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PubMed2002

Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues.

The cAMP pathway plays a major role in the development of endocrine tissues and various molecular defects of key components of this pathway (G protein, receptors, PKA, etc.) have been observed in endocrine tumors. The ubiquitous transcription factor CREB (cAMP-response element binding protein) binds to the cAMP response element (CRE) and stimulates transcription after phosphorylation on Ser(133) by PKA. The CREB family of transcription factors contains three members: CREB, CREM, and ATF-1. Targeted expression of dominant-negative mutants of CREB in transgenic mice leads to somatotrophs or thyroid hypoplasia. GH-secreting adenomas are benign secreting tumors expressing an activated mutant G alpha s protein (Gsp) in about 40% of cases. In GH-secreting adenomas CREB is always expressed and often highly phosphorylated. The CREM isoform ICER is stimulated by cAMP, and its expression is increased in Gsp-harboring tumors. After transfection in pituitary somatotroph cells, activating mutations of Gs protein (Gsp) and overexpression of wild-type G alpha S stimulate transcription of various CRE-containing promoters via CREB in a Ser(133)-specific-dependent manner. Activation of the cAMP pathway by ACTH is required for adrenal cortex (AdCx) maintenance and steroidogenesis. CREB is expressed in normal AdCx. Alterations of CRE binding proteins with loss of CREB expression and compensatory overexpression of CREMtau is observed in the human adrenocortical cancer cell line H295R. Similar alterations are found at the protein level in human malignant adrenocortical tumors. In conclusion, the CREB family of transcription factors plays an important role in the development, differentiation, and proliferation of endocrine tissues. Various alterations of the CREB family of transcription factors can be observed in endocrine tumors.

Amino Acid Sequence↗
PubMed2002

Death receptor signaling giving life to ectodermal organs.

A new tumor necrosis factor (TNF) pathway has been identified that has an important function in the regulation of embryonic development. Three key components of this pathway are previously unknown proteins: the TNF ligand ectodysplasin (also known as EDA), its death domain-containing receptor EDAR, and the death domain adapter molecule EDARADD. This pathway was discovered and delineated through the cloning of genes that cause human hypohidrotic ectodermal dysplasia (HED) syndromes and by analysis of the corresponding mouse mutants (Tabby, downless, and crinkled) showing defects in hair, teeth, and several exocrine glands. EDAR signaling is mediated by the activation of nuclear factor kappa B, but other downstream targets are not known. Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth. It is also necessary for the development of fish scales, indicating that this pathway and its function have been conserved during the evolution of ectodermal organs.

Animals↗
PubMed2004

Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes.

Recent studies have led to a model of the molecular pathway that specifies the endoderm during vertebrate gastrulation. The HMG box transcription factor Sox17 is a key component of this pathway and is essential for endoderm formation; however, the molecular events controlled by Sox17 are largely unknown. We have identified several direct transcriptional targets of Sox17, including Foxa1 and Foxa2. We show that beta-catenin, a component of Wnt signaling pathway, physically interacts with Sox17 and potentiates its transcriptional activation of target genes. We identify a motif in the C terminus of Sox17, which is conserved in all the SoxF subfamily of Sox proteins, and this motif is required for the ability of Sox17 to both transactivate target genes and bind beta-catenin. Nuclear beta-catenin is present in endoderm cells of the gastrula, and depletion of beta-catenin from embryos results in a repression of Sox17 target genes. These data suggest that in a mechanism analogous to Tcf/Lef interacting with beta-catenin, Sox17 and beta-catenin interact to transcribe endodermal target genes.

Amino Acid Motifs↗
PubMed2005

Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro.

