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PubMed1995

Short-term effect of testosterone treatment on reduced bone density in boys with constitutional delay of puberty.

We studied bone mineral content (BMC), bone mineral density (BMD), cortical thickness/total width (CT/TW) ratio and cortical area/total area (CA/TA) ratio in boys with constitutional delay of puberty and the effect of short-term testosterone treatment on bone mass. Seventeen boys (age 13.1-15.8 years) who met the family history and the clinical criteria of constitutional delay of puberty were selected and enrolled in the study. All subjects were eating a diet assuring an adequate intake of calories and calcium. A subset of 8 boys (group A) was treated with testosterone depot (100 mg/month x 6 months) while 9 boys (group B) were not. At inclusion, BMC and BMD were reduced in the patients according to their chronological age (BMC -4.04 +/- 1.34 standard deviation scores [SDS]; BMD -2.95 +/- 0.56 SDS), statural age (BMC -1.75 +/- 0.79 SDS; BMD -1.69 +/- 0.78 SDS), and bone age (BMC -1.80 +/- 0.65 SDS; BMD -1.86 +/- 0.68 SDS). No significant differences between the groups were found (group A: BMC 0.480 +/- 0.57 g/cm, BMD 0.488 +/- 0.037 g/cm2, CT/TW ratio 0.43 +/- 0.4, CA/TA ratio 0.68 +/- 0.04; group B: BMC 0.476 +/- 0.060, p = NS vs. group A; BMD 0.491 +/- 0.036 g/cm2, p = NS vs. group A). At 12 months of follow-up, BMC, BMD, CT/TW ratio, and CA/TA ratio significantly increased in group A (BMC 0.70 +/- 0.13 g/cm, delta +41.1 +/- 28.8%, p < 0.003 vs. 0 month; BMD 0.617 +/- 0.082 g/cm2, delta +26.2 +/- 13.6%, p < 0.005 vs. 0 month; CT/TW ratio 0.52 +/- 0.05, delta +20.59 +/- 10.65%, p < 0.001 vs. 0 month; CA/TA ratio 0.77 +/- 0.05 vs. 0 month; CT/TW ratio 13.60 +/- 6.65%, p < 0.004 vs 0 month), but not in group B (BMC: 0.48 +/- 0.05 g/cm; delta +5.1 7.8%, p = NS vs. 00 month; BMD: 0.492 +/- 0.037 g/cm2; delta +0.54 +/- 8.7%, p = NS vs. 0 month; CT/TW ratio 0.44 +/- 0.04, delta +4.04 +/- 6.75%, p = NS vs. 0 month; CA/TA ratio 0.68 +/- 0.05, delta +2.39 +/- 5.90%, p = NS vs. 0 month). We conclude that boys with constitutional delay of puberty have reduced BMC and BMD. The delay in statural and bone ages did not totally account for the decreased bone mass. Testosterone treatment for 6 months significantly increased BMC, BMD, CT/TW ratio, and CA/TA ratio in these patients, but definitive conclusions on the efficacy of the treatment in improving adult bone mass can be drawn only when our patients reach early childhood.

Adolescent↗
PubMed2004

Effect of overexpression and nuclear translocation of constitutively active PKB-alpha on cellular survival and proliferation in HepG2 cells.

Protein kinase B (Akt/PKB) is a key component in the PI 3-kinase mediated cell survival pathway and has oncogenic transformation potential. Although the over-expression of PKB-alpha can prevent cell death following growth factor withdrawal, the long-term effects of stable over-expression of PKB-alpha on cell survival in the absence of growth factors remain to be resolved. In the present study, we generated HepG2 cells with stable expression of active PKB-alpha and compared its characteristics with HepG2 cells. Basal as well as insulin-stimulated levels of Ser(473) and Thr(308) phosphorylation in PKB-alpha transfected HepG2 cells were much higher than HepG2 cells. Constitutive expression of active PKB-alpha enabled HepG2 cells to survive up to 96 h without serum in growth media while HepG2 cells fail to survive after 48 h of serum withdrawal. A strong positive correlation (R(2) = 0.71) between cell proliferation and phosphorylated form of PKB-alpha at Thr(308) was observed along with higher levels of phosphorylated 3'-phosphoinositide-dependent kinase-1 (PDK-1). HepG2 cells with constitutive expression of active PKB-alpha also showed higher levels of phosphorylated p65 subunit of nuclear factor-kappaB (NFkappaB) in comparison with HepG2 cells. Predominant nuclear localization of phosphorylated PKB-alpha was observed in stably transfected HepG2 cells. These results indicate that constitutive expression of active PKB-alpha renders HepG2 cells independent of serum based growth factors for survival and proliferation.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1991

