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At least 127 records · Page 7Linked to original sources
PubMed1993

Somatic cell hybrid mapping on mouse chromosome 11 (MMU11): assignment of markers relative to two breakpoints in band D.

Mouse x rat somatic cell hybrids were generated by fusing mouse cell lines that are heterozygous for reciprocal translocations involving the T42H and T9Ad breakpoints on mouse chromosome 11 (MMU11) to a thymidine kinase-negative (Tk-) rat cell line, RT2Tk-. Selection in HAT medium with geneticin disulfate (G418) resulted in some hybrid clones retaining only one derivative translocation chromosome with that part of MMU11 carrying the Tk-1 locus. Southern blot and PCR analyses of these hybrids were used to map the two breakpoints and 30 markers relative to them. The T42H breakpoint has been localized between Mpo and the Cola-1/Hox-2 cluster of loci and is proximal to the T9Ad breakpoint. The T9Ad breakpoint is proximal to the distal loci Tk-1, Gaa, D11Jkn1, and P4hb. The positions of 14 loci (Hox-2, Cola-1, Rara, Phb, Erba, Rnula-1, D11Pas1, Gfap, D11Mit13, D11Mit11, D11Mit12, Myla, Empb3 and Gh) have been further refined by their localization between the two breakpoints in band D. This study therefore improves the correlation of the genetic and physical maps of MMU11 and extends the known homology between MMU11 and human chromosome 17 (HSA17) by the assignment of three additional HSA17 markers, the profilin gene, Pfn, an anonymous marker, D17s28h, and the Crk oncogene, to above the T42H breakpoint; and the prohibitin gene, Phb, to between the T42H and T9Ad breakpoints in band D on MMU11.

Animals↗
PubMed2002

The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease.

Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins, Phblp and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both Phblp and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation, immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless, because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes. Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect their true function more accurately.

Aging↗
PubMed2006

"Tissue" transglutaminase contributes to the formation of disulphide bridges in proteins of mitochondrial respiratory complexes.

In this study we provide the first in vivo evidences showing that, under physiological conditions, "tissue" transglutaminase (TG2) might acts as a protein disulphide isomerase (PDI) and through this activity contributes to the correct assembly of the respiratory chain complexes. Mice lacking TG2 exhibit mitochondrial energy production impairment, evidenced by decreased ATP levels after physical challenge. This defect is phenotypically reflected in a dramatic decrease of motor behaviour of the animals. We propose that the molecular mechanism, underlying such a phenotype, resides in a defective disulphide bonds formation in ATP synthase (complex V), NADH-ubiquinone oxidoreductase (complex I), succinate-ubiquinone oxidoreductase (complex II) and cytochrome c oxidase (complex IV). In addition, TG2-PDI might control the respiratory chain by modulating the formation of the prohibitin complexes. These data elucidate a new pathway that directly links the TG2-PDI enzymatic activity with the regulation of mitochondrial respiratory chain function.

Adenosine Triphosphate↗
PubMed2004

Yeast replicative life span--the mitochondrial connection.

Mitochondria have been associated with aging in many experimental systems through the damaging action of reactive oxygen species. There is more, however, to the connection between mitochondria and Saccharomyces cerevisiae longevity and aging. Induction of the retrograde response, a pathway signaling mitochondrial dysfunction, results in the extension of life span and postponement of the manifestations of aging, changing the metabolic and stress resistance status of the cell. A paradox associated with the retrograde response is the simultaneous triggering of extrachromosomal ribosomal DNA circle (ERC) production, because of the deleterious effect these circles have on yeast longevity. The retrograde response gene RTG2 appears to play a pivotal role in ERC production, linking metabolism and genome stability. In addition to mother cell aging, mitochondria are important in establishment of age asymmetry between mother and daughter cells. The results more generally point to the existence of a mechanism to "filter" damaged components from daughter cells, a form of checkpoint control. Mitochondrial integrity is affected by the PHB1 and PHB2 genes, which encode inner mitochondrial membrane chaperones called prohibitins. The Phb1/2 proteins protect the cell from imbalances in the production of mitochondrial proteins. Such imbalances appear to cause a stochastic stratification of the yeast population with the appearance of short-lived cells. Ras2p impacts this process. Maintenance of mitochondrial membrane potential and the provision of Krebs cycle intermediates for biosyntheses appear to be crucial elements in yeast longevity. In sum, it is clear that mitochondria lie at the nexus of yeast longevity and aging.

DNA, Ribosomal↗
PubMed2002

Membrane protein degradation by AAA proteases in mitochondria.

