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1.
Free Radic Biol Med ; 147: 102-113, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31863909

ABSTRACT

Redox imbalance results in damage to cellular macromolecules and interferes with signaling pathways, leading to an inflammatory cellular and tissue environment. As such, the cellular oxidative environment is tightly regulated by several redox-modulating pathways. Many viruses have evolved intricate mechanisms to manipulate these pathways for their benefit, including HIV-1, which requires a pro-oxidant cellular environment for optimal replication. One such virulence factor responsible for modulating the redox environment is the HIV Transactivator of transcription (Tat). Tat is of particular interest as it is actively secreted by infected cells and internalized by uninfected bystander cells where it can elicit pro-oxidant effects resulting in inflammation and damage. Previously, we demonstrated that Tat regulates basal expression of Superoxide Dismutase 2 (sod2) by altering the binding of the Sp-transcription factors at regions relatively near (approx. -210 nucleotides) upstream of the transcriptional start site. Now, using in silico analysis and a series of sod2 promoter reporter constructs, we have identified putative clusters of Sp-binding sites located further upstream of the proximal sod2 promoter, between nucleotides -3400 to -210, and tested their effect on basal transcription and for their sensitivity to HIV-1 Tat. In this report, we demonstrate that under basal conditions, maximal transcription requires a cluster of Sp-binding sites in the -584 nucleotide region, which is extremely sensitive to Tat. Using chromatin immunoprecipitation (ChIP) we demonstrate that Tat results in altered occupancy of Sp1 and Sp3 at this distal Tat-sensitive regulatory element and strongly stimulated endogenous expression of SOD2 in human pulmonary artery endothelial cells (HPAEC). We also report altered expression of Sp1 and Sp3 in Tat-expressing HPAEC as well as in the lungs of HIV-1 infected humanized mice. Lastly, Tat co-immunoprecipitated with endogenous Sp3 but not Sp1 and did not alter the acetylation state of Sp3. Thus, here, we have defined a novel and important cis-acting factor in HIV-1 Tat-mediated regulation of SOD2, demonstrated that modulation of Sp1 and Sp3 activity by Tat promotes SOD2 expression in primary human pulmonary artery endothelial cells and determined that pulmonary levels of Sp3 as well as SOD2 are increased in the lungs of a mouse model of HIV infection.


Subject(s)
Endothelial Cells , HIV Infections , Animals , Binding Sites , Endothelial Cells/metabolism , Gene Products, tat , HIV Infections/genetics , Humans , Mice , Protein Binding , Pulmonary Artery/metabolism , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/metabolism , Sp3 Transcription Factor , Superoxide Dismutase , tat Gene Products, Human Immunodeficiency Virus
2.
Clin Genet ; 94(1): 187-188, 2018 07.
Article in English | MEDLINE | ID: mdl-29532936

ABSTRACT

Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions.


Subject(s)
Agenesis of Corpus Callosum/diagnosis , Hearing Loss, Sensorineural/diagnosis , Hernias, Diaphragmatic, Congenital/diagnosis , Hypercalciuria/diagnosis , Myopia/diagnosis , Nephrolithiasis/diagnosis , Phenotype , Proteinuria/diagnosis , Renal Tubular Transport, Inborn Errors/diagnosis , Adolescent , Aged , Agenesis of Corpus Callosum/genetics , Alleles , Diagnosis, Differential , Genetic Association Studies , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Hernias, Diaphragmatic, Congenital/genetics , Humans , Hypercalciuria/genetics , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Male , Myopia/genetics , Nephrolithiasis/genetics , Proteinuria/genetics , Renal Tubular Transport, Inborn Errors/genetics
3.
Br J Cancer ; 110(11): 2708-15, 2014 May 27.
Article in English | MEDLINE | ID: mdl-24809782

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome. METHODS: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-ß and ß-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out. RESULTS: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-ß at transcription and protein level was observed, whereas for ß-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis. CONCLUSIONS: SERPINB3 is overexpressed in the subset of the most aggressive HCCs.


Subject(s)
Antigens, Neoplasm/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Serpins/metabolism , Transforming Growth Factor beta1/metabolism , beta Catenin/metabolism , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/genetics , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Disease-Free Survival , Female , Gene Expression , Gene Expression Profiling , Hep G2 Cells , Humans , Kaplan-Meier Estimate , Liver/metabolism , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/prevention & control , Prognosis , Proportional Hazards Models , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serpins/genetics , Transforming Growth Factor beta1/genetics , beta Catenin/genetics
4.
Br J Cancer ; 102(8): 1300-5, 2010 Apr 13.
Article in English | MEDLINE | ID: mdl-20386541

ABSTRACT

BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process. PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR. RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (P<0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r=-0.24, P=0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P=0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P=0.03). CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Genomic Instability , Telomere/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Intestinal Mucosa/ultrastructure , Male , Middle Aged , Telomerase/antagonists & inhibitors , Telomerase/metabolism
5.
Leukemia ; 21(5): 965-72, 2007 May.
Article in English | MEDLINE | ID: mdl-17344921

ABSTRACT

Activation of telomerase reverse transcriptase (hTERT) is essential for unlimited cell growth and plays a critical role in tumorigenesis. We investigated hTERT gene expression in 134 B-cell chronic lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression). Real-time PCR assays to quantify either all hTERT transcripts (AT) or only the full length (FL) transcript encoding the functional protein were developed. hTERT-AT levels strongly correlated with hTERT-FT levels (r=0.743, P<0.0001); both inversely correlated with the percentage of IgVH mutation (P<0.005) and were significantly higher in unmutated than in mutated cases (P=0.004 and P=0.001, respectively). The hTERT values which best discriminated between the unmutated and mutated IgVH cases were 150 and 40 copies for hTERT-AT and hTERT-FL, respectively. Using these cut-off values, there was a significant difference in the survival of patients with high or low hTERT levels (P<0.0001). Unmutated cases with low hTERT levels had an overall survival close to mutated cases with high hTERT levels. Thus, this work identifies hTERT-RNA level as a new prognostic marker in B-CLL, and may be used to identify previously unrecognized patient groups with the same IgVH mutation status and different disease outcomes.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Telomerase/genetics , ADP-ribosyl Cyclase 1/analysis , Adult , Aged , B-Lymphocytes/enzymology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , ZAP-70 Protein-Tyrosine Kinase/analysis
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