Constitutively activated neu oncoprotein tyrosine kinase interferes with growth factor-induced signals for gene activation.

The neu receptor oncoprotein tyrosine kinase, capable of transforming cultured fibroblasts and causing mammary carcinomas in transgenic mice, carries a point mutation in its transmembrane domain and shows a constitutive tyrosine kinase activity. We analyzed the neu tyrosine kinase and its substrates in transfected NIH 3T3 fibroblasts by phosphotyrosine immunoblotting. Tyrosine phosphorylated proteins were similar but not identical in epidermal growth factor (EGF)-stimulated cells expressing the human EGF receptor (EGFR) or a chimeric EGFR/neu receptor but differed from phosphotyrosyl proteins constitutively expressed in neu oncogene-transformed cells. The neu oncoprotein in the latter cells was phosphorylated in tyrosine in a ligand-independent manner and had a shortened half-life in comparison with the normal neu protein. Tumor promoter pretreatment inhibited ligand-induced receptor tyrosine phosphorylation and decreased tyrosine phosphorylated neu oncoprotein. Prolonged pretreatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) also prevented the induction of immediate early growth factor-regulated genes in response to neu activation. Expression of the neu oncogene but not the protooncogene in NIH 3T3 cells was associated with enhanced levels of the jun and fos oncoproteins and loss of serum growth factor induction of immediate early mRNA responses. The constitutively activated neu oncoprotein tyrosine kinase thus deregulates cellular genomic responses to growth factors.

Animals↗
PubMed2002

Constitutive expression of heterologous N-methyl-D-aspartate receptor subunits in rat adrenal medulla.

An RT-PCR analysis revealed constitutive expression of mRNA for N-methyl-D-aspartate (NMDA) receptor (NR)-1, NR-2C, and NR-2D subunits in rat adrenal and pituitary glands, in addition to brain and retina. Constitutive expression of mRNA was detected for the NR-2A subunit in pituitary but not adrenal gland. Although on Western blotting assays adrenal medulla exhibited expression of NR-1 subunit protein without expression of NR-2C and NR-2D subunit proteins, an immunohistochemical investigation clearly showed selective localization of proteins for NR-1, NR-2C, and NR-2D subunits in adrenal medulla but not in adrenal cortex. Prior treatment with different glycosidases invariably resulted in a marked increase in immunoreactivity to the anti-NR-1 antibody in both hippocampus and adrenal medulla. An intraperitoneal injection of a blocker of NMDA receptor channel, but not NMDA itself, led to marked potentiation of DNA binding activity of the transcription factor activator protein-1 in adrenal nuclear extracts 2 hr after administration. These results suggest that heteromeric NMDA receptor channels may be constitutively and functionally expressed with glycosylation of NR-1 subunit under the influence of tonic stimulation by circulating agonists such as L-glutamate in rat adrenal medulla.

Adrenal Medulla↗
PubMed2007

Translocation of constitutively expressed heat shock protein Hsc70 to synapse-enriched areas of the cerebral cortex after hyperthermic stress.

Hsp70 is a multi-gene family composed of stress-inducible members (Hsp70) and other members that are constitutively expressed (Hsc70). The heat shock proteins Hsp70 and Hsc70 exhibit similar molecular structure and biochemical functions. Constitutively expressed Hsc70 is enriched in the mammalian nervous system compared with non-neural tissues and present at high levels in neuronal cell bodies. After thermal stress, Hsc70 is translocated to synapse-enriched areas of the cerebral cortex where it associates with Hsp40 to form a complex that can refold denaturated proteins. These results suggest that the heat shock response in the nervous system involves not only the synthesis of stress-inducible Hsps but also the translocation of constitutively expressed Hsc70 to synapse-enriched areas where it could participate in neuroprotective mechanisms that preserved synaptic function during times of stress.

