Publications by authors named "Jose L Fernandez-Luna"

33 Publications

Hypoxia Can Induce Migration of Glioblastoma Cells Through a Methylation-Dependent Control of Gene Expression.

Front Oncol 2019 10;9:1036. Epub 2019 Oct 10.

Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.

The transmembrane protein ODZ1 has been associated with the invasive capacity of glioblastoma (GBM) cells through upregulation of RhoA/ROCK signaling, but the mechanisms triggering the ODZ1 pathway remain elusive. In addition, it is widely accepted that hypoxia is one of the main biological hallmarks of the GBM microenvironment and it is associated with treatment resistance and poor prognosis. Here we show that hypoxic tumor regions express higher levels of ODZ1 and that hypoxia induces ODZ1 expression in GBM cells by regulating the methylation status of the ODZ1 promoter. Hypoxia-induced upregulation of ODZ1 correlates with higher migration capacity of GBM cells that is drastically reduced by knocking down ODZ1. methylation of the promoter decreases its transactivation activity and we found a functionally active CpG site at the 3'end of the promoter. This site is hypermethylated in somatic neural cells and mainly hypomethylated in GBM cells. Mutagenesis of this CpG site reduces the promoter activity in response to hypoxia. Overall, we identify hypoxia as the first extracellular activator of ODZ1 expression and describe that hypoxia controls the levels of this migration-inducer, at least in part, by regulating the methylation status of the ODZ1 gene promoter.
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http://dx.doi.org/10.3389/fonc.2019.01036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795711PMC
October 2019

Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells.

J Oncol 2019 29;2019:1740763. Epub 2019 Jul 29.

Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.
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http://dx.doi.org/10.1155/2019/1740763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699388PMC
July 2019

GENYOi004-A: An induced pluripotent stem cells (iPSCs) line generated from a patient with autism-related ADNP syndrome carrying a pTyr719* mutation.

Stem Cell Res 2019 05 22;37:101446. Epub 2019 Apr 22.

Gene Regulation, Stem Cells and Development Group, Department of Genomic Oncology, GENYO: Centre for Genomics and Oncological Research-Pfizer, University of Granada, Junta de Andalucía, PTS, 18016 Granada, Spain; Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, 18016 Granada, Spain. Electronic address:

ADNP syndrome is an intellectual disability associated with Autism spectrum disorder caused by mutations in ADNP. We generated an iPSC line from an ADNP syndrome pediatric patient harboring the mutation p.Trp719* (GENYOi004-A). Peripheral blood mononuclear cells were reprogrammed using a non-transmissible form of Sendai viruses expressing the four Yamanaka factors (Oct3/4, SOX2, KLF4 and c-MYC). Characterization of GENYOi004-A included mutation analysis of ADNP by allele-specific PCR, genetic identity by Short Tandem Repeats polymorphism profiling, alkaline phosphatase enzymatic activity, expression of pluripotency-associated factors and pluripotency studies in vivo. GENYOi004-A will be useful to evaluate ADNP syndrome alterations at early developmental stages.
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http://dx.doi.org/10.1016/j.scr.2019.101446DOI Listing
May 2019

Cellular and animal models of skin alterations in the autism-related ADNP syndrome.

Sci Rep 2019 01 24;9(1):736. Epub 2019 Jan 24.

Genetics Unit, Hospital Valdecilla, 39008, Santander, Spain.

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy control. Adnp haploinsufficient mice (Adnp) mimicked the human condition showing reduced dermal thickness. Intranasal administration of NAP significantly increased dermal thickness and normalized the levels of cell cycle and differentiation markers. Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients.
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http://dx.doi.org/10.1038/s41598-018-36859-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346103PMC
January 2019

NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4.

Sci Rep 2018 04 20;8(1):6341. Epub 2018 Apr 20.

Genetics Unit Hospital Valdecilla and Instituto de Investigacion Valdecilla (IDIVAL), Av. Valdecilla s/n, 39008, Santander, Spain.

We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity.
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http://dx.doi.org/10.1038/s41598-018-24444-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910430PMC
April 2018

Evaluation of Toll-like-receptor gene family variants as prognostic biomarkers in rheumatoid arthritis.