The inner membrane of mitochondria is one of the protein's richest cellular membranes. The biogenesis of the respiratory chain and ATP-synthase complexes present in this membrane is an intricate process requiring the coordinated function of various membrane-bound proteins including protein translocases and assembly factors. It is therefore not surprising that a distinct quality control system is present in this membrane that selectively removes nonassembled polypeptides and prevents their possibly deleterious accumulation in the membrane. The key components of this system are two AAA proteases, membrane-embedded ATP-dependent proteolytic complexes, which expose their catalytic sites at opposite membrane surfaces. Other components include the prohibitin complex with apparently chaperone-like properties and a regulatory function during proteolysis and a recently identified ATP-binding cassette (ABC) transporter that exports peptides derived from the degradation of membrane proteins from the matrix to the intermembrane space. All of these components are highly conserved during evolution and appear to be ubiquitously present in mitochondria of eukaryotic cells, indicating important cellular functions. This review will summarize our current understanding of this proteolytic system and, in particular, focus on the mechanisms guiding the degradation of membrane proteins by AAA proteases.

ATP-Dependent Proteases↗
PubMed2002

Introducing antisense oligonucleotides into Pneumocystis carinii.

To improve the knowledge on Pneumocystis carinii growth, a homologous P. carinii transformation system would provide a tool to promote replication of this fungus. Antisense oligonucleotides have been successfully introduced by electroporation or direct uptake in order to downregulate the prohibitin negative function on cell cycle.

Animals↗
PubMed2001

AAA proteases of mitochondria: quality control of membrane proteins and regulatory functions during mitochondrial biogenesis.

An ubiquitous and conserved proteolytic system regulates the stability of mitochondrial inner membrane proteins. Two AAA proteases with catalytic sites at opposite membrane surfaces form a membrane-integrated quality control system and exert crucial functions during the biogenesis of mitochondria. Their activity is modulated by another membrane-protein complex that is composed of prohibitins. Peptides generated upon proteolysis in the matrix space are transported across the inner membrane by an ATP-binding cassette transporter. The function of these conserved components is discussed in the present review.

Chloroplasts↗
PubMed2001

Profiling of genes expressed in human monocytes and monocyte-derived dendritic cells using cDNA expression array.

Using a human cDNA expression array, we obtained expression profiles of 588 genes in CD14+ monocytes and monocyte-derived dendritic cells (DCs). Overall, 22 genes were upregulated, and nine genes were downregulated in DCs of both samples from two different individuals. Many of the genes that were upregulated in DCs encode proteins that are related to differentiation, cell structure, migration, termination of cell cycle as well as proliferation, e.g. tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor receptor II (TNFRII), thymosin beta-10, epithelial discoidin domain receptor 1, replication factor C, putative transcription factor DB1, alpha catenin, transforming growth factor-beta 1, prohibitin, p53-regulating protein and neu differentiation factor. Among the downregulated genes in DCs were genes that encode proteins of cell cycle regulation: mitotic growth and transcription activator, platelet-derived growth factor receptor-beta subunit, interleukin 2 receptor (IL-2R)-gamma subunit, IL-7R-alpha subunit, leucocyte interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR). Semi-quantitative reverse transcription-polymerase chain reaction method confirmed the upregulated expression levels in DCs for TNFRII, TNF-alpha, alpha catenin and downregulation of IFN-gamma, GM-CSFR on four different donor samples of DCs and monocytes. Moreover, our data show the presence of a 'switch-on' step for the TNF-alpha and TNFRII gene expression in immature DCs for further differentiation into mature DCs.

Cell Cycle↗
PubMed2003

Comparative proteomic profiling of murine skin.

Mammalian skin is regularly exposed to different environmental stresses, each of which results in specific compensatory changes in protein expression that can be assessed by proteomic analysis. We have established a reference proteome map of BALB/c murine skin allowing the resolution of greater than 500 protein spots in a single two-dimensional polyacrylamide gel. Forty-four protein spots, corresponding to 28 different cutaneous proteins, were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the Mascot online database searching algorithm. Twenty-five proteins were expressed at higher levels in the epidermis, whereas only nine were found predominantly in the subepidermal tissues. A subset of protein spots exhibited strain-specific expression. Proteins of diverse function were identified, including those involved in stress response, apoptosis, growth inhibition, the maintenance of structural integrity, translational control, energy metabolism, calcium binding, cholesterol transport, and the scavenging of free radicals. Prohibitin expression was detected cutaneously, with more abundant protein and mRNA levels in the epidermis. Five molecular chaperones including protein di-sulfide isomerase, 78 kDa glucose-regulated protein precursor, heat shock protein 60 (HSP60), HSP70, and HSP27 were also identified. Of these, HSP27 expression was confined mainly to the epidermis, and expression of protein disulfide isomerase was found primarily in the subepidermal tissues. Proteomic analysis of skin following heat or cold shock resulted in increased levels of HSP27, HSP60, and HSP70 suggesting involvement of these chaperones in the cutaneous response mechanism to temperature stress. These data establish numerous reference markers within the proteome map of murine skin and provide an important framework for future efforts aimed at characterization of the epidermal and subepidermal responses to environmental changes.