Animals↗
PubMed1990

Expression of heat shock genes (hsp70) in the mammalian brain: distinguishing constitutively expressed and hyperthermia-inducible mRNA species.

The mammalian genome contains both constitutively expressed and heat-shock-inducible members of the hsp70 gene family. Riboprobes derived from members of these two classes of heat shock genes were utilized in Northern blot studies to analyze brain mRNA isolated from control rabbits and rats and from animals subjected to hyperthermic treatment. A riboprobe derived from a constitutively expressed hsp70 gene detected a 2.5 kilobase (kb) mRNA in brain tissue from control rabbits and a 2.3 kb mRNA species in control rat brain. These brain mRNAs showed little change in abundance in animals which were subjected to hyperthermic treatment. A riboprobe derived from a heat-shock-inducible hsp70 gene detected an abundant 2.7 kb brain transcript in hyperthermic rabbits which was not apparent in control animals. A time course study revealed that the induction of this mRNA species was transient and paralleled the rise and fall in body temperature. Peak induction was observed at 1 hr. The level of this message had greatly decreased by 5 hr and only trace levels were present at 10 and 24 hr. In the rat brain the induced hsp70 mRNA species was slightly larger than that observed in rabbit (2.9 kb vs. 2.7 kb). The riboprobe which detected the hyperthermia-inducible mRNA species was highly specific and did not cross react to the constitutively expressed mRNA species under the conditions employed in the Northern blot studies.

Animals↗
PubMed1995

Localization of constitutive and hyperthermia-inducible heat shock mRNAs (hsc70 and hsp70) in the rabbit cerebellum and brainstem by non-radioactive in situ hybridization.

Neural expression of constitutive hsc70 mRNA and hyperthermia-inducible hsp70 mRNA is examined using radioactive and non-radioactive in situ hybridization procedures. A strong induction of hsp70 mRNA was noted in cell populations in cerebellar layers and in the brainstem which demonstrated expression of mRNA encoding proteolipid protein, an oligodendrocyte marker. The non-radioactive in situ hybridization procedure using digoxigenin (DIG)-UTP-labeled riboprobes permitted improved signal localization, and stress-inducible hsp70 mRNA was detected at the cytoplasmic cap areas of individual oligodendrocytes. Cell types which express constitutive members of the hsc/hsp70 multigene family were also identified. Neurons in the brainstem and in the deep white matter and molecular layer of the cerebellum showed expression of hsc70 mRNA while signal was not detected in adjacent glial cells. A neuron-specific enolase riboprobe aided in the identification of neuronal cell types. The non-radioactive DIG riboprobe revealed that hsc70 mRNA was highly localized to the cytoplasm of individual neurons. High constitutive levels of hsc70 in certain neurons may dampen hsp70 induction after hyperthermia in these cell populations.

Animals↗
PubMed2003

Creation, expression, and characterization of a constitutively active mutant of the human serotonin 5-HT6 receptor.

The serotonin 5-HT(6) receptor, a G-protein-coupled receptor, displays high affinity for antipsychotic, antidepressant, and psychotropic drugs. We created a constitutively active form of the human 5-HT(6) receptor in order to probe the molecular domains of receptor activation and to determine if inverse agonist activities of antipsychotic drugs contribute to their clinical profile. Previous studies from our laboratory support a critical role for the c-terminal region of the third intracellular loop (il3) in the activation of G(q)-coupled serotonin receptors. In the present study, PCR-based mutagenesis was used to mutate serine 267 (S6.34) in the c-terminal region of il3 to lysine (S267K). The native and S267K 5-HT(6) receptors were expressed in COS-7 cells to study the functional effects of the mutation. The S267K receptor shows 10-fold higher affinity for serotonin than the native receptor and demonstrates agonist-independent activity. Clozapine decreased the basal activity of the S267K receptor to vector control levels. Therefore, we can conclude that the S267K mutation renders the 5-HT(6) receptor constitutively active and that clozapine is an inverse agonist at the mutant 5-HT(6) receptor. These results indicate that the c-terminal region of il3 of the G(s)-coupled 5-HT(6) receptor is a key domain for G-protein coupling, similar to the G(q)-coupled 5-HT receptors. The inverse agonist action of clozapine indicates that drugs displaying competitive antagonist activity at native 5-HT(6) receptors may display inverse agonist activity at the constitutively activated form of the receptor.

