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At least 631 records · Page 35Linked to original sources
PubMed2004

Focal divergent chondrosarcomatous differentiation in a primary pleomorphic liposarcoma and expression of transforming growth factor beta.

A rare case of primary pleomorphic liposarcoma of the thigh with a myxoid component, in which divergent differentiation to a well-differentiated chondrosarcoma was focally present, is described. Presence of heterologous elements has mainly been recognized in the context of dedifferentiated liposarcomas. Few cases of benign mesenchymal tissue have also been reported in well-differentiated and myxoid liposarcomas, while divergent sarcomatous differentiation in liposarcomas appears to be also rare in the absence of dedifferentiation. Positive immunostaining of transforming growth factor-beta, which seems to play a role in the formation of bone and cartilage, was demonstrated in our case. Review of the existing literature on the subject has been carried out.

Aged↗
PubMed2004

Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene EGR-1, which results in the up-regulation of NAG-1, an antitumorigenic protein.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to have chemopreventive activity, but the mechanisms involved are not clearly understood. Although NSAIDs inhibit cyclooxygenase activity, they also increase the expression of a divergent member of the transforming growth factor-beta superfamily, termed NSAID-activated gene 1 (NAG-1), a protein with an antitumorigenic and proapoptotic activity that could in part be linked to the chemoprevention activity of NSAIDs. NAG-1 is induced by some NSAIDs, but the mechanisms responsible are not clear. In this report, we have identified a cis-acting element responsive to NSAIDs located within the -73 to -51 region of the NAG-1 promoter. This region contains overlapping EGR-1 and Sp1 binding sites, and mutations in this region suggest that the transcription factors have an important role in NSAID-induced NAG-1 expression. EGR-1 was found to play a critical role in the induction of NAG-1 by sulindac sulfide and other NSAIDs. NSAIDs increase EGR-1 protein expression that occurs before the induction of NAG-1 expression, supporting the hypothesis that EGR-1 is necessary for NSAID-induced NAG-1 expression. Thus, NSAIDs induce the expression of EGR-1, a tumor suppressor gene, providing a novel mechanism to explain, in part, the antitumorigenic properties of some NSAIDs. NAG-1 seems to be an important downstream target protein of this transcription factor, EGR-1, and may mediate the chemopreventive activity of some NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Effect of dietary protein on the liver content and subunit composition of the branched-chain alpha-ketoacid dehydrogenase complex.

Levels of expression of two subunits of the liver branched-chain alpha-ketoacid dehydrogenase complex in response to extremes of dietary protein intake (50% versus 0% protein diet) were determined by quantitative immunoblotting. Dietary protein deficiency decreased the amount of E1 alpha protein to a greater extent than E2 protein. The ratio of E1 alpha to E2 was below 1 in the liver of animals starved for protein and above 1 in the liver of animals fed the high-protein diet. Supplementation of the 0% protein diet with 5% leucine (but not 5% valine) had the same effect as the 50% protein diet. The extremes of dietary protein also resulted in a divergent pattern of expression of the mRNAs for the subunits of the complex. The E1 beta message showed the expected corollary of being greater in the liver of the high-protein-fed rats than the no-protein-fed rats. In contrast, the E2 message was not affected by the two extremes of dietary protein and the E1 alpha message was greater in the liver of the no-protein-fed rats than the high-protein-fed rats. Thus, coordinate regulation of gene expression of the subunits of the complex does not occur in response to dietary protein. Post-transcriptional regulatory mechanisms most likely determine the amount of the complex and the ratio of its subunits. The decrease in E1 alpha/E2 protein ratio that occurs in dietary protein deficiency may increase sensitivity of the complex to phosphorylation-mediated inhibition by branched-chain alpha-ketoacid dehydrogenase kinase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1979

Effects of gold, dapsone, and prednisone on serum C-reactive protein and haptoglobin and the erythrocyte sedimentation rate in rheumatoid arthritis.

