PubMed Health⌕ Search

Biomedical subjects

C Brenner

Publications and source records attributed to C Brenner.

At least 19 recordsLinked to original sources
PubMed2006

GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a pleiotropic enzyme that is overexpressed in apoptosis and in several human chronic pathologies. Here, we report that the protein accumulates in mitochondria during apoptosis, and induces the pro-apoptotic mitochondrial membrane permeabilization, a decisive event of the intrinsic pathway of apoptosis. GAPDH was localized by immunogold labeling and identified by matrix-assisted laser desorption/ionization-time of flight and nano liquid chromatography mass spectroscopy/mass spectroscopy in the mitochondrion of various tissues and origins. In isolated mitochondria, GAPDH can be imported and interact with the voltage-dependent anion channel (VDAC1), but not the adenine nucleotide translocase (ANT). The protein mediates a cyclosporin A-inhibitable permeability transition, characterized by a loss of the inner transmembrane potential, matrix swelling, permeabilization of the inner mitochondrial membrane and the release of two pro-apoptotic proteins, cytochrome c and apoptosis-inducing factor (AIF). This novel function of GAPDH might have implications for the understanding of mitochondrial biology, oncogenesis and apoptosis.

Amino Acid Sequence↗
PubMed2006

The permeability transition pore complex in cancer cell death.

The permeability transition pore (PTP) is a multi-protein complex at contact sites of the inner with the outer mitochondrial membrane. Research over the past years has led to the concept that the PTP occupies a central role in cell death induction. Numerous apoptosis signals convert this protein aggregate into an unspecific pore, thus activating mitochondria for the cellular self-destruction process. Here, we describe the evidence for this and the various approaches being undertaken to elucidate its subunit composition and mode of regulation. In particular, we review data that indicate a role of specific PTP subunits for apoptosis inhibition during tumorigenesis.

Animals↗
PubMed2006

Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.

The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.

Amino Acid Sequence↗
PubMed2006

DNA methyltransferases: facts, clues, mysteries.

DNA methylation plays a pivotal role during development in mammals and is central to transcriptional silencing. The DNA methyltransferases (DNMTs) are responsible for the generation of genomic methylation patterns leading to gene silencing, but the underlying molecular basis remains largely shrouded in mystery. Here we review our current understanding of the mechanisms by which DNMTs repress transcription and how they are targeted to preferred DNA sequences. Emerging evidence points to an essential and intricate web of interactions between DNMTs and the chromatin environment in which they function. The recent identification of novel transcription factors recruiting the DNMTs may open new avenues of research into the origin of DNA methylation patterns. Thanks to these emerging clues, researchers have begun to lift the veil on the multi-faceted DNMTs, but there remains fascinating work ahead for whoever wants to fully understand DNMTs and their role in the mammalian cell.

Animals↗
PubMed2005

Radiological associations with dermatological disease.

Skin disease and its treatment may have radiological connotations. Though this article is not a comprehensive account of dermatological and radiological associations, it provides an eclectic selection of some common and some rare clinical entities, which the practicing radiologist may recognize or remember.

Arthritis, Psoriatic↗
PubMed2005

Reactive oxygen species and the mitochondrial signaling pathway of cell death.

Reactive oxygen species (ROS) are produced as a by-product of cellular metabolic pathways and function as a critical second messenger in a variety of intracellular signaling pathways. Thus, a defect or deficiency in the anti-oxidant defense system on the one hand and/or the excessive intracellular generation of ROS on the other renders a cell oxidatively stressed. As a consequence, direct or indirect involvement of ROS in numerous diseases has been documented. In most of these cases, the deleterious effect of ROS is a function of activation of intracellular cell-death circuitry. To that end, involvement of ROS at different phases of the apoptotic pathway, such as induction of mitochondrial permeability transition and release of mitochondrial death amplification factors, activation of intracellular caspases and DNA damage, has been clearly established. For instance, the ROS-induced alteration of constitutive mitochondrial proteins, such as the voltage-dependent anion channel (VDAC) and/or the adenine nucleotide translocase (ANT) can induce the pro-apoptotic mitochondrial membrane permabilization. Not only do these observations provide insight into the intricate mechanisms underlying a variety of disease states, but they also present novel opportunities for the design and development of more effective therapeutic strategies.

Aging↗
PubMed2004

Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults.

Vanishing white matter is a leukoencephalopathy that usually affects young children. Five genes were found recently for this disease, allowing a DNA-based diagnosis. The authors describe six patients homozygous for the Arg113His mutation in eIF2Bepsilon. Only one had a childhood onset; four had a later onset and a protracted disease course; one adult still has no symptoms. Our data suggest that the Arg113His mutation is particularly mild and should be considered in the differential diagnosis of adult diffuse leukoencephalopathies, independent of whether there are associated clinical signs, an episodic course, or MRI shows white matter rarefaction/cystic degeneration.

Adult↗
PubMed2002

Mitochondrial permeability transition as a novel principle of hepatorenal toxicity in vivo.

