Showing papers in "Biochemistry and Cell Biology in 2004"
TL;DR: This review focuses on the roles of Sp1 and Sp3 in the regulation of gene expression, and in vitro and in vivo studies reveal that these transcription factors have strikingly different functions.
Abstract: The Sp family of transcription factors is united by a particular combination of three conserved Cys2His2 zinc fingers that form the sequence-specific DNA-binding domain. Within the Sp family of transcription factors, Sp1 and Sp3 are ubiquitously expressed in mammalian cells. They can bind and act through GC boxes to regulate gene expression of multiple target genes. Although Sp1 and Sp3 have similar structures and high homology in their DNA binding domains, in vitro and in vivo studies reveal that these transcription factors have strikingly different functions. Sp1 and Sp3 are able to enhance or repress promoter activity. Regulation of the transcriptional activity of Sp1 and Sp3 occurs largely at the post-translational level. In this review, we focus on the roles of Sp1 and Sp3 in the regulation of gene expression.
430 citations
TL;DR: This review article highlights important new findings on the individual enzymes and the corresponding genes of phosphatidylcholine synthesis via its two major biosynthetic pathways: the CDP-choline pathway and the methylation pathway.
Abstract: Identification of the genes and gene products involved in the biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine has lagged behind that in many other fields because of difficulties encountered in purifying the respective proteins. Nevertheless, most of these genes have now been identified. In this review article, we have highlighted important new findings on the individual enzymes and the corresponding genes of phosphatidylcholine synthesis via its two major biosynthetic pathways: the CDP-choline pathway and the methylation pathway. We also review recent studies on phosphatidylethanolamine biosynthesis by two pathways: the CDP-ethanolamine pathway, which is active in the endoplasmic reticulum, and the phosphatidylserine decarboxylase pathway, which operates in mitochondria. Finally, the two base-exchange enzymes, phosphatidylserine synthase-1 and phosphatidylserine synthase-2, that synthesize phosphatidylserine in mammalian cells are also discussed.Key words: phosphatidy...
336 citations
TL;DR: The molecular mechanisms that regulate these enzymes in vivo and in vitro are focused on, especially the roles of oxidants (glutathione, peroxide, nitric oxide), proteins, and lipids (diacylglycerol, arachidonic acid, and ceramide).
Abstract: Ceramide, an emerging bioactive lipid and second messenger, is mainly generated by hydrolysis of sphingomyelin through the action of sphingomyelinases. At least two sphingomyelinases, neutral and a...
326 citations
TL;DR: More recent data addressing the role of caveolin-1 in cellular signaling and the development of diseases like cancer will be preferentially discussed.
Abstract: Caveolae were initially described some 50 years ago. For many decades, they remained predominantly of interest to structural biologists. The identification of a molecular marker for these domains, ...
221 citations
TL;DR: Interestingly, histone deacetylase (HDAC) inhibitors, agents with well-documented anti-cancer activity, repress SRC transcription in a wide variety of human cancer cell lines.
Abstract: Human pp60c-Src (or c-Src) is a 60 kDa nonreceptor tyrosine kinase encoded by the SRC gene and is the cellular homologue to the potent transforming v-Src viral oncogene. c-Src functions at the hub of a vast array of signal transduction cascades that influence cellular proliferation, differentiation, motility, and survival. c-Src activation has been documented in upwards of 50% of tumors derived from the colon, liver, lung, breast, and pancreas. Therefore, a major focus has been to understand the mechanisms of c-Src activation in human cancer. Early studies concentrated on post-translational mechanisms that lead to increased c-Src kinase activity, which often correlated with overexpression of c-Src protein. More recently, the discovery of an activating SRC mutation in a small subset of advanced colon tumors has been reported. In addition, elevated SRC transcription has been identified as yet another mechanism contributing significantly to c-Src activation in a subset of human colon cancer cell lines. Interestingly, histone deacetylase (HDAC) inhibitors, agents with well-documented anti-cancer activity, repress SRC transcription in a wide variety of human cancer cell lines. Analysis of the mechanisms behind HDAC inhibitor mediated repression could be utilized in the future to specifically inhibit SRC gene expression in human cancer.
157 citations
TL;DR: This review will examine mechanisms including regulated expression and assembly of CK2 subunits, phosphorylation of CK1, and interactions with small molecules or cellular proteins that could contribute to the local regulation of distinct CK2 populations.
Abstract: CK2 is a highly conserved, ubiquitously expressed protein serine/threonine kinase present in all eukaryotes. Circumscribed as having a vast array of substrates located in a number of cellular compa...
150 citations
TL;DR: It appears that the binding of Ca2+ is essential for exposing amino acid residues that are important in forming protein-protein interactions with effector molecules that promote cancer progression through specific roles in cell survival and apoptosis pathways.