Amino Acid Substitution↗
PubMed2005

Development of a semi-quantitative plate-based alpha-galactosidase gene reporter for Schizosaccharomyces pombe and its use to isolate a constitutively active Mam2.

To extend the tools available for biochemical and genetical analysis in the fission yeast Schizosaccharomyces pombe we have investigated the development of gene reporter systems using the secreted alpha-galactosidase encoded by the Sz. pombe ORF SPAC869.07c (CAB60017), which we propose naming Mel1p to reflect its structural and functional similarity to MEL1p in Saccharomyces cerevisiae. The alpha-galactosidase activity can be monitored in liquid assays and converted the colourless substrate 5-bromo-4-chloro-3-indolyl-alpha-D-galactopyranoside (X-alpha-gal) into an insoluble blue product that was suitable for semi quantitative plate-based assays; colonies expressing the highest levels of alpha-galactosidase developed the most intense blue colour. Unlike assays based on beta-galactosidase, the Sz. pombe colonies develop the blue colouration under normal growth conditions, avoiding the need to replicate colonies to fresh plates for analysis. It is therefore suitable for screening large numbers of colonies. To illustrate the use of mel1 as a reporter we linked expression to the sxa2 gene promoter to provide a convenient readout for signalling through the pheromone response pathway. The sxa2 > mel1 strain identified constitutively active Mam2 pheromone receptors from a randomly mutagenised library. There was an approximate correlation between the intensity of the blue colour developed by each mutant colony and its level of constitutive activity and we identified a subset of mutants with low constitutive activity that could not have been isolated by a previous screen using nutritional selection. The mel1 alpha-galactosidase activity identified and characterised in this study can be easily adapted to provide a gene reporter for many biological processes and is a new addition to the research tools available in Sz. pombe.

Amino Acid Sequence↗
PubMed1991

Constitutive expression of the Saccharomyces cerevisiae CUP1 gene in Kluyveromyces lactis.

Shuttle plasmids, pE1.CUP1B and pE1.CUP1E of 10.6 kb, have been constructed between the metallothionein-encoding CUP1 gene of Saccharomyces cerevisiae and a vector capable of replication in Kluyveromyces lactis. Introduction of these plasmids into K. lactis confers resistance to copper as well as to cadmium and silver. Resistance to these latter metal ions, in the absence of induction by copper, suggested that the CUP1 gene is constitutively expressed in the foreign background. Introduction of the lacZ reporter gene from Escherichia coli into a cloning site downstream from the CUP1 promoter showed that expression of this gene is constitutive in K. lactis but in S. cerevisiae induction by copper is necessary. Sequences upstream from the CUP1 promoter are involved in the constitutive expression since deletion of 91 nucleotides from this region abolishes metal resistance. It is suggested that a K. lactis protein, normally involved in activating transcription of the resident CUP1 gene in the presence of copper, can promote transcription in the absence of metal ion by binding to the upstream activation sequence of the introduced CUP1 gene.

Amino Acid Sequence↗
PubMed1993

Galactose inhibition of the constitutive transport of hexoses in Saccharomyces cerevisiae.

