inmunohistoquímica , Hibridación in Situ , Mutación , Células PC12 , ARN Mensajero/metabolismo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia Arriba
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