Immunol Lett 2017 07 7;187:35-40. Epub 2017 May 7.

Unidad de Genética, Hospital Universitario Marqués de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain. Electronic address:

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main feature is persistent joint inflammation. Toll-like receptors (TLRs) play critical roles in the activation of innate and adaptive immune responses, and influence the activity of NFκB, a key player in chronic inflammation. We aimed at investigating the association of TLR allelic variants with susceptibility and severity of RA through a systematic, high-throughput, analysis of TLR genes. All coding exons and flanking regions of nine members of the TLR family (TLR1-9) were analyzed in 66 patients with RA and 30 healthy controls by next generation sequencing. We focussed on three single allelic variants, N248S in TLR1, Q11L in TLR7 and M1V in TLR8 based on the allelic frequencies in both patient and control populations, the predicted impact on protein function and the novelty in RA research. Analysis of these selected variants in a larger cohort of 402 patients with RA and in 208 controls revealed no association with susceptibility. However, the M1V allele was associated with a lower need for disease-modifying antirheumatic drugs (DMARDs) (p=0.008) and biologic treatments (p=0.021). Functional studies showed that the M1V variant leads to a reduced production of inflammatory cytokines, IL-1β, IL-6 and TNFα, in response to TLR8 agonists. Thus, the presence of this variant confers a significant protective effect on disease severity. These results show for the first time the association between the M1V variant of TLR8 and reduced disease severity in RA, which could have prognostic value for these patients.
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http://dx.doi.org/10.1016/j.imlet.2017.04.011DOI Listing
July 2017

A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis.

Arthritis Res Ther 2016 10 4;18(1):221. Epub 2016 Oct 4.

Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain.

Background: Toll-like receptor (TLR) family members are key players in inflammation. TLR10 has been poorly studied in chronic inflammatory disorders, and its clinical relevance in rheumatoid arthritis (RA) is as yet unknown. We aimed at identifying TLR10 variants within all coding regions of the gene in patients with RA as well as studying their functional and clinical significance.

Methods: TLR10 gene variants were studied by performing sequencing of 66 patients with RA and 30 control subjects. A selected variant, I473T, was then analyzed in 1654 patients and 1702 healthy control subjects. The capacity of this TLR10 variant to modify the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) was determined by using a luciferase reporter assay and analyzing the expression of NFkB target genes by quantitative polymerase chain reaction. Differences between groups were analyzed by using the Mann-Whitney U test and the unpaired two-tailed Student's t test.

Results: We detected ten missense variants in the TLR10 gene and focused on the I473T substitution based on allele frequencies and the predicted functional impact. I473T variant is not associated with susceptibility to RA, but it significantly correlates with erosive disease in patients seropositive for antibodies to citrullinated protein antigens (p = 0.017 in the total cohort and p = 0.0049 in female patients) and with a lower response to infliximab treatment as measured by the change in Disease Activity Score in 28 joints (p = 0.012) and by the European League Against Rheumatism criteria (p = 0.049). Functional studies showed that TLR10 reduced activation of the NFkB inflammatory pathway in hematopoietic cells, whereas the I473T variant lacked this inhibitory capacity. Consistently, after exposure to infliximab, cells expressing the I437T variant showed higher NFkB activity than cells carrying wild-type TLR10.

Conclusions: A TLR10 allelic variant, I473T, has impaired NFkB inhibitory activity and is highly associated with disease severity and low response to infliximab in patients with RA.
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http://dx.doi.org/10.1186/s13075-016-1113-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050569PMC
October 2016

A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis.

J Immunol 2015 Dec 26;195(11):5415-20. Epub 2015 Oct 26.

Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain;

Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.
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http://dx.doi.org/10.4049/jimmunol.1501532DOI Listing
December 2015

Inhibition of Cancer Cell Migration by Multiwalled Carbon Nanotubes.

Adv Healthc Mater 2015 Aug 11;4(11):1640-4. Epub 2015 Jun 11.

Departamento de Biología Molecular, Universidad de Cantabria-IDIVAL, 39011, Santander, Spain.

