Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells.

The SN 1 alkylating agents activate the mismatch repair system leading to delayed G2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT1, an anti-proliferative and pro-apoptotic transcription factor is known to potentiate p53 and to affect DNA-damage cellular response. We studied whether STAT1 may modulate cell fate following activation of the mismatch repair system upon exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).

Easily controlled grafting of oligonucleotides on γFe2O3 nanoparticles: physicochemical characterization of DNA organization and biological activity studies.

We report a one-step process to functionalize superparamagnetic iron oxide nanoparticle (SPIO-NP) surfaces with a controlled number of oligonucleotides. For this study, we use a specific oligonucleotide targeting the signal transducer and activator of transcription 3 (STAT3), a key regulator of cell survival and proliferation. This oligonucleotide is self-complementary and can adopt a hairpin structure.

Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives.

Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play.

STAT3 inhibitors for cancer therapy: Have all roads been explored?

The signal transducer and activator of transcription STAT3 is a transcription factor which plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Activated STAT3 is phosphorylated on tyrosine and forms a dimer through phosphotyrosine/src homology 2 (SH2) domain interaction. The dimer enters the nucleus via interaction with importins and binds target genes.

A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line.

Background: The Signal Transducer and Activator of Transcription 3 (STAT3) is activated in tumor cells, and STAT3-inhibitors are able to induce the death of those cells. Decoy oligodeoxynucleotides (dODNs), which bind to the DNA Binding Domain (DBD) of STAT3, are efficient inhibitors. However, they also inhibit STAT1, whose activity is essential not only to resistance to pathogens, but also to cell growth inhibition and programmed cell death processes.

Electrostatic assembly of a DNA superparamagnetic nano-tool for simultaneous intracellular delivery and in situ monitoring.

Unlabelled: A superparamagnetic γFe(2)O(3) nanocarrier was developed, characterized by spectroscopic methods and evaluated for the delivery of a decoy oligonucleotide (dODN) in human colon carcinoma SW 480 cells. This nanoparticle-dODN bioconjugate (γFe(2)O(3)@dODN) was designed to target the signal transducer and activator of transcription 3, STAT3, a key regulator of cell survival and proliferation. We exploited a simple precipitation-redispersion mechanism for the direct and one-step complexation of a labeled decoy oligonucleotide with iron oxide nanoparticles (NPs).

Biological and prognostic relevance of mitogen-activated protein kinases in pancreatic adenocarcinoma.

Objectives: The aims of this study were to study the biological and clinical significance of 3 main proteins of the mitogen-activated protein kinase (MAPK) signaling pathway, ERK1/2, P38, and MKK4, in a series of patients having pancreatic adenocarcinomas treated by surgery.

Methods: We examined the immunohistochemical expression of 3 MAPK proteins, ERK1/2, P38, and MKK4 in 99 surgically resected pancreatic ductal adenocarcinomas. Tumor protein expression was studied with regard to pathological characteristics and to postsurgical recurrence-free and overall survivals.

A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB.

Background: The transcription factor STAT3 (signal transducer and activator of transcription 3) is frequently activated in tumor cells. Activated STAT3 forms homodimers, or heterodimers with other TFs such as NF-κB, which becomes activated. Cytoplasmic STAT3 dimers are activated by tyrosine phosphorylation; they interact with importins via a nuclear localization signal (NLS) one of which is located within the DNA-binding domain formed by the dimer.

Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma.

Background: The deregulation of several transcription factors contribute to the aggressive course of mantle cell lymphoma. This study focuses on survival signals emanating from the tumor environment and involving the signal transducer and activator of transcription (STAT) 3 through cytokines or antigen recognition.

Design And Methods: Primary mantle cell lymphoma cells were isolated from 20 leukemic patients.

STAT1-dependent IgG cell-surface expression in a human B cell line derived from a STAT1-deficient patient.

STAT1 is a key effector of cytokines involved in the resistance to pathogens; its identified transcriptional targets mediate the innate immune response involved in the defense against viruses and bacteria. Little is known about the role of STAT1 in adaptive immunity, including its impact on BCR or surface Ig expression. Analysis of this point is difficult in humans, as STAT1 deficiency is extremely rare.

STAT1 and pathogens, not a friendly relationship.

STAT1 belongs to the STAT family of transcription factors, which comprises seven factors: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT1 is a 91 kDa protein originally identified as the mediator of the cellular response to interferon (IFN) alpha, and thereafter found to be a major component of the cellular response to IFNgamma. STAT1 is, in fact, involved in the response to several cytokines and to growth factors.

Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene.

Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2.

Efficient killing of SW480 colon carcinoma cells by a signal transducer and activator of transcription (STAT) 3 hairpin decoy oligodeoxynucleotide--interference with interferon-gamma-STAT1-mediated killing.

The signal transducers and activators of transcription (STATs) convey signals from the membrane to the nucleus in response to cytokines or growth factors. STAT3 is activated in response to cytokines involved mostly in cell proliferation; STAT1 is activated by cytokines, including interferon-gamma, involved in defence against pathogens and the inhibition of cell proliferation. STAT3, which is frequently activated in tumour cells, is a valuable target with respect to achieving inhibition of tumour cell proliferation.