Sequential measurements of serum C-reactive protein (CRP), serum haptoglobin (Hp), and erythrocyte sedimentation rate (ESR) were made in 209 patients with rheumatoid arthritis (RA); 78 of them were treated with gold, 71 with dapsone, and 60 with prednisone. The results were expressed as proportional changes in the measurements at 28-day intervals after treatment began. The period of study was 140 days. During treatment with gold and dapsone there were statistically significant gradual and progressive falls of similar magnitude in serum CRP and ESR. During treatment with prednisone serum CRP and ESR fell abruptly by 28 days and thereafter altered little. At 140 days prednisone had had the largest proportional effect on both measurements. During gold treatment the fall in serum Hp was similar to that of the ESR. In contrast, prednisone had little effect on Hp levels despite large falls in serum CRP and the ESR. Either prednisone stimulates Hp synthesis or the divergence is an expression of the difference in type of effect between gold and prednisone on RA. The effect of dapsone on serum Hp was large and progressive; it partly reflects haemolysis and, since the haemolysis was not progressive, partly improvement in the RA. The results show the relative efficacy of the drugs and suggest that dapsone may be a useful alternative treatment for RA.

Arthritis, Rheumatoid↗
PubMed2004

Caspase-9 regulation: an update.

The complex sequence of events leading to apoptotic cell death is governed by an elaborate regulatory scheme involving the actions of both initiator and executioner proteases. Among the most intensively studied of the initiator caspases is caspase-9, an essential throughput element in the so-called intrinsic or mitochondrially gated pathway of apoptosis. Previous reviews have described the proteolytic processing and activation of this protease in much detail; here we provide an update on caspase-9 regulation. A comprehensive description of the intra- and intermolecular events involved in modulating protein expression and activity are presented. Particular emphasis is placed on the role alternative splicing plays in the expression of functionally divergent protein isoforms, as well as, the participation of specific post-translational events in regulating caspase-9 activity. Such discrete modulation in reported activity characterizes, not only the pivotal role of this protease in the final commitment process itself, but also emphasizes the more general interplay that exists between mutually opposing cytotoxic and cytoprotective influences in maintaining cellular homeostasis.

Alternative Splicing↗
PubMed1995

Co-ordinated regulation of amino sugar biosynthesis and degradation: the NagC repressor acts as both an activator and a repressor for the transcription of the glmUS operon and requires two separated NagC binding sites.

The NagC repressor controls the expression of the divergently transcribed nagE-nagBACD operons involved in the uptake and degradation of the amino sugars, N-acetyl-D-glucosamine (GlcNAc) and glucosamine (GlcN). The glmUS operon, encoding proteins necessary for the synthesis of GlcN (glmS) and the formation of UDP-GlcNAc (glmU), is transcribed from two promoters located upstream of glmU. In the absence of amino sugars both promoters are active. However, in the presence of GlcNAc, the glmU proximal promoter, P1, is inactive while the upstream promoter, P2, is subject to weak induction. Two binding sites for the NagC repressor are located at -200 and -47 bp upstream of P1. Mutations which prevent NagC binding to either of these sites eliminate expression from the P1 promoter. This shows that binding of NagC is necessary for expression of the glmU P1 promoter and implies that NagC is playing the role of activator for this promoter. Moreover, the location of the distal NagC site suggests that this site is behaving like an upstream activating sequence (UAS).

Acetylglucosamine↗
PubMed2005

Classical genotropic versus kinase-initiated regulation of gene transcription by the estrogen receptor alpha.