Abstract: The S100 gene family is composed of at least 20 members that share a common structure defined in part by the Ca2+ binding EF-hand motif. These genes which are expressed in a discriminate fashion in...
144 citations
TL;DR: The focus of this review is the leukocyte common antigen-related (LAR) subfamily of receptor PTPs (RPTPs), which is composed of three vertebrate homologs, LAR, RPTP-sigma, andRPTP-delta, as well as few invertebrates orthologs such as Dlar.
Abstract: The protein tyrosine phosphatases (PTPs) have emerged as critical players in diverse cellular functions. The focus of this review is the leukocyte common antigen-related (LAR) subfamily of receptor...
143 citations
TL;DR: This review focuses on the variations on this basic theme that give rise to the diversity of products produced by the pathway, including multiple mechanisms to generate unsaturated fatty acids and the accessory components required for branched-chain fatty acid synthesis in Gram-positive bacteria.
Abstract: Fatty acid biosynthesis is catalyzed in most bacteria by a group of highly conserved proteins known as the type II fatty acid synthase (FAS II) system. FAS II has been extensively studied in the Es...
138 citations
TL;DR: The contribution of phosphatidylcholine metabolism to the apoptotic program is discussed, analyzing the experimental evidence available and pointing out some controversies in the proposed mechanisms of action.
Abstract: The apoptotic program utilizes cellular membranes to transduce and generate operative signals Lipids are major components of cellular membranes and have the potential to control the effectiveness
137 citations
TL;DR: There are several distinct, differentially regulated phospholipases A2 in cells that mediate agonist-induced release of arachidonic acid, and these pathways are important in controlling cellular levels of free arachidsonic acid.
Abstract: Mammalian cells have developed specific pathways for the incorporation, remodeling, and release of arachidonic acid. Acyltransferase and transacylase pathways function to regulate the levels of est...
TL;DR: A number of hormones, including acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin are defined, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.
Abstract: That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-ad...
TL;DR: New information on the role of insulin-induced genes and the differential role and regulation of SREBP-1c and -2 may ultimately lead to novel strategies for the treatment of dyslipidemia and insulin resistance.
Abstract: Sterol regulatory element binding proteins (SREBPs) are a family of membrane-bound transcription factors that play a unique and fundamental role in both cholesterol and fatty acid metabolism, relev...
TL;DR: A model is suggested in which a general property of ORPs is to function at membrane contact sites, specialized zones of communication between two different organelles, which provides interesting clues to the mode of ORP action.
Abstract: Oxysterols are potent signalling lipids that directly bind liver X receptors (LXRs) and a subset of oxysterol binding protein (OSBP) related proteins (ORPs). It is relatively well established that the oxysterol-regulated function of LXRs is to control the expression of genes involved in reverse cholesterol transport, catabolism of cholesterol, and lipogenesis. In contrast, the mechanisms by which oxysterols and ORPs affect cellular lipid metabolism have remained poorly understood. In this review, we summarize the information available on function of the ORPs and compare the two families of proteins binding oxysterol to demonstrate the different responses that similar lipids can elicit within cells. The other focus is on the membrane targeting determinants and the protein interaction partners of ORPs, which provide interesting clues to the mode(s) of ORP action. Specifically, we suggest a model in which a general property of ORPs is to function at membrane contact sites, specialized zones of communication ...
TL;DR: The intent of this review is to discuss the enzymatic machinery involved in the biosynthesis of lipid A, transport of the molecule, and finally, those enzymesinvolved in the modification of its structure in response to environmental stimuli.
Abstract: Lipopolysaccharide (LPS) is the major surface molecule of Gram-negative bacteria and consists of three distinct structural domains: O-antigen, core, and lipid A. The lipid A (endotoxin) domain of L...
TL;DR: High serum lipid levels, especially the elevated level of low-density lipoprotein (LDL), have been shown to be strongly related to the development of atherosclerosis, and analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels.
Abstract: Atherosclerosis is the leading cause of death in North America and within the next two decades will be the leading cause worldwide. Atherosclerosis is characterized by vascular obstruction from the deposits of plaque, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of the arteries and cause heart attack. High serum lipid levels, especially the elevated level of low-density lipoprotein (LDL), have been shown to be strongly related to the development of atherosclerosis. It is generally accepted that atherosclerotic lesions are initiated via an enhancement of LDL uptake by monocytes and macrophages. In the liver, uptake of plasma LDL is mediated via specific LDL receptors, but a scavenger receptor system is employed by macrophages. Plasma LDL must be modified prior to uptake by macrophages. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated...
TL;DR: This review will focus on the function and regulation of the biosynthesis and resynthesis of mitochondrial phospholipids in the mammalian heart.