Inhibiting cancer cell migration and infiltration to other tissues makes the difference between life and death. Multiwalled carbon nanotubes (MWCNTs) display intrinsic biomimetic properties with microtubules, severely interfering with the function of these protein filaments during cell proliferation, triggering cell death. Here it is shown MWCNTs disrupt the centrosomal microtubule cytoskeletal organization triggering potent antimigratory effects in different cancer cells.
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http://dx.doi.org/10.1002/adhm.201500252DOI Listing
August 2015

Culture dimensionality influences the resistance of glioblastoma stem-like cells to multikinase inhibitors.

Mol Cancer Ther 2014 Jun 10;13(6):1664-72. Epub 2014 Apr 10.

Authors' Affiliations: Molecular Genetics Unit and Neurosurgery Service, Hospital Valdecilla and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain

Sunitinib, an inhibitor of kinases, including VEGFR and platelet-derived growth factor receptor (PDGFR), efficiently induces apoptosis in vitro in glioblastoma (GBM) cells, but does not show any survival benefit in vivo. One detrimental aspect of current in vitro models is that they do not take into account the contribution of extrinsic factors to the cellular response to drug treatment. Here, we studied the effects of substrate properties including elasticity, dimensionality, and matrix composition on the response of GBM stem-like cells (GSC) to chemotherapeutic agents. Thirty-seven cell cultures, including GSCs, parenchymal GBM cells, and GBM cell lines, were treated with nine antitumor compounds. Contrary to the expected chemoresistance of GSCs, these cells were more sensitive to most agents than GBM parenchymal cells or GBM cell lines cultured on flat (two-dimensional; 2D) plastic or collagen-coated surfaces. However, GSCs cultured in collagen-based three-dimensional (3D) environments increased their resistance, particularly to receptor tyrosine kinase inhibitors, such as sunitinib, BIBF1120, and imatinib. Differences in substrate rigidity or matrix components did not modify the response of GSCs to the inhibitors. Moreover, the MEK-ERK and PI3K-Akt pathways, but not PDGFR, mediate at least in part, this dimensionality-dependent chemoresistance. These findings suggest that survival of GSCs on 2D substrates, but not in a 3D environment, relies on kinases that can be efficiently targeted by sunitinib-like inhibitors. Overall, our data may help explain the lack of correlation between in vitro and in vivo models used to study the therapeutic potential of kinase inhibitors, and provide a rationale for developing more robust drug screening models.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0854DOI Listing
June 2014

Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1.

BMC Med Genet 2013 Nov 25;14:121. Epub 2013 Nov 25.

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Background: The hereditary hemorrhagic telangiectasia syndrome (HHT), also known as the Rendu-Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. Diagnostic clinical criteria include: epistaxis, telangiectases in mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and familial inheritance. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively).

Methods: We have carried out a genetic analysis of four independent Spanish families with HHT clinical criteria, which has permitted the identification of new large deletions in ENG. These mutations were first detected using the MLPA technique and subsequently, the deletion breakpoints were mapped using a customized copy number variation (CNV) microarray. The array was designed to cover the ENG gene and surrounding areas.

Results: All tested families carried large deletions ranging from 3-kb to 100-kb, involving the ENG gene promoter, several ENG exons, and the two downstream genes FGSH and CDK9. Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.

Conclusions: The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.
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http://dx.doi.org/10.1186/1471-2350-14-121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222255PMC
November 2013

Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells.

PLoS One 2013 14;8(10):e77098. Epub 2013 Oct 14.

Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain ; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796557PMC
June 2014

Cellular plasticity confers migratory and invasive advantages to a population of glioblastoma-initiating cells that infiltrate peritumoral tissue.

Stem Cells 2013 Jun;31(6):1075-85

Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain.

Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators αVβ3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, β3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVβ3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.
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http://dx.doi.org/10.1002/stem.1349DOI Listing
June 2013

Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin.

J Biol Chem 2012 Aug 20;287(32):26495-505. Epub 2012 Jun 20.

Molecular Genetics Unit, Hospital Valdecilla, and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, 39011 Santander, Spain.

Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.
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http://dx.doi.org/10.1074/jbc.M112.376319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410991PMC
August 2012

The NFκB pathway: a therapeutic target in glioblastoma.

Oncotarget 2011 Aug;2(8):646-53

Molecular Genetics Unit, Hospital Valdecilla-IFIMAV, Santander, Spain.

Cancer initiating cells have been described to be the only cell population with tumorigenic capacity in glioblastoma multiforme, one of the most aggressive and untreatable cancers. Recent work from our group described that NFκB pathway was activated in glioblastoma initiating cells undergoing differentiation, and that blockade of this activation promoted senescence of differentiating cells. NFκB activation in cancer may be the result of either exposure to proinflammatory stimuli in the tumor microenvironment or upregulation of the signaling pathway by upstream regulators. Appropriate control of NFκB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NFκB related tumors, including glioblastoma. Here, we summarize the current knowledge of the relevance of NFκB in cancer and its possible role as a target of therapeutic intervention..
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248209PMC
http://dx.doi.org/10.18632/oncotarget.322DOI Listing
August 2011

A novel pathway of TEF regulation mediated by microRNA-125b contributes to the control of actin distribution and cell shape in fibroblasts.

PLoS One 2011 Feb 11;6(2):e17169. Epub 2011 Feb 11.

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Instituto de Formacion e Investigacion Marques de Valdecilla, Servicio Cantabro de Salud, Santander, Spain.

Background: Thyrotroph embryonic factor (TEF), a member of the PAR bZIP family of transcriptional regulators, has been involved in neurotransmitter homeostasis, amino acid metabolism, and regulation of apoptotic proteins. In spite of its relevance, nothing is known about the regulation of TEF.

Principal Findings: p53-dependent genotoxic agents have been shown to be much more harmful for PAR bZIP-deficient mice as compared to wild type animals. Here we demonstrate that TEF expression is controlled by p53 through upregulation of microRNA-125b, as determined by both regulating the activity of p53 and transfecting cells with microRNA-125b precursors. We also describe a novel role for TEF in controlling actin distribution and cell shape in mouse fibroblasts. Lack of TEF is accompanied by dramatic increase of cell area and decrease of elongation (bipolarity) and dispersion (multipolarity). Staining of actin cytoskeleton also showed that TEF (-/-) cells are characterized by appearance of circumferential actin bundles and disappearance of straight fibers. Interestingly, transfection of TEF (-/-) fibroblasts with TEF induced a wild type-like phenotype. Consistent with our previous findings, transfection of wild type fibroblasts with miR-125b promoted a TEF (-/-)-like phenotype, and a similar but weaker effect was observed following exogenous expression of p53.

Conclusions/significance: These findings provide the first evidence of TEF regulation, through a miR-125b-mediated pathway, and describes a novel role of TEF in the maintenance of cell shape in fibroblasts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017169PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037971PMC
February 2011

Association of the aromatase gene alleles with BMD: epidemiological and functional evidence.

J Bone Miner Res 2009 Oct;24(10):1709-18

Department of Internal Medicine, Hospital U. M. Valdecilla, University of Cantabria, Av. Valdecilla s/n, Santander 39008, Spain.

BMD has a strong heritable component. Estrogen activity depends on the aromatization of androgenic precursors in nongonadal tissues both in postmenopausal women and men. Therefore, aromatase is an appealing candidate gene to explain, in part, the genetic component of BMD. In fact, an association between aromatase polymorphisms and BMD has been previously reported in some relatively small groups. In this study, we explored the relationship between several SNPs in the aromatase region and hip BMD in 1163 postmenopausal women. We found significant differences across genotypes, particularly in older women. The BMD differences between homozygous women with opposing genotypes were 4.2% in the whole group and 7.3% in women >67 yr of age. Body weight was significantly associated with BMD also, but there was no evidence for a statistically significant interaction between body weight and aromatase polymorphisms. Electrophoretic mobility shift assays suggested the binding of the CEBPss transcription factor to the C/G rs1062033 locus, located approximately 12 kb upstream of the translation start site. Experiments of transient transfection of osteoblastic cells with luciferase reporters showed differences in the transcriptional activity of alleles C and G at this locus, with different responses to the co-transfection of a CEBPss expression vector. Furthermore, evidence for differential allelic expression was found in bone tissue samples. In conclusion, polymorphisms in a 12-kb region of the aromatase gene are associated with BMD in postmenopausal women, particularly during the late postmenopausal period. In vitro functional studies point to rs1062033 as a true regulatory polymorphism.
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http://dx.doi.org/10.1359/jbmr.090404DOI Listing
October 2009

Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia.