The relationship between the pathways of glucose and galactose utilization in Saccharomyces cerevisiae has been studied. Galactose (which is transported and phosphorylated by inducible systems) is a strong inhibitor of the utilization of glucose, fructose and mannose (which have the same constitutive transport and phosphorylation systems). Conversely, all these three hexoses inhibit the utilization of galactose, though with poor efficiency. These cross-inhibitions only occur in yeast adapted to galactose or in galactose-constitutive mutants. The efficiency of galactose as inhibitor is even greater than the efficiencies of the other three hexoses to inhibit the utilization of each other. Phosphorylation is not involved in the inhibition and the transport of sugars is the affected step. The cross-inhibitions between galactose and either glucose, fructose or mannose do not implicate utilization of one hexose at the expense of the other, as it occurs in the mutual interactions between the latter three sugars. It seems that, by growing the yeast in galactose, a protein component is synthesized, or alternatively modified, that once bound to either galactose or any one of the other three hexoses (glucose, fructose or mannose), cross-interacts respectively with the constitutive or the inducible transport systems, impairing their function.

Adaptation, Biological↗
PubMed2000

Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization.

Cytochrome P4502E (P4502E), the major ethanol-inducible P450 metabolizes ethanol to acetaldehyde and bioactivates procarcinogens to ultimate carcinogens. Metabolism of ethanol to acetaldehyde in the brain could be deleterious since it can react with cytoskeletal proteins, forming adducts. In the present study, rats were administered ethanol chronically to evaluate its effect on chlorzoxazone hydroxylation in rat brain regions. Chlorzoxazone hydroxylation in brains from the treated rats was induced in hippocampus and cortex, downregulated in brainstem, and unchanged in cerebellum, striatum, and thalamus. The presence of functionally active P4502E was also seen in human brain regions obtained at autopsy from traffic accident victims. Northern blot analysis of rat and human brain poly(A)(+) RNA hybridized with cDNA to rat CYP2E1 revealed the constitutive presence of a corresponding transcript in rat and human brain. Localization of CYP2E by fluorescence in situ hybridization demonstrated the constitutive expression of CYP2E preferentially in the neuronal cells in rat and human brain. CYP2E expression was seen in neurons within the cerebral cortex, Purkinje and granule cell layers of cerebellum, granule cell layer of dentate gyrus, and pyramidal neurons of CA1, CA2, and CA3 subfields of hippocampus in both rat and human brain. The present studies demonstrate constitutive expression of P4502E1 in brain, its differential induction in rat brain regions by chronic ethanol treatment, and its topographic distribution in rat and human brain.

Adult↗
PubMed2000

In Euglena gracilis, a heat-shock protein related to hsc73 is constitutive and stress inducible.

Using monoclonal antibodies directed against different cytoplasmic isoforms of hsp70 proteins, namely, the constitutive hsc73 and the inducible hsp72 isoforms, we found that one isoform related to hsc73 was present in Euglena gracilis. This hsc73-like protein is expressed with a higher rate of synthesis in cells growing under heat shock than in control cells. Moreover, in cadmium-resistant cells, cultured at normal growth temperature, the rate of synthesis of this protein is constitutively increased. These results indicate that a heat-shock protein related to hsc73 is present in an ancestral eukaryote, Euglena gracilis, and that this protein may be constitutive and stress inducible as well.

Animals↗
PubMed1995

Constitutive activation of the thyrotropin receptor by deletion of a portion of the extracellular domain.

Mutations involving the transmembrane domain of the thyrotropin receptor (TSHR) confer constitutive activation of the receptor and can cause human diseases. Naturally occurring activating mutations identified to date are located only in the transmembrane domain of the receptor. We now report a mutant involving the extracellular domain of the TSHR which also shows constitutive activation. This mutation is missing residues 339-367 located in the C-terminal portion of the extracellular domain. When expressed in COS-7 cells, the mutated TSHR (M3B) retained similar TSH binding ability to that of the wild-type receptor. However, the basal cAMP production without TSH stimulation in COS-7 cells transfected with M3B cDNA was significantly higher than that of COS-7 cells with wild-type receptor, indicating that the mutant receptor is constitutively activated. Our results provide new insight into the mechanism of receptor activation.

Animals↗
PubMed1997

Synergism of the ATF/CRE site and GC box in the housekeeping Na,K-ATPase alpha1 subunit gene is essential for constitutive expression.

