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PubMedDate not supplied

[The Constitutional Court and new scenarios of biomedicine. (Constitutional reflections on the decision of the Constitutional Tribunal 116/1999, June 17)].

The recent ruling by the Constitutional Court (116/1999, 17 June) ended the process which had been initiated by the challenge filed by 63 conservative MPs against Law 35/1988, 22 November, on the Law on Human Assisted Reproduction Techniques. In our opinion, this ruling helps define the scope of the constitutional provisions used by the appellants in their challenge, provisions which had already been interpreted in lower rulings. The considerations given in this article are designed to establish the terms and framework which lawmakers and law experts should bear in mind when they prepare future, as will necessarily be the case. In view of some of the arguments used in the ruling, we believe it is appropriate to draw attention to some of the most salient constitutional aspects, such as the scope of the Constitutional Court's role as the ultimate judge of constitutionality, and the exact nature of the constitutional notion of fundamental right which, although complicated at times, is nonetheless a precise and accurate legal concept.

Embryo, Mammalian↗
PubMed1986

[Constitution and nutrition. III: On the constitution and nutrition of the Germans in early history].

This documentation is part of an inquiry about constitution and nutrition in Germany since early history. In this documentation, authorities of antiquity and modern researches about constitution and nutrition in early Teutonic history were collected and then possible influences of nutrition of that period on constitution of early Teutons were analysed. The early Teutons were characterised by great and strong stature, tendence to dolichocephalie and were of spectacular vigour. Their food was characterised by vitality and growth stimulating ingredients (like milk, meat, barley, oats, millet), but with differences in quantity in course of the year. A comparisation between nutrition and constitution of early Teutons shows a connection among typical patterns of early-Teuton-constitution and these nutrition. Differences in constitution to the southern neighbours, Celts and Romans, were not so marked, that constitutional changes in Germany, especially in southern Germany, in the middle ages can be explained by mixed race.

Body Constitution↗
PubMed2001

Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma.

Vascular endothelial growth factor (VEGF) is a key angiogenic molecule that plays an important role in the growth and metastasis of many types of human cancer, including pancreatic adenocarcinoma. In this study, we explored the regulation of VEGF in human pancreatic cancer cells. Over 70% of the human pancreatic cancer cell lines studied in vitro secreted constitutively high levels of VEGF. High VEGF-secreting cells also generally expressed an elevated steady-state level of VEGF mRNA. Kinetic analysis revealed that the elevated steady-state level of VEGF mRNA was due to enhanced VEGF gene transcription and increased constitutive VEGF promoter activity. Deletive mutation analyses of the VEGF promoter revealed that the region from -109 to -38 bp was essential for constitutive VEGF promoter activity. Further deletion and point mutation analyses indicated that mutation of individual or all of the putative Sp1 binding sites reduced or eliminated the constitutive VEGF promoter activity and abrogated the differential activity of the promoter in high and low VEGF-expressing cells. Consistent with the constitutive VEGF transcription activation, a high level of constitutive Sp1 expression and activity was detected in pancreatic cancer cell lines and pancreatic cancer tissue specimens overexpressing VEGF. Collectively, our data demonstrated that constitutive Sp1 activation is essential for the differential overexpression of VEGF, which in turn plays an important role in the angiogenesis and progression of human pancreatic cancer.

Adenocarcinoma↗
PubMed1998

Analysis of constitutive and constitutive-like secretion in semi-intact pituitary cells.

To study biosynthetic transport through the constitutive and regulated secretory pathways, we have designed a semi-intact mammalian cell system that restores the transport of secretory proteins from the trans-Golgi/trans-Golgi network (TGN) to the cell surface. The mouse pituitary AtT-20 cell line is a suitable model to biochemically analyze molecular sorting in the secretory pathway. The prohormone proopiomelanocortin is sulfated on N-linked carbohydrate chains in the trans-Golgi prior to proteolytic processing in the secretory granule. Radiolabeling with [35S]sulfate therefore provides a convenient tool to selectively follow molecular events in the regulated secretory pathway without interference from earlier steps. Likewise, transport through the constitutive secretory pathway may be monitored using sulfate-labeled glycosaminoglycan chains. We show that export from the TGN is efficiently reconstituted in cells made semi-intact with streptolysin O, and is dependent on temperature, ATP and GTP hydrolysis, and cytosol. Packaging of proopiomelanocortin into immature secretory granules also activates the proteolytic processing machinery which eventually converts the prohormone to its bioactive mature product, adrenocorticotropic hormone. In addition, a large fraction of incompletely processed proopiomelanocortin is secreted as the processing intermediates from immature secretory granules. This process of constitutive-like secretion can be clearly distinguished from direct constitutive secretion from the trans-Golgi network by kinetic and compositional criteria. Furthermore, we have found that specific inhibitors of different protein phosphatases and kinases are potent blockers of constitutive and constitutive-like secretion. This experimental model should provide a valuable system to elucidate the molecular mechanism regulating post-Golgi traffic during secretory granule biogenesis.

