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PubMed1990

Effect of two consecutive administrations of GHRH in children with constitutional growth delay.

It has been suggested that children with constitutional growth delay might have a transient immaturity of the neurotransmitter pathways necessary for the control of growth hormone releasing hormone (GHRH) secretion. In this study we evaluated the effects of two consecutive GHRH boluses (1 microgram/kg, i.v.) in nine prepubertal boys with constitutional growth delay. Growth hormone (GH) responses to GHRH administration were similar to that observed in normal children (first GHRH bolus, GH net incremental area under the curve (nAUC) +/- SE: 788 +/- 244 vs 984 +/- 242 ng/ml per hour; second bolus, GHnAUC: 657 +/- 122 vs 541 +/- 129 ng/ml per hour, respectively). These data suggest that no relevant abnormalities in the mechanisms determining the somatotroph sensitivity to GHRH are present in children with constitutional growth delay.

Adolescent↗
PubMed1995

Arabidopsis heat shock factor is constitutively active in Drosophila and human cells.

Heat shock factors (HSF) are the transcriptional activators of the heat shock response. The conversion of constitutively expressed HSF to a form that can bind DNA requires the trimerization of the protein, involving leucine zipper interactions as shown for yeast, Drosophila, chicken and human HSFs. Like other metazoan HSFs, the endogenous Arabidopsis HSF displays heat shock-inducible DNA-binding activity in gel retardation assays. The heat shock-inducible binding of a recombinant Arabidopsis HSF (ATHSF1) expressed in Arabidopsis plants suggests that ATHSF1 is the major heat shock factor regulating the heat stress response. However, on transient expression in Drosophila and human cells, ATHSF1 fails to exhibit proper regulation, as demonstrated by constitutive binding to DNA, and by constitutive expression of a chloramphenicol acetyltransferase (CAT) reporter gene under the control of the Drosophila hsp70 promoter. These results suggest that the regulation of ATHSF1 is normally dependent on a specific factor that inhibits the DNA-binding and transcriptional activities under non-heat shock conditions.

Animals↗
PubMed1981

Liver chromatin fractions in Mus and Akodon. The concept of constitutive heterochromatin.

The liver chromatin from Mus musculus and Akodon molinae was separated in 8 fractions by differential centrifugation. Like fractions from both species showed approximately similar contents of DNA, equivalent ratios of histone to non-histone proteins, corresponding template activities and equal amounts of positive C-banded material. On the other hand, heavy chromatin fractions of Mus were highly enriched in satellite DNA whereas no satellite DNA was found in Akodon chromatin. Heavy chromatin fractions isolated by differential sedimentation have been usually homologued with the constitutive heterochromatin. The properties of the constitutive chromatin are discussed and the validity of the foregoing concept is challenged. It is proposed to define the constitutive heterochromatin as those chromatin regions comprising highly repeated DNA sequences clustered in restricted areas of chromosomes and not transcribed (satellite DNA).

Animals↗
PubMed1996

Hepatic transport of serum bilirubin, bromsulfophthalein, and indocyanine green in patients with congenital non-hemolytic hyperbilirubinemia and patients with constitutional indocyanine green excretory defect.

We carried out a retrospective study of 71 patients with congenital non-hemolytic hyperbilirubinemia who had been treated at our institution over the 25 years from 1965 to 1990. Twenty patients had Gilbert's syndrome, 1 had Crigler-Najjar syndrome, 1 had new type unconjugated hyperbilirubinemia, 21 had Dubin-Johnson syndrome, and 28 had Rotor's syndrome. We also reviewed 20 patients with constitutional indocyanine green (ICG) excretory defect. The study focused on the hepatic transport of serum bilirubin, bromsulfophthalein (BSP), and ICG. In Dubin-Johnson syndrome, a defect appeared in late-stage transport, while uptake and storage capacity were normal. In Rotor's syndrome, defects were found in the early stage, and storage capacity was reduced, while excretion into bile was slightly suppressed. A secondary rise in serum ICG was seen in 5 of the 10 patients with Dubin-Johnson syndrome. The transport defect in Gilbert's syndrome was unclear. It could not be considered to be homogeneous, but it may exist at multiple sites, from the conjugation with serum proteins to excretion into bile. Following phenobarbital administration, the ICG secondary rise in the 5 patients with Dubin-Johnson syndrome disappeared, and ICG was rapidly cleared from blood. However, in patients with Dubin-Johnson syndrome, BSP clearance in serum did not show any change before and after phenobarbital administration. ICG excretion in patients with constitutional ICG excretory defect was due only to the impairment o ICG transport, and the defect was suggested to be hepatic uptake. These results indicate that studies of the hepatic transport of bilirubin, BSP, and ICG are useful for determining the etiological factors involved in congenital hyperbilirubinemia and constitutional ICG excretory defect.