Multipotential stem cells can be selected from the bone marrow by plastic adhesion, expanded, and cultured. They are able to differentiate not only into multiple cell types, including cartilage, bone, adipose and fibrous tissues, and myelosupportive stroma, but also into mesodermal (endothelium), neuroectodermal, or endodermal (hepatocytes) lineages. Our goal was to characterize the multipotential capacities of human mesenchymal stem cells (hMSCs) and to evaluate their ability to differentiate into insulin-secreting cells in vitro. hMSCs were obtained from healthy donors, selected by plastic adhesion, and phenotyped by fluorescence-activated cell sorter and reverse transcription-polymerase chain reaction analysis before and after infection with adenoviruses coding for mouse IPF1, HLXB9, and FOXA2 transcription factors involved early in the endocrine developmental pathway. We found that native hMSCs have a pluripotent phenotype (OCT4 expression and high telomere length) and constitutively express NKX6-1 at a low level but lack all other transcription factors implicated in beta-cell differentiation. In all hMSCs, we detected mRNA of cytokeratin 18 and 19, epithelial markers present in pancreatic ductal cells, whereas proconvertase 1/3 mRNA expression was detected only in some hMSCs. Ectopic expression of IPF1, HLXB9, and FOXA2 with or without islet coculture or islet-conditioned medium results in insulin gene expression. In conclusion, our results demonstrated that in vitro human bone marrow stem cells are able to differentiate into insulin-expressing cells by a mechanism involving several transcription factors of the beta-cell developmental pathway when cultured in an appropriate microenvironment.

Adenoviridae↗
PubMed2004

Interactions within the ubiquitin pathway of Caenorhabditis elegans.

The ubiquitin system is a well-conserved and pervasive process for post-synthetic modification of proteins. Three key components of the pathway are required for ubiquitination to occur: the E1 ubiquitin activating enzyme, the E2 ubiquitin conjugating enzyme, and the E3 ubiquitin ligase. There are several different E2 ubiquitin conjugating enzymes and an even greater number of E3 ubiquitin ligases. Interactions between these two groups are critical for substrate ubiquitination. This study reports a two-hybrid analysis of interactions within the ubiquitin system of Caenorhabditis elegans. Forty-three RING finger proteins (presumed E3 ubiquitin ligases) and 14 predicted E2 ubiquitin conjugating enzymes were included in the screen. A total of 31 E2-E3 interactions were uncovered. In addition, the UBC-13 conjugating enzyme was observed to interact with two different E2s, UEV-1 and UBC-1. The interaction of UBC-1 and UBC-13 was confirmed with in vitro ubiquitination reactions. Using NHL-1 as the E3 in the assays, ubiquitination was observed when both UBC-1 and UBC-13 were present but not with either alone. These data imply that some E2s require dimerization in order to function.

Amino Acid Sequence↗
PubMed2005

Mannheimia haemolytica leukotoxin induces apoptosis of bovine lymphoblastoid cells (BL-3) via a caspase-9-dependent mitochondrial pathway.

Mannheimia haemolytica is a key pathogen in the bovine respiratory disease complex. It produces a leukotoxin (LKT) that is an important virulence factor, causing cell death in bovine leukocytes. The LKT binds to the beta(2) integrin CD11a/CD18, which usually activates signaling pathways that facilitate cell survival. In this study, we investigated mechanisms by which LKT induces death in bovine lymphoblastoid cells (BL-3). Incubation of BL-3 cells with a low concentration of LKT results in the activation of caspase-3 and caspase-9 but not caspase-8. Similarly, the proapoptotic proteins Bax and BAD were significantly elevated, while the antiapoptotic proteins Bcl-2, Bcl(XL) and Akt-1 were downregulated. Following exposure to LKT, we also observed a reduction in mitochondrial cytochrome c and corresponding elevation of cytosolic cytochrome c, suggesting translocation from the mitochondrial compartment to the cytosol. Consistent with this observation, tetramethylrhodamine ethyl ester perchlorate staining revealed that mitochondrial membrane potential was significantly reduced. These data suggest that LKT induces apoptosis of BL-3 cells via a caspase-9-dependent mitochondrial pathway. Furthermore, scanning electron micrographs of mitochondria from LKT-treated BL-3 cells revealed lesions in the outer mitochondrial membrane, which are larger than previous reports of the permeability transition pore through which cytochrome c is usually released.