BMC Med Genet 2008 Aug 1;9:75. Epub 2008 Aug 1.

Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu, 9, Madrid 28040, Spain.

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes.

Methods: Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT.

Results: We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM) in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model.

Conclusion: Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy), but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.
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http://dx.doi.org/10.1186/1471-2350-9-75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518546PMC
August 2008

Regulation of pro-apoptotic BH3-only proteins and its contribution to cancer progression and chemoresistance.

Cell Signal 2008 Nov 8;20(11):1921-6. Epub 2008 May 8.

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, 39008 Santander, Spain.

The BH3-only members of the Bcl-2 protein family function as damage sensors in the cell and initiate the apoptotic cascade. Apoptosis is the primary mechanism by which the body gets rid of genetically defective cells and is critical for preventing the accumulation of cells with tumorigenic potential. BH3-only proteins have evolved to respond to distinct forms of cellular stress or DNA damage by inactivating the protective function of the prosurvival members of the Bcl-2 family. Therefore, a downregulated expression or activity of these proteins may favour tumor development. Moreover, the pro-apoptotic proteins are required for the success of most cancer treatments, including chemotherapy. Resistance to chemotherapy, a common feature of cancer, often reflects an inability of tumor cells to undergo apoptosis. Deciphering the regulation and activity of the BH3-only proteins may provide the basis for novel therapeutic strategies aimed at promoting tumor cell death or enhancing susceptibility to chemotherapeutic agents. This review summarizes the current knowledge of BH3-only proteins and their contribution to tumorigenesis and chemoresistance.
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http://dx.doi.org/10.1016/j.cellsig.2008.04.015DOI Listing
November 2008

NLRP2, an inhibitor of the NF-kappaB pathway, is transcriptionally activated by NF-kappaB and exhibits a nonfunctional allelic variant.

J Immunol 2007 Dec;179(12):8519-24

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain.

NLRP2 has been shown to inhibit the NF-kappaB signaling pathway, and thus may contribute to modulate the inflammatory response, where NF-kappaB plays a major role. In this study, we report that expression of NLRP2 is induced upon differentiation of CD34+ hemopoietic progenitors into granulocyte or monocyte/macrophages. We also found that NLRP2 was up-regulated following differentiation of mesenchymal stem cells toward adipocytes. Notably, stimulation of HEK293T cells with TNF-alpha or overexpression of the p65 subunit of NF-kappaB resulted in up-regulation of NLRP2 and the formation of NF-kappaB-NLRP2 promoter complexes. Moreover, ectopic expression of p65 but not of other transcriptional regulators induced transactivation of the NLRP2 promoter. Thus, NLRP2 may control NF-kappaB activation through a regulatory loop. Nucleotide changes within the NACHT domain of other NLRP proteins have been associated with hereditary fever syndromes and chronic inflammatory diseases. We identified five single nucleotide polymorphisms present in the NACHT domain of NLRP2 by sequencing genomic DNA from 319 healthy controls. The frequencies of the rare alleles varied between 0.2 and 10%. Of note, one of these variants, I352S was unable to block the transcriptional activity of NF-kappaB and the formation of NF-kappaB-DNA-binding complexes following stimulation with TNF-alpha. Overall, our findings provide molecular insight into the expression of NLRP2 by NF-kappaB and suggest that a polymorphism within the NACHT domain of NLRP2 may contribute to the amplification of inflammatory responses due to a reduction of inhibitory signals on the NF-kappaB pathway.
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http://dx.doi.org/10.4049/jimmunol.179.12.8519DOI Listing
December 2007

Deficiency of the NF-kappaB inhibitor caspase activating and recruitment domain 8 in patients with rheumatoid arthritis is associated with disease severity.