Elucidation of kinase-initiated routes by which the estrogen receptors alpha and beta (ERalpha and ERbeta) control gene transcription, along with evidence of distinct biologic outcomes in response to ligands that can selectively activate nongenotropic signaling of the ERs or the androgen receptor, suggest that the ERs control a range of genes wider than that regulated by their direct association with DNA. To ascertain the extent and significance of nongenotropic ER-mediated transcription, we employed transduced HeLa cells expressing wild-type ERalpha or the ligand binding domain of ERalpha localized to the cell membrane (E-Mem), the OB-6 osteoblastic cell line, MCF-7 breast carcinoma cells and uteri from mice treated with 17beta-estradiol (E(2)), or the nongenotropic signaling activator 4-estren-3alpha,17beta-diol (estren). E(2) and estren induced ERK1/2 and Akt phosphorylation in ERalpha or E-Mem stably transfected HeLa cells; however, the phosphorylation kinetics differed between the two cell lines. In all four models, nongenotropic ER actions regulated a population of genes distinct from those regulated by genotropic ER actions. Specifically, the expression of Wnt2, Frizzled10, Egr-1, and c-Fos was strongly up-regulated in E-Mem-containing HeLa cells treated with E(2) or estren, or in ERalpha-containing HeLa cells treated with estren. Up-regulation of Frizzled10 by estren was reproduced in MCF-7 cells. Egr-1 was up-regulated by both estren and E(2); but complement 3, only by E(2) in the uteri. Estren had no effect on complement 3, cathepsin D, progesterone receptor, bcl-2, and cyclin D1 in MCF-7 cells, whereas E(2) up-regulated all these estrogen response element or activating protein-1-containing genes. These results support an extensive divergence in gene expression depending on the mode of ER activation.

Animals↗
PubMed2000

Factors controlling cyclin B expression.

Cyclins control the transition between the phases of the eukaryotic cell cycle as regulatory subunits of the cyclin-dependent kinases (CDKs). Phase-specific activation of the CDK is in part regulated by phase-specific expression of their cyclin component. In most eukaryotic cells including higher plant, B-type cyclin genes are expressed specifically at G2/M phase during the cell cycle. Promoters from yeast, plant and animal B-type cyclin genes are all activated in a cell cycle-regulated manner. In yeast, a transcription factor, Mcm1, in cooperation with an uncloned factor SFF, regulates the cell cycle-dependent promoter activation of mitotic B-type cyclin genes, CLB1 and CLB2. Activity of the human cyclin B1 promoter is regulated by a complex mechanism involving multiple cis-acting elements, none of which are sufficient for G2/M-specific promoter activation. In contrast, plants employ a simple mechanism for cell cycle-regulated promoter activation of B-type cyclin genes. Plant B-type cyclin gene promoters contain a common cis-acting element, called the MSA element, which is necessary and sufficient for the phase-specific promoter activation. MSA-like sequences are also found in the promoters of G2/M-specific genes encoding kinesin-like proteins, suggesting that a defined set of G2/M-specific genes are co-regulated by a common MSA-mediated mechanism in plants. Thus, the molecular mechanisms regulating B-type cyclin gene expression are evolutionarily divergent, and the MSA-mediated mechanism seems to be specific to plants. The consensus sequence of the MSA element resembles the binding sites of animal Myb transcription factors. A set of our data suggest the possibility that plant Myb may have unexpected roles in G2/M by inducing B-type cyclin genes, together with other cell cycle-related genes in plants.

Animals↗
PubMed1991

Primary structure and domain organization of human alpha and beta adducin.

Adducin is a membrane-skeletal protein which is a candidate to promote assembly of a spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. The complete sequence of both subunits of human adducin, alpha (737 amino acids), and beta (726 amino acids) has been deduced by analysis of the cDNAs. The two subunits have strikingly conserved amino acid sequences with 49% identity and 66% similarity, suggesting evolution by gene duplication. Each adducin subunit has three distinct domains: a 39-kD NH2-terminal globular protease-resistant domain, connected by a 9-kD domain to a 33-kD COOH-terminal protease-sensitive tail comprised almost entirely of hydrophilic amino acids. The tail is responsible for the high frictional ratio of adducin noted previously, and was visualized by EM. The head domains of both adducin subunits exhibit a limited sequence similarity with the NH2-terminal actin-binding motif present in members of the spectrin superfamily and actin gelation proteins. The COOH-termini of both subunits contain an identical, highly basic stretch of 22 amino acids with sequence similarity to the MARCKS protein. Predicted sites of phosphorylation by protein kinase C include the COOH-terminus and sites at the junction of the head and tail. Northern blot analysis of mRNA from rat tissues, K562 erythroleukemia cells and reticulocytes has shown that alpha adducin is expressed in all the tissues tested as a single message size of 4 kb. In contrast, beta adducin shows tissue specific variability in size of mRNA and level of expression. A striking divergence between alpha and beta mRNAs was noted in reticulocytes, where alpha adducin mRNA is present in at least 20-fold higher levels than that of beta adducin. The beta subunit thus is a candidate to perform a limiting role in assembly of functional adducin molecules.