Adult↗
PubMed1992

Interleukin-8 is constitutively and commonly produced by various human carcinoma cell lines.

We examined the production of interleukin-8 and interleukin-6 by 30 human carcinoma cell lines. Serum levels of interleukin-8 were measured in 14 patients with hepatocellular carcinoma by enzyme-linked immunosorbent assay and Northern blotting. Furthermore, serum interleukin-8 was also investigated in a nude mouse bearing a tumor of the HuH7 hepatoma cell line producing interleukin-8. Of the 30 cell lines, 29 (96.7%) constitutively produced interleukin-8, and 19 of the 29 (65.5%) were high producers (> 1 ng/ml culture supernatant). Among the high producers, 4 cell lines released both interleukin-8 and interleukin-6. Interleukin-6 was constitutively produced by 17 of the 30 (56.7%) cell lines, 4 of which (23.5%) were high producers (> 1 ng/ml). By Northern blot analysis, mRNAs of interleukin-8 and interleukin-6 were detected in producing cell lines. Of 14 patients with hepatocellular carcinoma 4 (28.5%) showed increased levels of serum interleukin-8. Furthermore, inoculation of the HuH7 hepatoma cell line which produced the highest amount of interleukin-8 into a nude mouse resulted in tumor production accompanied by an elevated level of human interleukin-8 (646 pg/ml) in the peripheral blood. Thus, interleukin-8 is constitutively and commonly produced by various carcinoma cell lines. The production of interleukin-8 by carcinoma cells may be related to the elevation of serum interleukin-8 in patients with hepatocellular carcinoma. Finally, these cell lines may be valuable for studying the relationship between interleukin-8 and cancer.

Animals↗
PubMed2005

Constitutive alpha-amylase producing mutant and recombinant haploid strains of thermophilic fungus Thermomyces lanuginosus.

Morphological, developmental and antimetabolite-resistant mutants of T. lanuginosus were characterized and used for screening with the aim to develop constitutive alpha-amylase-hyperproducing strains. The protoplast fusion of two spontaneous mutants of T. lanuginosus, characterized as asporulating and resistant to 2-deoxy-D-glucose (2DG), resulted in sporulating, 2DG sensitive heterokaryotic fusants. A recombinant haploid strain F64fB developed there from produced alpha-amylase constitutively in glucose-containing medium. Constitutive alpha-amylase-hyperproducing mutant (III8) obtained after cyclic mutagenesis and screening yielded approximately 20 fold more alpha-amylase in a glycerol-containing medium than the wild strain.

Ascomycota↗
PubMed2003

Constitutively activated Rho guanosine triphosphatases regulate the growth and morphology of hairy cell leukemia cells.

Hairy cell leukemia (HCL) is a rare type of chronic B-cell leukemia characterized by the hairy morphology of the leukemia cells. All of 5 HCL samples and an HCL-derived cell line, BNBH-I, showed serrated edges and hairlike projections in May-Grünwald Giemsa stain and protruding actin spikes and lamellipodia in phalloidin stain. These structures were hardly detected on B-cell chronic lymphocytic leukemia (B-CLL) and precursor B-cell acute lymphocytic leukemia (B-ALL) cells. Because Rho guanosine triphosphatases (GTPases) regulate the formation of these structures, we examined the expression levels and activation states of Rho GTPases in HCL cells. RhoA, Rac1, and Cdc42 were overexpressed and constitutively activated in HCL samples and BNBH-I cells but not in B-CLL or precursor B-ALL cells. Next we overexpressed dominant-negative (DN)-RhoA, DN-Rac1, and DN-Cdc42 in BNBH-I. As a result, each DN mutant repressed the growth of BNBH-I cells by more than 50% and inhibited actin spike formation, but only DN-Racl suppressed lamellipodia formation. We also found that enforced expression of constitutively active-RhoA, Rac, or Cdc42 in the proB-cell line Ba/F3 was sufficient to induce actin spike formation, whereas none of these molecules produced lamellipodia. These results indicated that constitutively activated Rho GTPases regulate the growth and unique morphology of HCL cells.

Actins↗
PubMed2002

Removal of the carboxy terminus of the A2A-adenosine receptor blunts constitutive activity: differential effect on cAMP accumulation and MAP kinase stimulation.