Atractyloside (Atr) binds to the adenine nucleotide translocator (ANT) and inhibits ANT-mediated ATP/ADP exchange on the inner mitochondrial membrane. In addition, Atr can trigger opening of a non-specific ion channel, within the ANT-containing permeability transition pore complex (PTPC), which is subject to redox regulation and inhibited by cyclosporin A (CsA). Here we show that the cytotoxic effects of Atr, both in vivo and in vitro, are determined by its capacity to induce PTPC opening and consequent mitochondrial membrane permeabilization (MMP). Thus, the Atr-induced MMP and death of cultured liver cells are both inhibited by CsA as well as by glutathione (GSH) and enhanced by GSH depletion. Similarly, the hepatorenal toxicity of Atr, assessed in vivo, was reduced by treating mice with CsA or a diet rich in sulfur amino acids, a regime which enhances mitochondrial GSH levels. Atr injection induced MMP in hepatocytes and proximal renal tubular cells, and MMP was reduced by either CsA or GSH. Acetaminophen (paracetamol)-induced acute poisoning was also attenuated by CsA and GSH, both in vitro and in vivo. Altogether these data indicate that PTPC-mediated MMP may determine the hepatorenal toxicity of xenobiotics in vivo.

Animals↗
PubMed2002

Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria.

The genus Propionibacterium is composed of dairy and cutaneous bacteria which produce short-chain fatty acids (SCFA), mainly propionate and acetate, by fermentation. Here, we show that P. acidipropionici and freudenreichii, two species which can survive in the human intestine, can kill two human colorectal carcinoma cell lines by apoptosis. Propionate and acetate were identified as the major cytotoxic components secreted by the bacteria. Bacterial culture supernatants as well as pure SCFA induced typical signs of apoptosis including a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species, caspase-3 processing, and nuclear chromatin condensation. The oncoprotein Bcl-2, which is known to prevent apoptosis via mitochondrial effects, and the cytomegalovirus-encoded protein vMIA, which inhibits apoptosis and interacts with the mitochondrial adenine nucleotide translocator (ANT), both inhibited cell death induced by propionibacterial SCFA, suggesting that mitochondria and ANT are involved in the cell death pathway. Accordingly, propionate and acetate induced mitochondrial swelling when added to purified mitochondria in vitro. Moreover, they specifically permeabi-lize proteoliposomes containing ANT, indicating that ANT can be a critical target in SCFA-induced apoptosis. We suggest that propionibacteria could constitute probiotics efficient in digestive cancer prophylaxis via their ability to produce apoptosis-inducing SCFA.

Acetates↗
PubMed2001

DNA Commission of the International Society of Forensic Genetics: recommendations on forensic analysis using Y-chromosome STRs.

During the past few years, the DNA Commission of the International Society of Forensic Genetics has published a series of documents providing guidelines and recommendations concerning the application of DNA polymorphisms to the problems of human identification. This latest report addresses a relatively new area - namely, Y-chromosome polymorphisms, with particular emphasis on short tandem repeats (STRs). This report addresses nomenclature, use of allelic ladders, population genetics and reporting methods.

Alleles↗
PubMed2001

Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437.

An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20+/-7, 100+/-30, and 47+/-7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F(0)F(1)ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F(0)F(1)ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.

Antineoplastic Agents↗
PubMed2001

The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal.

Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) may be involved in the pathological demise of cells via apoptosis. Apoptosis induced by these agents is inhibited by Bcl-2, suggesting the involvement of mitochondria in the death pathway. In vitro, NO, peroxynitrite and HNE can cause direct permeabilization of mitochondrial membranes, and this effect is inhibited by cyclosporin A, indicating involvement of the permeability transition pore complex (PTPC) in the permeabilization event. NO, peroxynitrite and HNE also permeabilize proteoliposomes containing the adenine nucleotide translocator (ANT), one of the key components of the PTPC, yet have no or little effects on protein-free control liposomes. ANT-dependent, NO-, peroxynitrite- or HNE-induced permeabilization is at least partially inhibited by recombinant Bcl-2 protein, as well as the antioxidants trolox and butylated hydroxytoluene. In vitro, none of the tested agents (NO, peroxynitrite, HNE, and tert-butylhydroperoxide) causes preferential carbonylation HNE adduction, or nitrotyrosylation of ANT. However, all these agents induced ANT to undergo thiol oxidation/derivatization. Peroxynitrite and HNE also caused significant lipid peroxidation, which was antagonized by butylated hydroxytoluene but not by recombinant Bcl-2. Transfection-enforced expression of vMIA, a viral apoptosis inhibitor specifically targeted to ANT, largely reduces the mitochondrial and nuclear signs of apoptosis induced by NO, peroxynitrite and HNE in intact cells. Taken together these data suggest that NO, peroxynitrite, and HNE may directly act on ANT to induce mitochondrial membrane permeabilization and apoptosis.

Aldehydes↗
PubMed2001

Molecular cloning of Ian4: a BCR/ABL-induced gene that encodes an outer membrane mitochondrial protein with GTP-binding activity.