Amino Acid Sequence↗
PubMed2006

Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells.

Activity of voltage-gated K(+) (K(V)) channels in pulmonary artery smooth muscle cells (PASMC) plays an important role in control of apoptosis and proliferation in addition to regulating membrane potential and pulmonary vascular tone. Bone morphogenetic proteins (BMPs) inhibit proliferation and induce apoptosis in normal human PASMC, whereas dysfunctional BMP signaling and downregulated K(V) channels are involved in pulmonary vascular medial hypertrophy associated with pulmonary hypertension. This study evaluated the effect of BMP-2 on K(V) channel function and expression in normal human PASMC. BMP-2 (100 nM for 18-24 h) significantly (>2-fold) upregulated mRNA expression of KCNA5, KCNA7, KCNA10, KCNC3, KCNC4, KCNF1, KCNG3, KCNS1, and KCNS3 but downregulated (at least 2-fold) KCNAB1, KCNA2, KCNG2, and KCNV2. The most dramatic change was the >10-fold downregulation of KCNG2 and KCNV2, two electrically silent gamma-subunits that form heterotetramers with functional K(V) channel alpha-subunits (e.g., KCNB1-2). Furthermore, the amplitude and current density of whole cell K(V) currents were significantly increased in PASMC treated with BMP-2. It has been demonstrated that K(+) currents generated by KCNB1 and KCNG1 (or KCNG2) or KCNB1 and KCNV2 heterotetramers are smaller than those generated by KCNB1 homotetramers, indicating that KCNG2 and KCNV2 (2 subunits that were markedly downregulated by BMP-2) are inhibitors of functional K(V) channels. These results suggest that BMP-2 divergently regulates mRNA expression of various K(V) channel alpha-, beta-, and gamma-subunits and significantly increases whole cell K(V) currents in human PASMC. Finally, we present evidence that attenuation of c-Myc expression by BMP-2 may be involved in BMP-2-mediated increase in K(V) channel activity and regulation of K(V) channel expression. The increased K(V) channel activity may be involved in the proapoptotic and/or antiproliferative effects of BMP-2 on PASMC.

Apoptosis↗
PubMed2003

Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma.

Breast and prostate cancer often metastasise to the skeleton. Interestingly, the histopathological characteristics of the bone lesions that arise from these two cancer types differ. Breast tumours give rise to metastases in the skeleton with a mixed lytic/sclerotic pattern, whereas a predominantly sclerotic pattern is seen in metastases from prostate tumours. Osteopontin (OPN) and bone sialoprotein (BSP) are bone matrix proteins that have been implicated in the selective affinity of cancer cells for bone. In the present study, 21 patient cases with skeletal metastasis and their respective primary tumours (12 with breast cancer, 9 with prostate cancer) were investigated by immunohistochemistry in order to assess the level of OPN and BSP. Moderate to strong OPN expression was found in 42% of all breast tumours and in 56% of all prostate tumours. Significantly more breast cancer bone metastases exhibited high OPN expression, 83%, as compared with prostate tumour bone metastases, 11% (P = 0.0019). In contrast, moderate to strong BSP expression was found in 33% of breast tumours and in 89% of prostate tumours. In the bone lesions, only 33% of breast tumour metastases showed moderate/strong BSP expression compared to 100% of prostate tumour metastases (P = 0.0046). This divergent pattern of OPN/BSP expression could be an important determinant for the different characteristics of these two types of bone metastasis, i.e., lytic vs. sclerotic, consistent with the proposed role of OPN in differentiation and activation of osteoclasts and of BSP as a stimulator of bone mineralisation.

Adult↗
PubMed2006

Transcription factor profiling in individual hematopoietic progenitors by digital RT-PCR.