Novel function of STAT1beta in B cells: induction of cell death by a mechanism different from that of STAT1alpha.

Alternate splicing of STAT1 produces two isoforms: alpha, known as the active form, and beta, previously shown to act as a dominant-negative factor. Most studies have dealt with STAT1alpha, showing its involvement in cell growth control and cell death. To examine the specific function of either isoform in cell death, a naturally STAT1-deficient human B cell line was transfected to express STAT1alpha or STAT1beta.

Progressive pulmonary sarcoidosis is associated with over-expression of TYK2 and p21Waf1/Cip1.

Background And Aim Of The Work: Sarcoidosis is a multisystemic disorder of unknown aetiology with diverse clinical phenotypes characterised by granulomatous formation in involved organs. The factors controlling the evolution of pulmonary involvement -- a major point in the progression of sarcoidosis -- are poorly understood. The aim of our study was to identify alterations of gene expression associated with the progression of the granulomatous process in pulmonary sarcoidosis.

Cell death in NF-kappaB-dependent tumour cell lines as a result of NF-kappaB trapping by linker-modified hairpin decoy oligonucleotide.

The transcription factor NF-kappaB is frequently activated in cancer, and is therefore a valuable target for cancer therapy. Decoy oligodeoxynucleotides (ODNs) inhibit NF-kappaB by preventing its binding to the promoter region of target genes. Few studies have used NF-kappaB-targeting with ODNs in cancer.

C-myc activation impairs the NF-kappaB and the interferon response: implications for the pathogenesis of Burkitt's lymphoma.

Deregulation of the proto-oncogene c-myc is a key event in the pathogenesis of many tumors. A paradigm is the activation of the c-myc gene by chromosomal translocations in Burkitt lymphoma (BL). Despite expression of a restricted set of Epstein-Barr viral (EBV) antigens, BL cells are not recognized by antigen-specific cytotoxic T cells (CTLs) because of their inability to process and present HLA class I-restricted antigens.

Effect of tumor necrosis factor alpha and infliximab on apoptosis of B lymphocytes infected or not with Epstein-Barr virus.

Chronic inflammation and immunosuppressive therapies increase the risk of non-Hodgkin's lymphoma associated or not with Epstein-Barr virus (EBV) infection. A possible link between infliximab treatment and increased risk of lymphoma has been suggested. Indeed, infliximab induces apoptosis of monocytes and activated T lymphocytes, but its effect on B lymphocytes infected or not with EBV is unknown.

Latent membrane protein 1 regulates STAT1 through NF-kappaB-dependent interferon secretion in Epstein-Barr virus-immortalized B cells.

Constitutive activation of signal transducer and activator of transcription 1 (STAT1) is a distinctive feature of Epstein-Barr virus (EBV)-immortalized B cells (lymphoblastoid cell lines [LCLs]). The expression of STAT1 in these cells is modulated by the latent membrane protein 1 (LMP1), but the mechanism of STAT1 activation has remained unclear. We demonstrate that the tyrosine phosphorylation of STAT1 in LCLs results from an indirect pathway encompassing an NF-kappaB-dependent secretion of interferons (IFNs).

Differential roles of STAT1alpha and STAT1beta in fludarabine-induced cell cycle arrest and apoptosis in human B cells.

Signal transducer and activator of transcription 1 (STAT1), a transcription factor known to participate in antiviral responses, acts as a tumor suppressor inhibiting cell growth and promoting apoptosis. To study the role of STAT1 in DNA damage-induced apoptosis in B lymphocytes, its active form, STAT1alpha, was specifically inhibited by the overexpression of STAT1beta, the STAT1alpha truncated inhibitory isoform. An episomal vector with a tetracycline-inducible bidirectional promoter was created to induce the expression of 2 proteins, STAT1beta and enhanced green fluorescence protein (EGFP).

Specific covalent binding of a NF-kappaB decoy hairpin oligonucleotide targeted to the p50 subunit and induction of apoptosis.

The NF-kappaB transcriptional factor regulates various functions such as immune responses, cellular growth and development, and is frequently activated in tumor cells. Thus, inhibition of NF-kappaB could suppress tumor cell growth. Using a decoy synthetic hairpin-shaped oligodeoxyribonucleotide (ODN) containing the kappaB site with an integrated single diphosphoryldisulfide linkage, we demonstrate its covalent binding to the p50 subunit of NF-kappaB.

Gene array identification of Epstein Barr virus-regulated cellular genes in EBV-converted Burkitt lymphoma cell lines.

Epstein Barr virus (EBV) is associated with various B-cell neoplasms such as post-transplant lymphoproliferative disease or Burkitt lymphoma. B-lymphocyte reprogramming by EBV involves the control of numerous cellular genes. To identify such EBV-deregulated genes, we have compared the gene expression profile of EBV-negative Burkitt lymphoma cell lines (BL) (BL2, BL30, BL70) with their EBV-converted counterpart (BL2-B95, BL30-B95, BL70-B95) by cDNA array.

Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells.

The Epstein-Barr virus (EBV) transforms B cells in part by inhibiting the cellular apoptotic programme. This is also observed when Burkitt lymphoma cell lines are infected with EBV. Induction of apoptosis is one of the mechanisms by which fludarabine inhibits the growth of cells with low proliferative capacity.