Abstract: Phospholipids are important structural and functional components of all biological membranes and define the compartmentation of organelles. Mitochondrial phospholipids comprise a significant propor...
TL;DR: This review will focus on just one subfamily, the Imitation Switch family, which is proving to be one of the most diverse groups of chromatin remodelers in both form and function.
Abstract: The yeast SWI/SNF ATP-dependent chromatin remodeling complex was first identified and characterized over 10 years ago (F. Winston and M. Carlson. 1992. Trends Genet. 8: 387–391.) Since then, the number of distinct ATP-dependent chromatin remodeling complexes and the variety of roles they play in nuclear processes have become dizzying (J.A. Martens and F. Winston. 2003. Curr. Opin. Genet. Dev. 13: 136–142; A. Vacquero et al. 2003. Sci. Aging Knowledge Environ. 2003: RE4) — and that does not even include the companion suite of histone modifying enzymes, which exhibit a comparable diversity in both number of complexes and variety of functions (M.J. Carrozza et al. 2003. Trends Genet. 19: 321–329; W. Fischle et al. 2003. Curr. Opin. Cell Biol. 15: 172–183; M. Iizuka and M.M. Smith. 2003. Curr. Opin. Genet. Dev. 13: 1529–1539). This vast complexity is hardly surprising, given that all nuclear processes that involve DNA — transcription, replication, repair, recombination, sister chromatid cohesion, etc. — must ...
TL;DR: It is proposed that signal transduction network wiring diagrams are valuable tools for hypothesis building and filtering physiologically relevant phenotypic responses from less connected protein relations in the regulation of MAPK pathways.
Abstract: Mitogen-activated protein kinase (MAPK) pathways are activated by a plethora of stimuli. The literature is filled with papers describing the activation of different MAPKs by almost any stimulus or ...
TL;DR: A recent review summarizes recent progress in this area and discusses how the above model might explain a role for MARCKS and MRP in activation of phospholipase D and other PIP2-dependent cellular processes.
Abstract: Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) are essential proteins that are implicated in coordination of membrane-cytoskeletal signalling events, such as cell adhesion, migration, secretion, and phagocytosis in a variety of cell types. The most prominent structural feature of MARCKS and MRP is a central basic effector domain (ED) that binds F-actin, Ca2+-calmodulin, and acidic phospholipids; phosphorylation of key serine residues within the ED by protein kinase C (PKC) prevents the above interactions. While the precise roles of MARCKS and MRP have not been established, recent attention has focussed on the high affinity of the MARCKS ED for phosphatidylinositol 4,5-bisphosphate (PIP2), and a model has emerged in which calmodulin- or PKC-mediated regulation of these proteins at specific membrane sites could in turn control spatial availability of PIP2. The present review summarizes recent progress in this area and discusses how the above model might explain a role for MARCKS and MRP in activation of phospholipase D and other PIP2-dependent cellular processes.
TL;DR: This review of sphingolipid metabolism in the budding yeast Saccharomyces cerevisiae contains information on the enzymes and the genes that encode them, as well as connections to other metabolic pathways.
Abstract: This review of sphingolipid metabolism in the budding yeast Saccharomyces cerevisiae contains information on the enzymes and the genes that encode them, as well as connections to other metabolic pa...
TL;DR: It is concluded that IFN-γ induces the expression of RIG-I, which may play a role in the immunological effects of IFn-γ, which has the potential to amplify the immunomodulatory effects.
Abstract: Retinoic acid-inducible gene-І (RIG-І) is a member of the DExH box family proteins, which have diverse roles in regulation of gene expression and cellular functions. We found RIG-I mRNA and protein...
TL;DR: The yeast Saccharomyces cerevisiae is a model eukaryotic organism for the study of the regulation of phospholipid synthesis and phosphorylation is a major mechanism by which enzymes and transcription factors are regulated.
Abstract: The yeast Saccharomyces cerevisiae is a model eukaryotic organism for the study of the regulation of phospholipid synthesis. The major phospholipids (phosphatidylcholine, phosphatidylethanolamine, ...
TL;DR: Mounting evidence indicates that the maintenance of telomere integrity and telomerase protect cells from apoptosis, and the possible mechanisms linking telomeres, telomersase and apoptosis are discussed in this review.
Abstract: Telomeres are specialized high-order chromatin structures that cap the ends of eukaryotic chromosomes. In vertebrates, telomeric DNA is composed of repetitions of the TTAGGG hexanucleotide, is bound to a set of specific proteins, and is elongated by the reverse transcriptase enzyme telomerase. Telomerase activity is promptly detected in cells with an indefinite replicative potential, such as cancer cells, while is almost undetectable in normal cells, which are characterized by a limited life span. Mounting evidence indicates that the maintenance of telomere integrity and telomerase protect cells from apoptosis. Disruption of the telomere capping function and (or) telomerase inhibition elicit an apoptotic response in cancer cells, while restoration of telomerase activity in somatic cells confers resistance to apoptosis. The possible mechanisms linking telomeres, telomerase and apoptosis are discussed in this review, together with the impact of this field in anticancer research.
