Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?

Numerous pro-apoptotic signal transducing molecules act on mitochondria and provoke the permeabilization of the outer mitochondrial membrane, thereby triggering the release of potentially toxic mitochondrial proteins. One of these proteins, apoptosis-inducing factor (AIF), is a phylogenetically old flavoprotein which, in healthy cells, is confined to the mitochondrial intermembrane space. Upon lethal signaling, AIF translocates, via the cytosol,to the nucleus where it binds to DNA and provokes caspase-independent chromatin condensation. The crystal structures of both human and mouse AIF have been determined, and the fine mechanisms accounting for its oxidoreductase activity and its electrostatic interaction with double-stranded DNA have been elucidated. Importantly, the apoptogenic and oxidoreductase functions of AIF can be dissociated. Thus, mutations that abolish the AIF-DNA interaction suppress AIF-induced chromatin condensation, yet have no effect on the NADH oxidase activity. Recent studies suggest AIF to be a major factor determining caspase-independent neuronal death, emphasizing the central role of mitochondria in the control of physiological and pathological cell demise

IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)

Human Isocitrate dehydrogenase (IDH) occurs in three isozymes, IDH1, located in the cytoplasm, and IDH2 and IDH3 located in the mitochondria. IDH functions as part of the tricarboxylic acid (TCA) cycle and catalyzes the reversible conversion of isocitrate to alpha ketoglutarate (α-KG)/2-oxoglutarate (2-OG), thus promoting the activity of dioxygenases that require α-KG as a cosubstrate. IDH1 and IDH2 use NADP+ as a cofactor, producing NADPH in the process (NADPH plays a vital role i

AFDN (afadin, adherens junction formation factor)

Afadin, the protein coded by AFDN (6q27), also known as AF6 or MLLT4, is a cytoskeletal and junction-associated protein that links nectins, transmembrane proteins, to the F-actin (actin cytoskeleton) in a type of cell-cell junctions: the adherens junctions (AJs). Afadin plays an important role in AJs integrity and apical-basal polarity. There is growing evidence of it's role in carcinogenesis

Network enrichment analysis: extension of gene-set enrichment analysis to gene networks

<p>Abstract</p> <p>Background</p> <p>Gene-set enrichment analyses (GEA or GSEA) are commonly used for biological characterization of an experimental gene-set. This is done by finding known functional categories, such as pathways or Gene Ontology terms, that are over-represented in the experimental set; the assessment is based on an overlap statistic. Rich biological information in terms of gene interaction network is now widely available, but this topological information is not used by GEA, so there is a need for methods that exploit this type of information in high-throughput data analysis.</p> <p>Results</p> <p>We developed a method of network enrichment analysis (NEA) that extends the overlap statistic in GEA to network links between genes in the experimental set and those in the functional categories. For the crucial step in statistical inference, we developed a fast network randomization algorithm in order to obtain the distribution of any network statistic under the null hypothesis of no association between an experimental gene-set and a functional category. We illustrate the NEA method using gene and protein expression data from a lung cancer study.</p> <p>Conclusions</p> <p>The results indicate that the NEA method is more powerful than the traditional GEA, primarily because the relationships between gene sets were more strongly captured by network connectivity rather than by simple overlaps.</p

The THAP–zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes

AbstractWe recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes. Silencing of endogenous THAP1 through RNA interference similarly inhibited EC proliferation and G1/S cell-cycle progression, and resulted in down-regulation of several pRB/E2F cell-cycle target genes, including RRM1, a gene required for S-phase DNA synthesis. Chromatin immunoprecipitation assays in proliferating ECs showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site found in the RRM1 promoter, indicating that RRM1 is a direct transcriptional target of THAP1. The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation. Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways

Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib : role of IL-15Rα and NKG2D triggering

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.peer-reviewe

Internet databases and resources for cytogenetics and cytogenomics

Review on Internet databases and resources for cytogenetics and cytogenomic

General resources in Genetics and/or Oncology

Review on General resources in Genetics and/or Oncolog

General resources in Genetics and/or Oncology

Review on General resources in Genetics and/or Oncolog