Animals↗
PubMed2001

Crystal structure of the Acidaminococcus fermentans 2-hydroxyglutaryl-CoA dehydratase component A.

Acidaminococcus fermentans degrades glutamate via the hydroxyglutarate pathway, which involves the syn-elimination of water from (R)-2-hydroxyglutaryl-CoA in a key reaction of the pathway. This anaerobic process is catalyzed by 2-hydroxyglutaryl-CoA dehydratase, an enzyme with two components (A and D) that reversibly associate during reaction cycles. Component A (CompA), a homodimeric protein of 2x27 kDa, contains a single, bridging [4Fe-4S] cluster and uses the hydrolysis of ATP to deliver an electron to the dehydratase component (CompD), where the electron is used catalytically. The structure of the extremely oxygen-sensitive CompA protein was solved by X-ray crystallography to 3 A resolution. The protein was found to be a member of the actin fold family, revealing a similar architecture and nucleotide-binding site. The key differences between CompA and other members of the actin fold family are: (i) the presence of a cluster binding segment, the "cluster helix"; (ii) the [4Fe-4S] cluster; and (iii) the location of the homodimer interface, which involves the bridging cluster. Possible reaction mechanisms are discussed in light of the close structural similarity to members of the actin-fold family and the functional similarity to the nitrogenase Fe- protein.

Actins↗
PubMed2002

Overexpression of muscle lipoprotein lipase and insulin sensitivity.

PURPOSE OF REVIEW: The number of people affected with obesity and type 2 diabetes has reached epidemic proportions worldwide. Insulin resistance, a common feature of both conditions, has come under intense investigation. This review focuses on our current understanding of the insulin signaling cascade and potential mechanisms of regulation. RECENT FINDINGS: Recent studies have concentrated on inhibition of insulin-stimulated glucose uptake by free fatty acids as the primary cause of insulin resistance, particularly in muscle, a major site of insulin-stimulated glucose disposal. Mouse models of muscle-specific lipoprotein lipase overexpression permit closer examination of the consequences of lipid oversupply to muscle. Such mice exhibit whole-body and muscle insulin resistance, accompanied by increased accumulation of intramyocellular triglyceride and other fatty acid metabolites (i.e. long-chain acyl coenzyme A, diacylglycerol, and ceramide). These molecules may impede glucose transport by interfering with insulin signal transduction. The mechanisms for the inhibitory effect of free fatty acids on insulin-stimulated glucose transport are complex, and multiple pathways may be involved. Although key molecules have been identified, no single, clearly defined pathway has been established. SUMMARY: The mouse model of muscle-specific lipoprotein lipase overexpression allows closer examination of increased free fatty acid delivery to the muscle and of effects on insulin sensitivity. Further study of this model may provide additional insight into the role that lipids play in the development of insulin resistance, and may possibly help to identify novel approaches to prevention or treatment.

Animals↗
PubMed2004

Identification of the Entner-Doudoroff pathway in an antibiotic-producing actinomycete species.

The metabolic network of the central carbon metabolism represents the backbone of cellular metabolism and provides the precursors and cofactors required for synthesis of secondary metabolites. It is therefore pivotal to map the operating metabolic network in the central carbon metabolism in order to design metabolic engineering strategies towards construction of more efficient producers of specific metabolites. In this context, methods that allow rapid and reliable mapping of the central carbon metabolism are valuable. In the present study, a (13)C labelling-based method was used to identify the primary metabolic pathways of the poorly characterized antibiotic-producing actinomycete Nonomuraea sp. ATCC 39727. Surprisingly, it was found that Nonomuraea sp. ATCC 39272 predominantly metabolizes glucose via the Entner-Doudoroff (ED) pathway. This represents the first time that the ED pathway has been recognized as the main catabolic pathway in an actinomycete. The Nonomuraea genes encoding the key enzymes of the ED pathway were subsequently identified, sequenced and functionally described.