Na,K-ATPase alpha1 subunit gene is constitutively expressed in a wide variety of tissues. Our previous studies revealed that the promoter region between -77 and +17 of the transcription initiation site of the rat Na,K-ATPase alpha1 subunit gene (Atp1a1) is sufficient for the promoter activity. In this region, an ATF/CRE site with an adjacent GC box exists. To elucidate how these sites are involved in the promoter activity, we analyzed effects of point mutations at these sites on transcription by in vitro transcription assays using nuclear extracts prepared from various rat tissues. Mutation at either site resulted in dramatic reduction of the promoter activity in all nuclear extracts, while mutation at both sites did not lead to further reduction. These results indicate that the ATF/CRE site and GC box are both essential for promoter activity and show synergistic activation. Electrophoretic mobility shift assay indicated that Sp1 and/or Sp3 bind to the GC box, and ATF1-CREB heterodimer binds to the ATF/CRE site. Since an element, ATF/CRE site-GC box, is conserved in mammalian Na,K-ATPase alpha1 subunit genes and in other constitutive promoters, we propose that this element is a critical unit for constitutive expression.

Activating Transcription Factors↗
PubMed1998

AP-1 and ATF-2 are constitutively activated via the JNK pathway in Theileria parva-transformed T-cells.

Bovine T-cells infected by the protozoan parasite Theileria parva undergo lymphoblastoid transformation, and proliferate in an uncontrolled manner. While it has been established that the transcription factor NF-kappa B is constitutively activated in T. parva-infected T-cells, little is known about other transcription factors such as AP-1 and ATF-2. We demonstrated increased binding activity to the AP-1 and CREB/ATF-2 consensus binding sites and show that the AP-1 complex is composed of c-Jun, JunD, c-Fos, and ATF-2. The transcription factors c-Jun and ATF-2 are constitutively phosphorylated in a parasite-dependent manner. Both transcription factors can be phosphorylated by jun-NH2-terminal kinase (JNK), but ATF-2 is also a substrate for p38. We determined whether p38 is activated in T. parva-infected cells. Immunoblot analysis and inhibitor studies indicate that JNK, but not p38, is involved in ATF-2 phosphorylation. Based on these results and previous studies, we conclude that parasite interference with mitogen-activated protein kinase pathways is restricted to constitutive activation of JNK.

Activating Transcription Factor 2↗
PubMed1998

Markedly increased constitutive CYP1A1 mRNA levels in the fertilized ovum of the mouse.

Using a highly sensitive RT-PCR technique that measures mRNA (cDNA)-to-DNA ratios, we are able to detect constitutive CYP1A1 mRNA in adult mouse liver as well as in the oocyte. Twelve hours after fertilization of the ovum, there is a more than 100-fold increase in constitutive CYP1A1 mRNA levels; this dramatic increase completely disappears by the 2-cell stage at gestational day 1.5 (GD1.5), as well as in the blastocyst at GD3.5. The CYP1A1 enzyme has been shown to remove an endogenous ligand for the Ah receptor (AHR), and the AHR is known to play a role in cell cycle regulation and apoptosis. We therefore postulate that this striking abundance of constitutive CYP1A1 mRNA in the fertilized ovum at GD0.5 might be important for maintaining sufficient amounts of the CYP1A1 enzyme during the transition from maternal to zygotic control (GD0.5 to GD1.5 embryo); availability of catalytically active CYP1A1 would ensure that any (exogenous or endogenous) AHR ligand be rapidly degraded, so that all undesirable AHR-mediated gene transcription would be prevented during these very critical moments of early mammalian embryogenesis.

Animals↗
PubMed2000

Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery.

Using the Cre-lox system, we have generated a cytochrome P450 1A1 Cyp1a1(-/-) knockout mouse by deletion of the translated portions of the Cyp1a1 gene. These mice are viable and demonstrate no obvious phenotype, compared with wild-type littermates. As a first step toward characterizing genes that might be expected to compensate for loss of CYP1A1, constitutive expression of [Ah] gene battery members was examined. In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1. The [Ah] battery includes Cyp1a2, NAD(P)H:quinone oxidoreductase (Nqo1), and three other Phase II genes. Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1. We postulate that CYP1A1 and CYP1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP1A2 in the liver can compensate for the loss of CYP1A1.

Animals↗