The A(2A)-adenosine receptor has an extended carboxy terminus (approximately 120 amino acids), the role of which is poorly defined. In human endothelial cells and in HEK293 cells, the A(2A)-receptor controls at least two independent signalling pathways, i.e. increased cyclic adenosine 3',5'-monophosphate (cAMP) formation via its cognate G protein G(s) and increased phosphorylation of mitogen-activated protein kinase (MAP kinase) by recruiting p21(ras). In order to address the role of the carboxy terminus in signal transfer, we generated HEK293 cells that stably expressed the full-length (wt) receptor and truncated versions [A(2A)-R(1-360) and A(2A)-R(1-311)] at comparable levels (approximately 0.5 pmol/mg) in the plasma membrane. The effects of truncation were divergent with respect to the two effectors regulated by the receptor. In intact cells carrying A(2A)-R(wt) and A(2A)-R(1-360), cAMP accumulation was more potently activated by an A(2A)-agonist than in cells expressing A(2A)-R(1-311). Similarly, A(2A)-R(wt) and A(2A)-R(1-360)--but not A(2A)-R(1-311)--caused constitutive (=agonist-independent) elevation of cAMP which was reversed by the addition of A(2A)-antagonists. In membranes prepared from these cells, however, the three receptors displayed no constitutive activity in stimulating adenylyl cyclase and they did not differ in apparent agonist affinity. Truncation of the A(2A)-receptor did also not decrease the potency of an A(2A)-agonist to stimulate MAP kinase in intact cells. We conclude that the carboxy terminus defines both (a) the level of constitutive activity, i.e. the equilibrium R<--> R*, in intact cells only, indicating a role for a component that is lost upon cell lysis, and (b) the efficiency of signal transfer in alternative pathways.

Cell Line↗
PubMed2006

Reanalysis of constitutively active rat and human 5-HT7(a) receptors in HEK-293F cells demonstrates lack of silent properties for reported neutral antagonists.

The present study reinvestigated a series of 5-HT receptor antagonists at both constitutively active rat and human 5-HT7(a) receptors in HEK-293F cells using the cAMP signalling pathway as a functional read-out. Both rat and human 5-HT7(a) receptors were expressed in similar amounts ([3H]-LSD binding: 1.0 to 1.1 pmol/mg protein). Attenuation of basal cAMP formation by the inverse agonist SB-691673 (1 microM) was slightly larger by the human 5-HT7(a) (-73+/-3 %) than rat 5-HT7(a) receptor (-62+/-3 %). The 5-HT receptor antagonists investigated here displayed systematically inverse agonism. While methiothepin and SB-269970 displayed similar negative intrinsic activity to SB-691673 at the rat 5-HT7(a) receptor, the compounds SB-258719, mesulergine and metergoline displayed some lower negative intrinsic activity (between -38 and -49%). Inverse agonist properties were observed with potencies fitting with their respective binding pIC50 values and pKB values as estimated from antagonist studies with 5-HT. With the exception of SB-258719 and mesulergine, which remained a partial inverse agonist at the human 5-HT7(a) receptor, the other compounds behaved with a similar Emax value to the full inverse agonist SB-691673. In conclusion, none of the 5-HT receptor antagonists investigated displayed silent properties at the rat or human 5-HT7(a) receptor, when these are expressed in a system allowing detection of constitutive activity. They appear to be partial to full inverse agonists, further illustrating that an antagonist is preferentially an inverse agonist when investigated under constitutively active receptor conditions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

The constitutive AHSB4 promoter--a novel component of the Arxula adeninivorans-based expression platform.

An Arxula adeninivorans-AHSB4 gene, encoding histone H4, was isolated and characterized. The gene includes a coding sequence of 363 bp disrupted by a 51-bp intron, similar to the situation in other fungal H4 genes. The identity of the gene was confirmed by the high degree of homology of the derived amino acid sequence with that of other H4 histones. The gene is strongly and constitutively expressed, maintaining this expression profile under salt-stress conditions. The AHSB4 promoter was tested for suitability in heterologous gene expression using genes encoding the intracellular green fluorescent protein and the secreted human serum albumin (HSA) for assessment. Plasmids incorporating respective expression cassettes were used to transform the host strain A. adeninivorans LS3, which forms budding cells at 30 degrees C, and strain 135, which forms mycelia under these conditions. Transformants of both types were found to harbor a single copy of the heterologous DNA. Strong constitutive expression was observed during culture in salt-containing and salt-free media, as expected from the expression profile of AHSB4. In 200-ml shake-flask cultures, maximal HSA levels of 20 mg l(-1) culture medium were achieved. This productivity could be increased to 50 mg l(-1 )in strains harboring two copies of the expression cassette. The AHSB4 promoter thus provides an attractive component for constitutive heterologous gene expression under salt-free and salt-stress conditions.