We report here a systematic, quantitative population analysis of transcription factor expression within developmental progenitors, made possible by a microfluidic chip-based "digital RT-PCR" assay that can count template molecules in cDNA samples prepared from single cells. In a survey encompassing five classes of early hematopoietic precursor, we found markedly heterogeneous expression of the transcription factor PU.1 in hematopoietic stem cells and divergent patterns of PU.1 expression within flk2- and flk2+ common myeloid progenitors. The survey also revealed significant differences in the level of the housekeeping transcript GAPDH across the surveyed populations, which demonstrates caveats of normalizing expression data to endogenous controls and underscores the need to put gene measurement on an absolute, copy-per-cell basis.

Animals↗
PubMed2007

Compensatory evolution in response to a novel RNA polymerase: orthologous replacement of a central network gene.

A bacteriophage genome was forced to evolve a new system of regulation by replacing its RNA polymerase (RNAP) gene, a central component of the phage developmental pathway, with that of a relative. The experiment used the obligate lytic phage T7 and the RNAP gene of phage T3. T7 RNAP uses 17 phage promoters, which are responsible for all middle and late gene expression, DNA replication, and progeny maturation, but the enzyme has known physical contacts with only 2 other phage proteins. T3 RNAP was supplied in trans by the bacterial host to a T7 genome lacking its own RNAP gene and the phage population was continually propagated on naive bacteria throughout the adaptation. Evolution of the T3 RNAP gene was thereby prevented, and selection was for the evolution of regulatory signals throughout the phage genome. T3 RNAP transcribes from T7 promoters only at low levels, but a single mutation in the promoter confers high expression, providing a ready mechanism for reevolution of gene expression in this system. When selected for rapid growth, fitness of the engineered phage evolved from a low of 5 doublings/h to 33 doublings/h, close to the expected maximum of 37 doublings/h. However, the experiment was terminated before it could be determined accurately that fitness had reached an obvious plateau, and it is not known whether further adaptation could have resulted in complete recovery of fitness. More than 30 mutations were observed in the evolved genome, but changes were found in only 9 of the 16 promoters, and several coding changes occurred in genes with no known contacts with the RNAP. Surprisingly, the T7 genome adapted to T3 RNAP also maintained high fitness when using T7 RNAP, suggesting that the extreme incompatibility of T7 elements with T3 RNAP is not an invariant property of divergence in these expression systems.

Bacteriophage T3↗
PubMed1996

Separate cis-acting elements determine the expression of mouse Dbx gene in multiple spatial domains of the central nervous system.

Dbx, a divergent homeobox gene, is expressed in a regionally restricted pattern in the developing mouse central nervous system (CNS). In order to understand its spatial regulation, we have isolated a cis-regulatory region using a reporter gene analytical approach in transgenic mice. A 5.7 kb DNA fragment that contains the transcriptional start site of the Dbx gene is sufficient to direct the expression of the transgene to various domains of the CNS in a temporally regulated fashion. The transgene expression can be detected between 9.5 and 15.5 days post coitum in embryos in the fore-, mid- and hindbrain and spinal cord in regions where the endogenous gene is expressed. Additionally, transgene expression can also be detected in the oculomotor nerve (cranial nerve III). The expression of the transgene closely resembles that of the Dbx gene with minor, but interesting differences. These results suggest that major cis-acting elements reside within a 5.7 kb DNA fragment located 5' of the Dbx gene. Further deletion analysis shows that at least two independently regulated elements are present within this DNA fragment: an element that directs expression to the brain and spinal cord and a second element that directs expression to the oculomotor nerve.

Amino Acid Sequence↗
PubMed2004

Differential expression of duplicated opsin genes in two eyetypes of ostracod crustaceans.

In the first molecular study of ostracod (Crustacea) vision, we present partial cDNA sequences of ostracod visual pigment genes (opsins). We found strong support for differential expression of opsins in ostracod median and compound eyes and suggest that photoreceptor specific expression may be a general phenomenon in organisms with multiple receptors. We infer that eye-specific expression predates the divergence of the two species examined, Skogsbergia lerneri and Vargula hilgendorfii, because eye-specific opsin orthologs are present in both species. We found multiple opsin loci in ostracods, estimating that at least eight are present in Skogsbergia lerneri. All opsins from both ostracod species examined are more closely related to each other than to any other known opsin sequences. Because we find no evidence for gene conversion or alternative splicing, we suggest the occurrence of many recent gene duplications. Why ostracods may have retained multiple recent opsin gene duplicates is unknown, but we discuss several possible hypotheses.