J Immunol 2007 Oct;179(7):4867-73

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain.

Caspase activating and recruitment domain 8 (CARD8) potently inhibits NF-kappaB signaling, which plays a key role in inflammation, and may contribute to avoid a pathologic activation of NF-kappaB; however, the transcriptional mechanisms regulating CARD8 expression and the relevance of this protein in inflammatory diseases are poorly understood. We found a NF-kappaB-binding element within the human CARD8 promoter that was required for transcriptional activity in response to TNF-alpha and the p65 subunit of NF-kappaB. Moreover, TNF-alpha and overexpression of p65 induced the formation of NF-kappaB-CARD8 promoter complexes. Thus, CARD8 may control NF-kappaB activation through a regulatory loop. To study the relevance of CARD8 in chronic inflammatory disorders, we functionally characterized a deleterious polymorphism (p.C10X) and studied its association with rheumatoid arthritis (RA). Transfection of cell lines with the allelic variants of CARD8 revealed that full-length (CARD8-L) but not truncated (CARD8-S) protein inhibits NF-kappaB transcriptional activity, and abrogates the binding of NF-kappaB to its consensus site. Furthermore, in contrast to the full-length protein, CARD8-S did not modify the expression of NF-kappaB target genes (cIAP, A1), in response to TNF-alpha. We analyzed the p.C10X polymorphism in 200 patients with RA, and found that homozygous carriers of the CARD8-S allele have higher disease activity score (p = 0.014), more extra-articular manifestations (p = 0.03), and a lower probability of clinical remission (p = 0.03) than the CARD8-L allele carriers. Overall, our findings provide molecular insight into the expression of CARD8 by NF-kappaB, and suggest that a deleterious polymorphism of CARD8 may help predict the severity of RA.
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http://dx.doi.org/10.4049/jimmunol.179.7.4867DOI Listing
October 2007

A novel role for proline- and acid-rich basic region leucine zipper (PAR bZIP) proteins in the transcriptional regulation of a BH3-only proapoptotic gene.

J Biol Chem 2006 Dec 20;281(50):38351-7. Epub 2006 Oct 20.

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, 39008 Santander, Spain.

Proline- and acid-rich (PAR) basic region leucine zipper (bZIP) proteins thyrotroph embryonic factor (TEF), D-site-binding protein (DBP), and hepatic leukemia factor have been involved in neurotransmitter homeostasis and amino acid metabolism. Here we demonstrate a novel role for these proteins in the transcriptional control of a BH3-only gene. PAR bZIP proteins are able to transactivate the promoter of bcl-gS. This promoter is particularly responsive to TEF activation and is silenced by NFIL3, a repressor that shares the consensus binding site with PAR bZIP proteins. Consistently, transfection of TEF induces the expression of endogenous bcl-gS in cancer cells, and this induction is independent of p53. A naturally occurring variant of DBP (tDBP), lacking the transactivation domain, has been identified and shown to impede the formation of active TEF dimers in a competitive manner and to reduce the TEF-dependent induction of bcl-gS. Of note, treatment of cancer cells with etoposide induces TEF activation and promotes the expression of bcl-gS. Furthermore, blockade of bcl-gS or TEF expression by a small interfering RNA strategy or transfection with tDBP significantly reduces the etoposide-mediated apoptotic cell death. These findings represent the first described role for PAR bZIP proteins in the regulation of a gene involved in the execution of apoptosis.
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http://dx.doi.org/10.1074/jbc.M607004200DOI Listing
December 2006

Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells.

FEBS Lett 2006 Oct 2;580(25):5905-9. Epub 2006 Oct 2.

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Av. Valdecilla s/n, 39008 Santander, Spain.