Amino Acid Sequence↗
PubMed2001

Constitutive and inducible hydroxylase activities involved in the degradation of naphthalene by Cunninghamella elegans.

The non-ligninolytic fungus Cunninghamella elegans was investigated for its ability to produce naphthalene hydroxylase (NAH) and naphthol hydroxylase (NOH) activities under various conditions. When the organism was cultivated on a rich growth medium, the mycelia exhibited significant constitutive NAH activity in the late exponential growth phase, but not in the early-exponential-growth-phase. On incubating the early-exponential-growth-phase mycelia with naphthalene, NAH activity was increased five-fold; however, this increase did not occur in the presence of the protein synthesis inhibitor cycloheximide. Since incubation of the late-phase mycelia with naphthalene did not lead to a higher degradation rate of naphthalene, mycelia in this physiological state have apparently lost the ability to induce synthesis of the enzyme exhibiting NAH activity. This is not due to an overall inability to perform de novo protein synthesis, since NOH activity, non-constitutive at all growth phases, could be induced by incubating late-phase mycelia with naphthalene. Whether inducible and constitutive NAH activity originate from one and the same enzyme remains to be elucidated. It is suggested that naphthalene oxidizing enzyme(s) may also oxidize pyrene, but not anthracene or benzo[a]pyrene, although the latter are degradable by C. elegans.

Biodegradation, Environmental↗
PubMed2005

Correlation between 99mTc-(V)-DMSA uptake and constitutive level of phosphorylated focal adhesion kinase in an in vitro model of cancer cell lines.

PURPOSE: Although a number of prognostic indicators have been developed, it is still difficult to predict the biological behaviour of all cancer types.( 99m)Tc-(V)-DMSA (V DMSA) uptake and focal adhesion kinase (FAK) expression and activation level could be potential agents for this purpose. We hypothesised the existence of a correlation between V DMSA, whose uptake is linked to phosphate ions, essential compounds for tumour growth and cell proliferation, and the adhesion protein FAK, whose elevated expression and level of constitutive activation are implicated in cancer progression. The aim of this study was to assess the relationship between V DMSA incorporation rate and FAK expression and activation by phosphorylation on tyrosine 397 residue. METHODS: We determined V DMSA uptake in six different cancer cell lines and we measured FAK expression and activation by using Western Blotting analysis. Correlations with factors known to be associated with poor prognosis, such as invasive potential, resistance to chemotherapy and proliferation rate, were also investigated. RESULTS: The cell lines exhibited different V DMSA incorporation rates. In addition, these cells showed the same FAK expression, but various degrees of activation. A correlation was observed between V DMSA uptake and level of FAK phosphorylation and between V DMSA or constitutive FAK activation and proliferation rate. However, no correlation was shown between these parameters and the other factors tested, i.e. invasive potential and anticancer drug resistance. CONCLUSION: The results of this in vitro study clearly demonstrate that phosphorylation of FAK, proliferation rate and V DMSA uptake are closely related. Because proliferation and a high level of constitutive FAK activation are linked to cancer progression, it can be assumed that in vivo V DMSA uptake reflects tumour aggressiveness.

Antineoplastic Agents↗
PubMed2006

Constitutional pericentric inversion of chromosome 9 and hematopoietic recovery after allogeneic stem cell transplantation.

Recent reports suggest that hemopoietic stem cells with constitutional pericentric inversion of chromosome 9 [inv(9)] may be related to delayed engraftment or hemopoietic defect after stem cell transplantation (SCT). We conducted a retrospective study on five allogeneic SCT in which constitutional inv(9) was detected either in the donor or the recipient. The results showed that hematologic recovery was within the expected time range for all our patients. However, one patient exhibited decreasing blood counts between day +45 and +272 after transplantation, possibly due to protracted cytomegalovirus (CMV) infection and gansiclovir and imatinib treatment. Our findings suggest that constitutional inv(9) may not be associated with delayed hemopoietic recovery after SCT.

Adult↗
PubMed2003

Two bipartite NLSs mediate constitutive nuclear localization of Mcm10.