TL;DR: Recent advances in PITP biology are reviewed and as yet unresolved issues in this field are discussed.
Abstract: Phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs) are ubiquitous and highly conserved proteins that are believed to regulate lipid-mediated signaling events. Their ubiquity and con...
TL;DR: A model of the molecular mechanism involved in the sperm chromatin remodelling activity of nucleoplasmin is proposed based on current crystallographic data, recent biophysical and functional studies, as well as in the previously available information.
Abstract: In this article, we briefly review the structural and functional information currently available on nucleoplasmin. Special emphasis is placed on the discussion of the molecular mechanism involved i...
TL;DR: It is becoming increasingly clear that H2A.Z does not necessarily act independently, but rather, in conjunction with trans-acting factors to elicit chromatin changes.
Abstract: Integration of histone variants into chromatin organization allows for functional specification of chromatin regions. Recent functional analyses of H2A.Z have ascribed to it a multiplicity of compl...
TL;DR: In conclusion, inhibitors of NHE offer substantial promise for clinical development that will attenuate acute responses to myocardial postinfarction and chronic pos t infarction, which evolve toward heart failure.
Abstract: The major mechanism by which the heart cell regulates intracellular pH is the Na+H+ exchanger (NHE) with the NHE-1 isoform as the primary cardiac subtype. Although NHE-1 has been implicated in mediating ischemic injury, more recent evidence implicates the antiporter as a key mediator of hypertrophy, which is produced by various autocrine, paracrine and hormonal factors such as endothelin-1, angiotensin II, and α1 adrenoceptor agonists. These agonists activate the antiporter via phosphorylation-dependent processes. NHE-1 inhibition is likely conducive to attenuating the remodelling process after myocardial infarction. These effects probably occur independently of infarct size reduction and involve attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE offer substantial promise for clinical development that will attenuate acute responses to myocardial postinfarction and chronic pos t infarction, which evolve toward heart failure. The regulation of NHE-1 is discussed as is its po...
TL;DR: Recent experiments in gene therapy using the HO gene suggest that interventions aimed at HO in the vessel wall could provide a novel therapeutic approach for the treatment or prevention of atherosclerotic disease.
Abstract: Several lines of evidence suggest that antioxidant processes and (or) endogenous antioxidants inhibit proatherogenic events in the blood vessel wall. Heme oxygenase (HO), which catabolizes heme to biliverdin, carbon monoxide, and catalytic iron, has been shown to have such antioxidative properties. The HO-1 isoform of heme oxygenase is ubiquitous and can be increased several fold by stimuli that induce cellular oxidative stress. Products of the HO reaction have important effects: carbon monoxide is a potent vasodilator, which is thought to play a role in modulation of vascular tone; biliverdin and its by-product bilirubin are potent antioxidants. Although HO induction results in an increase in catalytic free iron release, the enhancement of intracellular ferritin protein through HO-1 has been reported to decrease the cytotoxic effects of iron. Oxidized LDL has been shown to increase HO-1 expression in endothelial and smooth muscle cell cultures, and during atherogenesis. Further evidence of HO-1 expression associated with atherogenesis has been demonstrated in human, murine and rabbit atherosclerotic lesions. Moreover, genetic models of HO deficiency suggest that the actions of HO-1 are important in modulating the severity of atherosclerosis. Recent experiments in gene therapy using the HO gene suggest that interventions aimed at HO in the vessel wall could provide a novel therapeutic approach for the treatment or prevention of atherosclerotic disease.
TL;DR: The roles of different histone modifications have been explored extensively in a number of nuclear processes, particularly in transcriptional regulation, but the role of histone modification in signaling or facilitating DNA repair begun to be elucidated only recently.
Abstract: The roles of different histone modifications have been explored extensively in a number of nuclear processes, particularly in transcriptional regulation. Only recently has the role of histone modification in signaling or facilitating DNA repair begun to be elucidated. DNA broken along both strands in the same region, a double-strand break, is damaged in the most severe way possible and can be the most difficult type of damage to repair accurately. To successfully repair the double-strand break, the cell must gain access to the damaged ends of the DNA and recruit repair factors, and in the case of homologous recombination repair, the cell must also find, colocalize, and gain access to a suitable homologous sequence. In the repair of a double-strand break, the cell must also choose between homologous and non-homologous pathways of repair. Here, we will briefly review the mechanisms of double-strand-break repair, and discuss the known roles of histone modifications in signaling and repairing double-strand breaks.