Using the representation difference analysis technique, we have identified a novel gene, Ian4, which is preferentially expressed in hematopoietic precursor 32D cells transfected with wild-type versus mutant forms of the Bcr/Abl oncogene. Ian4 expression was undetectable in 32D cells transfected with v-src, oncogenic Ha-ras or v-Abl. Murine Ian4 maps to chromosome 6, 25 cM from the centromere. The Ian4 mRNA contains two open reading frames (ORFs) separated by 5 nt. The first ORF has the potential to encode for a polypeptide of 67 amino acids without apparent homology to known proteins. The second ORF encodes a protein of 301 amino acids with a GTP/ATP-binding site in the N-terminus and a hydrophobic domain in the extreme C-terminus. The IAN-4 protein resides in the mitochondrial outer membrane and the last 20 amino acids are necessary for this localization. The IAN-4 protein has GTP-binding activity and shares sequence homology with a novel family of putative GTP-binding proteins: the immuno-associated nucleotide (IAN) family.

Amino Acid Sequence↗
PubMed2001

Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2.

Viral protein R (Vpr), an apoptogenic accessory protein encoded by HIV-1, induces mitochondrial membrane permeabilization (MMP) via a specific interaction with the permeability transition pore complex, which comprises the voltage-dependent anion channel (VDAC) in the outer membrane (OM) and the adenine nucleotide translocator (ANT) in the inner membrane. Here, we demonstrate that a synthetic Vpr-derived peptide (Vpr52-96) specifically binds to the intermembrane face of the ANT with an affinity in the nanomolar range. Taking advantage of this specific interaction, we determined the role of ANT in the control of MMP. In planar lipid bilayers, Vpr52-96 and purified ANT cooperatively form large conductance channels. This cooperative channel formation relies on a direct protein-protein interaction since it is abolished by the addition of a peptide corresponding to the Vpr binding site of ANT. When added to isolated mitochondria, Vpr52-96 uncouples the respiratory chain and induces a rapid inner MMP to protons and NADH. This inner MMP precedes outer MMP to cytochrome c. Vpr52-96-induced matrix swelling and inner MMP both are prevented by preincubation of purified mitochondria with recombinant Bcl-2 protein. In contrast to König's polyanion (PA10), a specific inhibitor of the VDAC, Bcl-2 fails to prevent Vpr52-96 from crossing the mitochondrial OM. Rather, Bcl-2 reduces the ANT-Vpr interaction, as determined by affinity purification and plasmon resonance studies. Concomitantly, Bcl-2 suppresses channel formation by the ANT-Vpr complex in synthetic membranes. In conclusion, both Vpr and Bcl-2 modulate MMP through a direct interaction with ANT.

Amino Acid Sequence↗
PubMed2001

Apoptosis induction by the photosensitizer verteporfin: identification of mitochondrial adenine nucleotide translocator as a critical target.

We report that the photosensitizer verteporfin kills lymphoma cells by an apoptotic process involving a dissipation of the mitochondrial inner transmembrane potential (deltapsim). Light-activated verteporfin-induced apoptosis was abolished by transfection with Bcl-2, a procedure reported to inhibit the mitochondrial permeability transition pore complex (PTPC). Verteporfin triggered the deltapsim loss in isolated mitochondria in vitro, and this effect was suppressed by bongrekic acid and cyclosporin A. Verteporfin plus light also permeabilized proteoliposomes containing the semipurified PTPC or the purified PTPC component adenine nucleotide translocator (ANT), yet had no effect on protein-free control liposomes. Verteporfin phototoxicity on ANT proteoliposomes was mediated by reactive oxygen species and was prevented by recombinant Bcl-2 or the adenine nucleotides ATP and ADP. In conclusion, verteporfin belongs to a class of clinically used chemotherapeutic agents acting on PTPC and ANT.

Animals↗
PubMed2001

The nitrilase superfamily: classification, structure and function.

The nitrilase superfamily consists of thiol enzymes involved in natural product biosynthesis and post-translational modification in plants, animals, fungi and certain prokaryotes. On the basis of sequence similarity and the presence of additional domains, the superfamily can be classified into 13 branches, nine of which have known or deduced specificity for specific nitrile- or amide-hydrolysis or amide-condensation reactions. Genetic and biochemical analysis of the family members and their associated domains assists in predicting the localization, specificity and cell biology of hundreds of uncharacterized protein sequences.

Amino Acid Sequence↗
PubMed2001

DNA commission of the International Society of Forensic Genetics: recommendations on forensic analysis using Y-chromosome STRs.

During the past few years the DNA commission of the International Society of Forensic Genetics has published a series of documents providing guidelines and recommendations concerning the application of DNA polymorphisms to the problems of human identification. This latest report addresses a relatively new area, namely Y-chromosome polymorphisms, with particular emphasis on short tandem repeats (STRs). This report addresses nomenclature, use of allelic ladders, population genetics and reporting methods.

Alleles↗