Some components of the pre-replicative complex (pre-RC) are in the nucleus only during the G1 phase, while others are constitutively nuclear throughout the cell cycle. A nuclear localization signal (NLS) mediating the G1-specific nuclear localization has been characterized. We report here the identification of bipartite NLSs in constitutively nuclear pre-RC components, including the origin recognition complex, Mcm10 and Noc3. Interestingly, in a subgroup of these pre-RC components, two putative NLSs were found in each protein. To examine whether multiple NLSs are required for these proteins to be nuclear throughout the cell cycle, we characterized the two NLSs in Mcm10. We show that at least one of the two NLSs is required for directing Mcm10 into the nucleus and that either of them is sufficient to bring the green fluorescence protein into the nucleus. Thus, Mcm10 contains two functional NLSs and either is sufficient for the constitutive nuclear localization of Mcm10.

Blotting, Western↗
PubMed2000

Alterations in the Saccharomyces MAL-activator cause constitutivity but can be suppressed by intragenic mutations.

The Saccharomyces MAL-activator regulates the maltose-inducible expression of the MAL structural genes encoding maltose permease and maltase. Constitutive MAL-activator mutant alleles of two types were identified. The first were truncation mutations deleting C-terminal residues 283-470 and the second contained a large number of alterations compared to inducible alleles scattered throughout the C-terminal 200 residues. We used site-directed in vitro mutagenesis of the inducible MAL63 and MAL63/23 genes to identify the residues responsible for the negative regulatory function of the C-terminal domain. Intragenic suppressors that restored the inducible phenotype to the constitutive mutants were identified at closely linked and more distant sites within the MAL-activator protein. MAL63/mal64 fusions of the truncated mutants suggest that residues in the N-terminal 100 residues containing the DNA-binding domain also modulate basal expression. Moreover, a transcription activator protein consisting of LexA(1-87)-Gal4(768-881)-Mal63(200-470) allowed constitutive reporter gene expression, suggesting that the C-terminal regulatory domain is not sufficient for maltose-inducible control of this heterologous activation domain. These results suggest that complex and very specific intramolecular protein-protein interactions regulate the MAL-activator.

Amino Acid Sequence↗
PubMed1999

Leu343Phe substitution in the Malx3 protein of Saccharomyces cerevisiae increases the constitutivity and glucose insensitivity of MAL gene expression.

To utilise maltose as a carbon source Saccharomyces cerevisiae needs one or more functional MAL loci that contain the MALx1 gene encoding maltose permease, MALx2 encoding maltase, and MALx3 encoding a transcriptional activator. Maltose causes a rapid MALx3-dependent induction of MAL gene transcription, and glucose represses this activation via Mig1p. A MALx3 gene conveying high MAL gene expression in the absence of maltose in a malx3 laboratory mutant strain has been isolated from baker's yeast. The construction of hybrid genes between the isolated gene and a highly regulated MALx3 gene showed that constitutivity was the result of multiple amino-acid alterations throughout the structural gene. The combined effect of these amino-acid alterations was shown to be stronger than the sum of their individual effects on constitutivity. Analysis in glucose-repressed conditions confirmed that increased MALx3 transcript levels increased the glucose insensitivity of MAL gene expression but did not affect constitutivity. Analysis of four mutations between aa 343 and 375, lying within a proposed negative regulatory domain, showed that the single mutation of Leu343Phe increased the glucose insensitivity of MAL gene expression by 30-fold. These results demonstrate that not only Mig1p modulation of MALx3 expression, but also the MALx3 protein structure, is involved in the glucose-insensitive expression of the MAL genes.

Amino Acid Sequence↗
PubMed2005

Comparison of four constitutive promoters for the expression of transgenes in the tropical nitrogen-fixing tree Allocasuarina verticillata.

Allocasuarina verticillata is an actinorhizal tree that lives in symbiotic association with a nitrogen fixing actinomycete called Frankia. In the search for promoters that drive strong constitutive expression in this tropical tree, we studied the organ specificity of four different constitutive promoters (CaMV 35S, e35S, e35S-4ocs and UBQ1 from Arabidopsis thaliana) in stably transformed A. verticillata plants. The ss-glucuronidase (gus) gene was used as a reporter and expression studies were carried out by histochemical analyses on shoots, roots and actinorhizal nodules. While the 35S promoter was poorly expressed in the shoot apex and lateral roots, both the e35S and e35S-4ocs were found to drive high constitutive expression in the transgenic non-nodulated plants. In contrast, the UBQ1 promoter was very poorly expressed and appeared unsuitable for A. verticillata. We also showed that none of the promoters studied were active in the nodule infected cells, whatever the developmental stage studied.

Agrobacterium tumefaciens↗
PubMed2000

Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo.

Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