Abdomen↗
PubMed2003

Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine.

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A(-/-) expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at approximately 8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase beta-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in obob mice and obese patients who are at risk for nonalcoholic steatohepatitis.

Animals↗
PubMed2006

Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels.

The prohibitin (PHB)-domain proteins are membrane proteins that regulate a variety of biological activities, including mechanosensation, osmotic homeostasis, and cell signaling, although the mechanism of this regulation is unknown. We have studied two members of this large protein family, MEC-2, which is needed for touch sensitivity in Caenorhabditis elegans, and Podocin, a protein involved in the function of the filtration barrier in the mammalian kidney, and find that both proteins bind cholesterol. This binding requires the PHB domain (including palmitoylation sites within it) and part of the N-terminally adjacent hydrophobic domain that attaches the proteins to the inner leaflet of the plasma membrane. By binding to MEC-2 and Podocin, cholesterol associates with ion-channel complexes to which these proteins bind: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. Both the MEC-2-dependent activation of mechanosensation and the Podocin-dependent activation of TRPC channels require cholesterol. Thus, MEC-2, Podocin, and probably many other PHB-domain proteins by binding to themselves, cholesterol, and target proteins regulate the formation and function of large protein-cholesterol supercomplexes in the plasma membrane.

Amino Acid Sequence↗
PubMed2002

Bcl-x(L) complements Saccharomyces cerevisiae genes that facilitate the switch from glycolytic to oxidative metabolism.

All eukaryotic organisms have mechanisms to adapt to changing metabolic conditions. The mammalian cell survival gene Bcl-x(L) enables cells to adapt to changes in cellular metabolism. To identify genes whose function can be substituted by Bcl-x(L) in a unicellular eukaryote, a genetic screen was performed using the yeast Saccharomyces cerevisiae. S. cerevisiae grows by anaerobic glycolysis when glucose is available, switching to oxidative phosphorylation when carbohydrate in the media becomes limiting (diauxic shift). Given that Bcl-x(L) appears to facilitate the switch from glycolytic to oxidative metabolism in mammalian cells, a library of yeast mutants was tested for the ability to efficiently undergo diauxic shift in the presence and absence of Bcl-x(L). Several mutants were identified that have a defect in growth when switched from a fermentable to a nonfermentable carbon source that is corrected by the expression of Bcl-x(L). These genes include the mitochondrial chaperonin TCM62, as well as previously uncharacterized genes. One of these uncharacterized genes, SVF1, promotes cell survival in mammalian cells in response to multiple apoptotic stimuli. The finding that TCM62 and the analogous human prohibitin gene also inhibit mammalian cell death following growth factor withdrawal implicates mitochondrial chaperones as regulators of apoptosis. Further characterization of the genes identified in this screen may enhance our understanding of Bcl-x(L) function in mammalian cells, and of cell survival pathways in general.

Animals↗
PubMed2003

Protein components of mitochondrial DNA nucleoids in higher eukaryotes.

Mitochondrial DNA (mtDNA) is not packaged in nucleosomal particles, but has been reported to associate with the mitochondrial inner membrane. Gentle lysis of Xenopus oocyte mitochondria with nonionic detergent liberates a nucleoprotein complex containing mtDNA associated with a previously characterized DNA binding partner, mitochondrial transcription factor A (mtTFA), as well as a series of inner membrane proteins identified by sequencing. More extensive detergent treatment stripped most of these proteins from the DNA, leaving a limited number of proteins in a nucleoid core. Sequencing of the major proteins retained in association with mtDNA revealed the expected mtDNA binding proteins, mtTFA and mitochondrial single-stranded DNA binding protein (mtSSB), as well as four proteins not previously reported to associate with mtDNA. These include adenine nucleotide translocator 1, the lipoyl-containing E2 subunits of pyruvate dehydrogenase and branched chain alpha-ketoacid dehydrogenase and prohibitin 2. The association of several of these proteins with mtTFA-containing mtDNA nucleoids was confirmed by immunoprecipitation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2001

Detection of early gene expression changes during activation of human primary lymphocytes by in vitro synthesis of proteins from polysome-associated mRNAs.

