排序方式: 共有37条查询结果,搜索用时 31 毫秒
1.
PARP-1 Regulates Metastatic Melanoma through Modulation of Vimentin-induced Malignant Transformation
María Isabel Rodríguez Andreína Peralta-Leal Francisco O'Valle José Manuel Rodriguez-Vargas Ariannys Gonzalez-Flores Jara Majuelos-Melguizo Laura López Santiago Serrano Antonio García de Herreros Juan Carlos Rodríguez-Manzaneque Rubén Fernández Raimundo G. del Moral José Mariano de Almodóvar F. Javier Oliver 《PLoS genetics》2013,9(6)
PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells. 相似文献
2.
Muñoz-Pinedo C Ruiz-Ruiz C Ruiz de Almodóvar C Palacios C López-Rivas A 《The Journal of biological chemistry》2003,278(15):12759-12768
Tumors display a high rate of glucose uptake and glycolysis. We investigated how inhibition of glucose metabolism could affect death receptor-mediated apoptosis in human tumor cells of diverse origin. We show that both substitution of glucose for pyruvate and treatment with 2-deoxyglucose enhanced apoptosis induced by tumor necrosis factor (TNF)-alpha, CD95 agonistic antibody, and TNF-related apoptosis-inducing ligand (TRAIL). Inhibition of glucose metabolism enhanced killing of myeloid leukemia U937, cervical carcinoma HeLa, and breast carcinoma MCF-7 cells upon death receptor ligation. Caspase activation, mitochondrial depolarization, and cytochrome c release were increased under these conditions. Glucose deprivation-mediated sensitization to apoptosis was prevented in MCF-7 cells overexpressing BCL-2. Interestingly, the human B-lymphoblastoid cell line SKW6.4, a prototype for mitochondria-independent death receptor-induced apoptosis, was also sensitized to anti-CD95 and TRAIL-induced apoptosis under glucose-free conditions. Changes in c-FLIP(L) and cFLIPs levels were observed in some but not all the cell lines studied following glucose deprivation. Glucose deprivation enhanced death receptor-triggered formation of death-inducing signaling complex and early processing of procaspase-8. Altogether, these results suggest that the glycolytic pathway may be an important target for therapeutic intervention to sensitize tumor cells to selectively toxic soluble death ligands or death ligand-expressing cells of the immune system by facilitating the activation of initiator caspase-8. 相似文献
3.
4.
Hormogastridae earthworms are highly important for the functioning of the Mediterranean soil system. However, little is known about the species distribution and genetic diversity of these soil invertebrates. In the present study, the genetic differentiation and gene flow were studied among populations of hormogastrids from the central Iberian Peninsula. A 648-bp portion of the mitochondrial cytochrome c oxidase I gene was sequenced for 82 individuals from 7 localities, resulting in the identification of 38 haplotypes exclusive to localities. All of the individuals were morphologically identified as Hormogaster elisae , but the high genetic divergence found among populations (up to 20.20%) suggests the occurrence of more than one cryptic species within this region. Further analysis of the phylogenetic relationships revealed six different evolutionary lineages coincident with geographical location, including the two nearest populations Molar and Redueña as one evolutionary unit. From these results, at least three new species could be inferred, in addition to the morphospecies H. elisae s.s . Partitioning of genetic variance among populations indicated that isolation by distance was the primary agent for differentiation of the investigated hormogastrid populations. Our data suggest that the evolutionary lineages for H. elisae s.l. originated between the late Miocene and the early Pleistocene, but that mtDNA genealogies coalesce on a more recent scale of a few thousand years. 相似文献
5.
Siles E Martinez-Lara E Núñez MI Muñoz-Gámez JA Martín-Oliva D Valenzuela MT Peinado MA Ruiz de Almodóvar JM Javier Oliver F 《Journal of cellular biochemistry》2005,96(4):709-715
3-nitrotyrosine (NO2-Tyr) is thought to be a specific marker of cell injury during oxidative damage. We have evaluated the role of poly(ADP-ribose)polymerase-1 (PARP-1) in protein nitration after treatment of immortalized fibroblasts parp-1+/+ and parp-1-/- with the alkylating agent 2'-methyl-2'-nitroso-urea (MNU). Both cell lines showed increased iNOS expression following MNU treatment in parallel with a selective induction of tyrosine nitration of different proteins. PARP-1 deficient cells displayed a delayed iNOS accumulation, reduced number of nitrated proteins, and a lower global nitrotyrosine "footprint." We have identified the mitochondrial compartment as the major site of oxidative stress during DNA damage, being MnSOD one of the NO2-Tyr-modified proteins, but not in parp-1-/- cells. These results suggest that NO-derived injury can be modulated by proteins involved in the response to genotoxic damage, such as PARP-1, and may account for the limited oxidative injury in parp-1 knockout mice during carcinogenesis and inflammation. 相似文献
6.