Actinobacteria↗
PubMed1994

Role of three rab5-like GTPases, Ypt51p, Ypt52p, and Ypt53p, in the endocytic and vacuolar protein sorting pathways of yeast.

The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mammalian cells. Using a PCR approach to identify rab5 homologs in Saccharomyces cerevisiae, two genes encoding proteins with 54 and 52% identity to rab5, YPT51 and YPT53 have been identified. Sequencing of the yeast chromosome XI has revealed a third rab5-like gene, YPT52, whose protein product exhibits a similar identity to rab5 and the other two YPT gene products. In addition to the high degree of identity/homology shared between rab5 and Ypt51p, Ypt52p, and Ypt53p, evidence for functional homology between the mammalian and yeast proteins is provided by phenotypic characterization of single, double, and triple deletion mutants. Endocytic delivery to the vacuole of two markers, lucifer yellow CH (LY) and alpha-factor, was inhibited in delta ypt51 mutants and aggravated in the double ypt51ypt52 and triple ypt51ypt52ypt53 mutants, suggesting a requirement for these small GTPases in endocytic membrane traffic. In addition to these defects, the here described ypt mutants displayed a number of other phenotypes reminiscent of some vacuolar protein sorting (vps) mutants, including a differential delay in growth and vacuolar protein maturation, partial missorting of a soluble vacuolar hydrolase, and alterations in vacuole acidification and morphology. In fact, vps21 represents a mutant allele of YPT51 (Emr, S., personal communication). Altogether, these data suggest that Ypt51p, Ypt52p, and Ypt53p are required for transport in the endocytic pathway and for correct sorting of vacuolar hydrolases suggesting a possible intersection of the endocytic with the vacuolar sorting pathway.

Amino Acid Sequence↗
PubMed2000

Cutting edge: gab2 mediates an inhibitory phosphatidylinositol 3'-kinase pathway in T cell antigen receptor signaling.

Phosphatidylinositol 3'-kinase (PI3K) is a key component of multiple signaling pathways, where it typically promotes survival, proliferation, and/or adhesion. Here, we show that in TCR signaling, the scaffolding adapter Gab2 delivers an inhibitory signal via PI3K. Overexpression of Gab2 in T cell lines inhibits TCR-evoked activation of the IL-2 promoter, blocking NF-AT- and NF-kappaB-directed transcription. Inhibition is abrogated by mutating the Gab2 p85-binding sites, by treatment with PI3K inhibitors or by cotransfection of phosphatase homolog of tensin. Our findings provide the first evidence of a negative function for a scaffolding adapter in T cells and identify Gab2/PI3K-containing complexes as novel regulators of TCR signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2000

From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease.

The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, G alpha(q) and downstream effectors, mitogen-activated protein kinase pathways, and the Ca(2+)-regulated phosphatase, calcineurin. In the past it has been difficult to discern which signaling molecules actually contributed to disease progression in vivo; however, the development of numerous transgenic and knockout mouse models of cardiomyopathy is now allowing the direct testing of stimulatory and inhibitory molecules in the mouse heart. From this work it has been possible to identify signaling molecules and pathways that are required for different aspects of disease progression in vivo. In particular, a number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocyte. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.

Animals↗
PubMed1990

Metabolic control analysis of mammalian serine metabolism.