BH3-only proteins are required for execution of apoptotic cell death. We have found that one of these proteins, Bik, is strongly induced in cancer cells treated with chemotherapeutic agents. Furthermore, we showed that chemotherapy-induced expression of bik is independent of p53. Consistent with its pro-apoptotic activity, blockade of bik expression reduces the adriamycin-mediated apoptotic cell death. We also found that the bik gene is transcriptionally activated by E2F proteins. Consistently, adriamycin induces the E2F-bik pathway. In addition, E2Fs transactivate bik by a p53-independent mechanism. Thus, our data indicate that transcriptional regulation of bik contributes to the efficient apoptotic response to chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.febslet.2006.08.088DOI Listing
October 2006

Identification of c-Kit gene mutations in patients with polycythemia vera.

Leuk Res 2006 Oct 7;30(10):1325-6. Epub 2006 Feb 7.

Imatinib mesylate has recently been reported to have clinical activity in the treatment of polycythemia vera (PV), suggesting the involvement of one of the kinases targeted by this inhibitor, including c-Kit and PDGFR. Activating c-Kit mutations have been identified in patients with mastocytosis and other myeloid disorders such as acute myeloid leukemia. Thus, we wanted to analyze the presence of mutations of c-Kit in polycythemia vera patients. We found that 7 out of 20 patients carried missense mutations in the c-Kit gene whereas no sequence variation was detected in 15 healthy controls.
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http://dx.doi.org/10.1016/j.leukres.2005.12.020DOI Listing
October 2006

Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L.

Cancer Res 2005 Sep;65(18):8151-7

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, Santander, Spain.

Epidermal growth factor receptor-1 (EGFR) and EGFR-2 (HER2) have become major targets for cancer treatment. Blocking antibodies and small-molecule inhibitors are being used to silence the activity of these receptors in different tumors with varying efficacy. Thus, a better knowledge on the signaling pathways activated by EGFR and HER2 may help unravel novel therapeutic targets and molecular markers of response. Here, we show that treatment of breast cancer cell lines with blocking antibodies against EGFR (cetuximab) or HER2 (trastuzumab) promotes the specific induction of proapoptotic Bnip3L and chemosensitization. Moreover, we found that the Bnip3L gene is transcriptionally activated by FoxO3a. Trastuzumab-mediated induction of Bnip3L and nuclear translocation of FoxO3a was also shown in pleural effusion cells from a breast cancer patient. Transfection of breast cancer cells with constitutively active FoxO3a or with Bnip3L promotes sensitization to chemotherapy-induced apoptosis. On the contrary, blockade of Bnip3L expression by a small interfering RNA strategy significantly diminished the chemosensitizing effect of cetuximab. We found also an inverse correlation between EGFR and Bnip3L expression in surgical specimens from patients with breast cancer. Therefore, blockading EGFR or HER2 specifically up-regulates Bnip3L, which is required for chemosensitization of breast cancer cells. This novel pathway provides also the rationale for therapeutic strategies aimed to induce the expression of Bnip3L.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-1134DOI Listing
September 2005

Defective binding of transcriptional repressor ZEB via DNA methylation contributes to increased constitutive levels of p73 in Fanconi anemia cells.

FEBS Lett 2005 Aug;579(21):4610-4

Unidad de Genética Molecular, Hospital Universitario Marques de Valdecilla, Edificio Escuela Universitaria de Enfermeria, Servicio Cantabro de Salud, Av. Valdecilla s/n, 39008 Santander, Spain.

Little is known about the molecular mediators of the Fanconi anemia (FA) pathway involved in the machinery that maintains genomic integrity. Here, we report that the levels of p73 and its target genes, are increased in cells derived from FA patients belonging to complementation group A (FA-A). Moreover, functional correction of FA-A cells by gene transfer reduces the expression of p73. We also demonstrate that DNA methylation contributes to increased levels of p73 in FA-A cells by hampering the binding of the transcriptional repressor ZEB to an intronic regulatory region of the p73 gene. Together, our data may help explain the susceptibility of these cells to DNA damaging agents.
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http://dx.doi.org/10.1016/j.febslet.2005.07.026DOI Listing
August 2005

NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells.

Biochem J 2004 Dec;384(Pt 2):281-6

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.