Amino Acid Sequence↗
PubMed1986

Molecular organization and expression of the genetic locus glued in Drosophila melanogaster.

The Glued locus of Drosophila melanogaster is genetically defined as the functional unit which is affected by the dominant Glued mutation Gl. Genomic DNA was cloned from the region of the Glued locus, at 70C2 on chromosome 3, by using a P element insertion in the region as a molecular marker. Three genes encoding polyadenylated transcripts were detected within a 30-kilobase span of the cloned DNA. The gene nearest the P element insertion site was identified as a Glued gene on the basis of alterations in its DNA and encoded transcript associated with the Gl mutation and with reversions of Gl which eliminate the dominant effect by inactivation of the mutant allele. Expression of the wild-type Gl+ gene is temporally regulated during development; the amount of the encoded transcript is highest in the embryonic stage, decreasing in the first and second larval instars, and then increasing in the third instar and pupal stages. There is a maternal contribution of the Gl+ transcript to the embryo, which probably accounts for the maternal lethal effect of Glued mutations on early development. In situ hybridizations of Gl+ DNA to RNA in tissue sections showed that the Gl+ transcript is present in virtually all tissues of the embryo, late larva, and pupa. The general distribution of this transcript is consistent with genetic evidence indicating that the Glued locus controls a generally essential cell function (P. J. Harte and D. R. Kankel, Genetics 101:477-501, 1982). Different Glued mutations produce distinct phenotypic effects, including adults with severe visual defects, larvae lacking imaginal discs, and early lethality. These diverse mutant phenotypes are discussed in terms of quantitative changes in the Glued function. Closely adjacent to Gl+ is another gene which is transcribed in a divergent direction and expressed coordinately with Gl+ throughout Drosophila development. It remains to be determined whether this gene is also involved with the Glued function.

Animals↗
PubMed2003

A mating-induced protein of Phytophthora infestans is a member of a family of elicitors with divergent structures and stage-specific patterns of expression.

Five members of an elicitor-like gene family from Phytophthora infestans were examined. The family was identified through the analysis of M81, a mating-induced gene. The predicted M81 product resembled a 42-kDa P. sojae glycoprotein known to elicit defense reactions in plants, including a host of P. infestans, potato. M81 was the most structurally and functionally divergent of the P. infestans genes compared with the P. sojae sequence. M81 lacked elicitor activity, had the lowest protein identity (47%), displayed mating-specific transcription, and had a novel C-terminal domain. The latter contained a 30-residue proline- and threonine-rich motif, which, remarkably, was tandemly repeated 24 to 36 times in different alleles. M81C, M81D, and M81E better resembled the P. sojae protein based on amino acid identity (63 to 75%) and conserved elicitor activity. M81C and M81D mRNA accumulated only during zoosporogenesis, while M81E expression was restricted to hyphae. M81B, an apparent pseudogene, was physically linked to M81. The protein products of each gene were predicted to be extracellular transglutaminases ranging in size from 436 to 1,607 amino acids. Genes with an elicitor, proline- and threonine-rich repeat, and both elicitor and repeat domains were widely distributed throughout Phytophthora infestans. These findings help explain the natural functions of elicitors in pathogen biology and plant-microbe interactions.

Algal Proteins↗
PubMed1997

Identification of a second promoter in the human c-ets-2 proto-oncogene.

We localized and characterized a new regulatory element with promoter activity in the human c-ets-2 intron 1. This promoter governs the expression of 5' divergent c-ets-2 transcripts through multiple start sites dispersed within 300 bp. Among the multiple start sites detected, three are major transcriptional initiation points. We detected transcripts initiated from this new promoter in various cell lines such as COLO 320, NBE, or HepG2 cells. This promoter exhibits transcriptional activity when linked to the CAT gene, and deletion constructs reveal that it contains activating and repressing elements. The sequence of the promoter reveals putative binding sites for ETS, MYB, GATA, and Oct factors. In addition, we show that this promoter is functionally conserved in the chicken.

Animals↗