(1) Mammalian serine metabolism is discussed in relation to its synthesis and utilization in proliferating cells, particularly during the nonmalignant proliferation of lymphocytes. (2) An analysis of the control of serine biosynthesis de novo under conditions of high pathway flux has been carried out using metabolic control theory. (3) The important and novel conclusions are that control of pathway flux is localized exclusively at the final step of this biosynthetic pathway, phosphoserine phosphatase. This conclusion challenges the frequently stated maxim that control of biosynthetic pathways is always directed at the first pathway enzyme in a sequence. In the case of phosphoserine phosphatase, the enzyme is inhibited uncompetitively by its product serine, and this feedback control mechanism has the most significant controlling influence on overall pathway flux. Thus, the serine biosynthesis pathway, under these conditions, is controlled by product demand (serine utilization) and not by substrate supply (glycolytic provision of 3-phosphoglycerate), despite the high rate of glycolysis associated with cell proliferation. (4) The control structure of the pathway is not immutable. As has been observed with other pathways analyzed by metabolic control theory, the key points of control in the pathway can shift according to physiological circumstances. At low pathway flux, the control of serine biosynthesis is shared between all the component enzymes of the pathway, and the responsiveness of flux shifts from product demand to substrate supply. (5) Serine utilization has been studied in mitogenically-stimulated human peripheral lymphocytes. Cell proliferation and serine utilization for nucleic acid synthesis have been shown to be responsive to serine concentrations in the normal plasma range. (6) It is concluded that the maintenance of normal plasma serine concentrations is an important factor in the rate of lymphocyte proliferation and hence the effectiveness with which the body can mount an immune response to an antigenic challenge, such as in infection.

Animals↗
PubMed1997

Dominant enhancers of Egfr in Drosophila melanogaster: genetic links between the Notch and Egfr signaling pathways.

The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed an F1 screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context.

Animals↗
PubMed2002

Potential methods to circumvent blocks in apoptosis in lymphomas.

We review our current understanding of the molecular determinants and mechanisms of lymphocyte apoptosis and identify the key regulators of these death-signaling pathways. In addition, we describe the key molecular aberrations that underlie the resistance of lymphomas to conventional therapy, and highlight the enormous promise of potential therapeutic strategies that could circumvent or overcome these genetic impediments to apoptosis.

Apoptosis↗
PubMed1983

Catabolic pathways for glucose, glycerol and 6-phosphogluconate in Mycobacterium leprae grown in armadillo tissues.

With radioisotopes, it was shown that suspensions of Mycobacterium leprae oxidized glycerol, 6-phosphogluconate, glucose, glucose 6-phosphate, and, at a low rate, gluconate, to CO2. The incubation period in these experiments was usually 20 h, but after 140 h up to five times more glucose and gluconate had been converted to CO2. Studies with differentially labelled glucose indicated that glycolysis and the hexose monophosphate pathway were used for glucose dissimilation. Key enzymes of glycolysis, the hexose monophosphate pathway and glycerol catabolism were detected in cell-free extracts from purified M. Leprae, but phosphoketolase, Entner-Doudoroff pathway activity and gluconate kinase were absent. All these enzymes were present also in host-tissue, but biochemical evidence is presented which indicates that all enzymes detected in extracts from M. leprae were authentic bacterial enzymes. Additionally, they could all be detected in extracts of M. leprae prepared by treatment with NaOH in which host enzymes adsorbed to M. leprae are inactivated.

Animals↗
PubMed2003

Bcl-xL as an antiapoptotic molecule for cardiomyocytes.

It is now widely accepted that two forms of cell death, apoptosis and necrosis, occur in cardiomyocytes, and increasing evidence indicates that apoptosis plays an important role in the pathophysiology of cardiovascular diseases. Currently, two major pathways in the induction of apoptosis are known to occur in cardiomyocytes, the mitochondrial pathway and the death receptor pathway. Bcl-2 family proteins are key regulators of apoptosis in the mitochondrial pathway. Among them, Bcl-x(L), which is structurally similar to Bcl-2 and functions as an antiapoptotic molecule, is involved in diseases such as ischemic heart diseases and heart failure. In this review, we focus on the role of Bcl-x(L) in apoptosis in cardiomyocytes and discuss the potential use of Bcl-x(L) as a cardioprotective therapy for cardiac diseases.

Apoptosis↗