NALP1 (also called DEFCAP, NAC, CARD7) has been shown to play a central role in the activation of inflammatory caspases and processing of pro-IL1b (pro-interleukin-1b). Previous studies showed that NALP1 is highly expressed in peripheral blood mononuclear cells. In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes. In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations. Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer. A search for consensus sites within the NALP1 promoter revealed a sequence for CREB (cAMP-response-element-binding protein) that was required for transcriptional activity. Moreover, treatment of TF1 myeloid leukaemia cells with protein kinase C and protein kinase A activators induced CREB phosphorylation and upregulated the mRNA and protein levels of NALP1. Conversely, ectopic expression of a dominant negative form of CREB in TF1 cells blocked the transcriptional activity of the NALP1 promoter and significantly reduced the expression of NALP1. Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli.
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http://dx.doi.org/10.1042/BJ20040867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1134111PMC
December 2004

Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells.

FEBS Lett 2004 Jun;568(1-3):79-82

Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Edificio Escuela Universitaria de Enfermeria, Av. Valdecilla s/n, 39008 Santander, Spain.

Ipaf has been associated with apoptosis, cytokine processing, and nuclear factor-kappaB activation. Here, we describe that Ipaf is highly expressed in myelomonocytic cells and that the mRNA levels of Ipaf progressively increase during differentiation of CD34(+) progenitors to granulocytes and monocytes. Additionally, treatment with tumor necrosis factor-alpha and exposure to UV radiation induced the transcriptional activation of Ipaf in human leukemia HL-60 cells. Thus, Ipaf may contribute to modulate the response of myeloid cells to genotoxic and pro-inflammatory stimuli.
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http://dx.doi.org/10.1016/j.febslet.2004.04.095DOI Listing
June 2004

Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells.

Mol Cancer Ther 2003 Sep;2(9):893-900

Grupo de Biología Molecular del Cáncer, Departamento de Biologia Molecular, Unidad de Biomedicina-CSIC, Universidad de Cantabria, Santander, Spain.

Amifostine is used as a cytoprotective agent in cancer treatments. Amifostine protects from apoptosis in some models and has been used as hematopoiesis stimulator in myeloid malignancies. As the apoptosis induced by many antitumoral agents is mediated by p53, we studied the effect of amifostine on p53-mediated apoptosis. We used human myeloid leukemia K562 and NB4 cells expressing the temperature-conditional p53-Val(135) mutant. Both cell lines undergo apoptosis at 32 degrees C due to the presence of p53 in wild-type conformation. We found that amifostine dramatically reduced apoptosis by p53 in both cell lines, as assessed by cell morphology, annexin V binding, fraction of sub-G(1) cells, and DNA laddering. To explore the mechanism responsible for this apoptosis protection, we tested the effect of amifostine on p53 transcriptional activity. We found that amifostine reduced p53-mediated transactivation of target promoters in NB4 and K562. Macroarray analysis confirmed that several p53 target genes as p21(Waf1), mdm2, gadd45, pig8, and pig3 were down-regulated at the mRNA level by amifostine in NB4 and K562. Also, c-myc was up-regulated by amifostine in K562 in the presence of p53, consistently with the impairment of p53-mediated apoptosis exerted by c-Myc in these cells. We conclude that amifostine impairs p53-dependent apoptosis of myeloid leukemia cells by reducing the activation of apoptosis-related genes. Our results open the possibility that amifostine could reduce the effectiveness of antitumoral treatments when it is dependent on active p53.
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September 2003

Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease.

Dement Geriatr Cogn Disord 2003 ;15(3):151-4

Unit of Neurology, 'Marqués de Valdecilla' University Hospital, University of Cantabria, Spain.

The H63D mutation in the hemochromatosis gene (HFE) has recently been considered as a risk factor in Alzheimer's disease (AD) with advancing age at onset of the disease, independently of the apolipoprotein E (ApoE) epsilon4 allele effect. We examined the distribution of the H63D mutation and ApoE genotypes as a function of age at AD onset in 328 patients with sporadic AD. Our data show that the mutant H63D allele potentially interacts with the ApoE epsilon4 allele to significantly reduce age at onset of AD compared to ApoE epsilon4 carriers alone, but has no effect on age at onset in ApoE epsilon4 non-carriers.
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http://dx.doi.org/10.1159/000068480DOI Listing
July 2003