The rapid increase in protein synthesis during the mitogenic stimulation of human peripheral blood lymphocyte is the result of global and specific translational control mechanisms. To study some of these mechanisms, we examined the in vitro translatability of mRNAs associated with the polyribosome fraction. Polyribosome fractions were isolated from lymphocytes after activation with ionomycin and the phorbol ester PMA. The associated PAmRNAs were translated in the presence of mRNA-depleted rabbit reticulocyte lysate and [(35)S]Met, and the protein products were analyzed by SDS--PAGE and autoradiography. There was little synthesis of protein from the PAmRNAs isolated from unactivated T cells, but the PAmRNAs isolated from activated T cells showed a rapid increase in translatability. Translation of the PAmRNAs was sensitive to edeine and m7GTP, suggesting their cap-dependent translation. With activation, the majority of proteins showed increasing in vitro translation, but two proteins, p72 and p33, were found to have increased synthesis within 30 min, which decreased in 1 h. Transcription inhibitors were used to ascertain if regulation of their expression was transcriptional or translational. To identify these proteins, we used biotinylated lysine during the in vitro translation reaction, and we extracted the biotinylated protein by using streptavidin magnetic beads. The protein product was analyzed by mass spectrometry. p33 was identified as a prohibitin-like protein (BAP37), but the identification of p72 was not found in the databases. The distinct up-regulation and down-regulation of their protein expression suggest their tightly controlled regulation during early T cell activation.

Animals↗
PubMed2006

S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver.

An early event that occurs in response to alcohol consumption is mitochondrial dysfunction, which is evident in changes to the mitochondrial proteome, respiration defects, and mitochondrial DNA (mtDNA) damage. S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive oxygen/nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial superoxide production, mtDNA damage, and inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of oxidant damage, SAM prevented alcohol-mediated losses in cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury: mitochondria dysfunction.

Animals↗
PubMed2004

Cloning and expression pattern of a novel microspore-specific gene encoding hypersensitive-induced response protein (LjHIR1) from the model legume, Lotus japonicus.

In order to understand the microspore and pollen development, recently, we have isolated a number of anther-specific genes in the model legume, Lotus japonicus. From these anther-specific genes, we identified one novel microspore-specific gene, LjImfb-c82. In order to determine the molecular characterization of LjImfb-c82, full-length cDNA clone was first isolated and sequenced. It encoded a protein of 286 amino acids (LjHIR1), which had sequence similarity to Hypersensitive-Induced Response like protein. LjHIR1 was specifically expressed in microspore on the in situ hybridization experiment. From the sequence similarity to prohibitin-domain protein, the LjHIR1 might be related to ion channel regulation in microspore development.

Amino Acid Sequence↗
PubMed2003

The proteomics approach to find biomarkers in gastric cancer.

Gastric cancer is a very serious disease and is naturally resistant to many anticancer drugs. To reduce the mortality and improve the effectiveness of therapy, many studies have tried to find key biomarkers. Proteomic technologies are providing the tools needed to discover and identify disease-associating biomarkers. The proteomic study of gastric cancer establishes any specific events that lead to cancer, and it provides a direct way to define the true function of genes. Using two dimensional (2-D) electrophoresis of the stomach cancer tissue, we have gained about 1,500 spots in each gel, and 140 protein spots also were identified. Among the identified proteins, there were seven over-expressed proteins in stomach cancer tissue: NSP3, transgelin, prohibitin, heat shock protein (hsp) 27 and variant, protein disulfide isomerase A3, unnamed protein product and glucose regulated protein. There were also seven under-expressed proteins in stomach cancer: Apolipoprotein A-1, p20, nucleoside diphosphate isomerase A, alpha 1 antitrypsin, desmin, serum albumin and serotransferrin.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The differential proteome profile of stomach cancer: identification of the biomarker candidates.

By comparative proteome analysis we searched for characteristic alterations of human stomach adenocarcinoma tissue and paired surrounding normal tissue. Selected differential protein spots were identified with peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and database searching. We identified protein alterations in 18 stomach cancer tissues compared with normal controls, comprising elevated levels of eight proteins, including 14-3-3 zeta, calcyclin, keratin, apolipoprotein A-1 precursor, proteasome activator complex subunit, nucleoside diphosphate kinase, nicotinamide N-methyltransferase, and pyridoxal kinase. Five proteins (CA11, prohibitin, peroxiredoxin 4, serum amyloid P component, and NADH-ubiquinone oxidoreductase 23 kDa subunit) were decreased. These data are valuable for identification of differentially expressed proteins involved in stomach cancer carcinogenesis, providing biomarker candidates to develop diagnostic and therapeutic tools.

Adult↗