Ruiz de Almodóvar C Ruiz-Ruiz C Rodríguez A Ortiz-Ferrón G Redondo JM López-Rivas A 《The Journal of biological chemistry》2004,279(6):4093-4101
Tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) is a decoy receptor for TRAIL, a member of the tumor necrosis factor family. In several cell types decoy receptors inhibit TRAIL-induced apoptosis by binding TRAIL and thus preventing its binding to proapoptotic TRAIL receptors. We studied the regulation of TRAIL-R3 gene expression in breast tumor cells treated with the genotoxic drug doxorubicin (DXR). The breast tumor cell line MCF-7 (p53 wild type) responded to DXR with a marked elevation of TRAIL-R3 expression at the mRNA, total protein, and cell surface levels. In contrast, in EVSA-T cells (p53 mutant) DXR did not induce increased expression of TRAIL-R3. In MCF-7 cells overexpressing the human papillomavirus protein E6, which causes p53 degradation, DXR-induced TRAIL-R3 expression was notably reduced. Furthermore, in MCF-7 cells overexpressing a temperature-sensitive p53 mutant (Val135), shifting the cultures to the permissive temperature was sufficient to induce the expression of TRAIL-R3. We also cloned and characterized a p53 consensus element located within the first intron of the human TRAIL-R3 gene. This element binds p53 and confers responsiveness to genotoxic damage to constructs of the TRAIL-R3 promoter in transient transfection experiments. Our results indicate that genotoxic treatments such as DXR, frequently used in cancer therapy, may also induce genes such as TRAIL-R3 that potentially have antiapoptotic actions and thus interfere with the TRAIL signaling system. This is particularly important in view of the proposed use of TRAIL in antitumor therapy. 相似文献
7.
8.
Factors controlling brown trout Salmo trutta recruitment in Mediterranean areas are largely unknown, despite the relevance this may have for fisheries management. The
effect of hydrological variability on survival of young brown trout was studied during seven consecutive years in five resident
populations from the southern range of the species distribution. Recruit density at the end of summer varied markedly among
year-classes and rivers during the study period. Previous work showed that egg density the previous fall did not account for
more than 50% of the observed variation in recruitment density. Thus, we expected that climatic patterns, as determinants
of discharge and water temperature, would play a role in the control of young trout abundance. We tested this by analyzing
the effects of flow variation and predictability on young trout survival during the spawning to emergence and the summer drought
periods. Both hatching and emergence times and length of hatching and emergence periods were similar between years within
each river but varied considerably among populations, due to differences in water temperature. Interannual variation in flow
attributes during spawning to emergence and summer drought affected juvenile survival in all populations, once the effect
of endogenous factors was removed. Survival rate was significantly related to the timing, magnitude and duration of extreme
water conditions, and to the rate of change in discharge during hatching and emergence times in most rivers. The magnitude
and duration of low flows during summer drought appeared to be a critical factor for survival of young trout. Our findings
suggest that density-independent factors, i.e., hydrological variability, play a central role in the population dynamics of
brown trout in populations from low-latitude range margins. Reported effects of hydrologic attributes on trout survival are
likely to be increasingly important if, as predicted, climate change leads to greater extremes and variability of flow regimes. 相似文献
9.
10.
Jorge Almodóvar Justin Mower Apurba Banerjee Ajoy K. Sarkar Nicole P. Ehrhart Matt J. Kipper 《Biotechnology and bioengineering》2013,110(2):609-618
Cortical bone allografts suffer from high rates of failure due to poor integration with host tissue, leading to non‐union, fracture, and infection following secondary procedures. Here, we report a method for modifying the surfaces of cortical bone with coatings that have biological functions that may help overcome these challenges. These chitosan‐heparin coatings promote mesenchymal stem cell attachment and have significant antibacterial activity against both S. aureus and E. coli. Furthermore, their chemistry is similar to coatings we have reported on previously, which effectively stabilize and deliver heparin‐binding growth factors. These coatings have potential as synthetic periosteum for improving bone allograft outcomes. Biotechnol. Bioeng. 2013; 110: 609–618. © 2012 Wiley Periodicals, Inc. 相似文献