Adenosine Triphosphate↗
PubMed1999

A strategy to make constitutively active MAP kinase by fusing with constitutively active MAP kinase kinase.

Classical mitogen-activated protein kinases (MAPKs) play a pivotal role in a variety of cellular signal transduction pathways. MAPKs are activated by phosphorylation at specific threonine and tyrosine residues catalyzed by upstream MAPK kinases (MAPKKs). Mutations of these two activation phosphorylation sites into acidic amino acids, however, do not convert MAPKs into constitutively active forms. Here, we report an approach to make a molecule with constitutive MAPK activity. The nuclear export signal-disrupted, constitutively active MAPKK was fused to the N-terminal end of wild-type MAPK. When the resulting fusion protein was expressed in Escherichia coli, the MAPK moiety became phosphorylated and the fusion protein was constitutively active as MAPK. Moreover, when expressed in mammalian cultured cells, the fusion protein was also activated as MAPK and was able to induce marked morphological changes in NIH-3T3 cells. These results suggest that the fusion protein can work as constitutively active MAPK and that this approach may be applicable to other members of the MAPK family to make constitutively active forms.

3T3 Cells↗
PubMed1994

A constitutively active mutant beta 2-adrenergic receptor is constitutively desensitized and phosphorylated.

The beta 2-adrenergic receptor (beta 2AR) can be constitutively activated by mutations in the third intracellular loop. Whereas the wild-type receptor exists predominantly in an inactive conformation (R) in the absence of agonist, the mutant receptor appears to spontaneously adopt an active conformation (R*). We now demonstrate that not only is the mutant beta 2AR constitutively active, it is also constitutively desensitized and down-regulated. To assess whether the mutant receptor can constitutively engage a known element of the cellular desensitization machinery, the receptor was purified and reconstituted into phospholipid vesicles. These preparations retained the essential properties of the constitutively active mutant receptor: agonist-independent activity [to stimulate guanine nucleotide-binding protein (Gs)-GTPase] and agonist-specific increase in binding affinity. Moreover, the purified mutant receptor, in the absence of agonist, was phosphorylated by recombinant beta AR-specific kinase (beta ARK) in a fashion comparable to the agonist-occupied wild-type receptor. Thus, the conformation of the mutated receptor is equivalent to the active conformation (R*), which stimulates Gs protein and is identical to the beta ARK substrate.

Adrenergic beta-Agonists↗
PubMed1998

[Animal protection in constitutional law?--On the necessity of including animal protection in the constitution].

The inclusion of animal protection in the constitution poses a lengthy legal-political demand, which is again being vehemently discussed at the present time. Under consideration of juristic aspects, the following treatise attempts to clarify the legal requirements which presently exist for anchoring animal protection in constitutional law. It is therefore necessary in the first instance to explain the present situation regarding animal protection law. The legal situation in this respect is marked by a fundamental collision between special democratic rights guaranteed by the constitution on the one hand, and the norms of animal protection law on the other hand, which tend to restrict these rights. Based on concrete examples taken from court decisions, it is shown that constitutional vacuum surrounding a major part of animal protection law greatly complicates or even renders impossible the application and enforcement of the latter in practice. A prerequisite for a proper legal framework for animal protection is that the different special basic democratic rights governing animal use must be counterpoised by animal protection laws backed up by the constitution. Only by this means it is possible to prevent the ineffectiveness of animal protection legislative norms in the long term.

Animal Welfare↗
PubMed1991

[Experimental study of the heat and cold constitutional types (II). A comparative observation on the heat and cold constitutional type rats on the DNA replication capacity after ultraviolet damage].

The cold-constitutional and the heat-constitutional type had selected in Wistar rats as the object of study. Using peripheral blood and spleen as materials by means of ultraviolet injury, isotope incorporation, cells incubation in vitro and liquid scintillation counting, the capacity of peripheral lymphocytes DNA replication after damage with ultraviolet radiation and the capacity of the spleen lymphocytes proliferation in vitro was observed. The results showed that the both capacities mentioned above were higher in the heat constitutional type rat than that in the cold type. It is suggested that the following conclusion in the Lingshu Jing is correct: "the capacity of tissue repair is higher in the heat constitutional type than in the cold."

Animals↗
PubMed2001

Inverse agonist up-regulates the constitutively active D3.49(164)Q mutant of the rat mu-opioid receptor by stabilizing the structure and blocking constitutive internalization and down-regulation.

We demonstrated previously that D3.49(164) mutations resulted in constitutive activation of the rat mu-opioid receptor and abolished receptor expression unless cells were pretreated with naloxone, an inverse agonist. In this study, we investigated the properties of the D3.49(164)Q mutant and the mechanisms underlying the effect of naloxone. Naloxone pretreatment up-regulated [(3)H]diprenorphine binding and protein expression of the D3.49(164)Q mutant in a time- and dose-dependent manner without affecting its mRNA level. After naloxone removal, binding and protein expression of the mutant declined with time with no effect on its mRNA level. Naloxone methiodide (a quaternary ammonium analog) caused a maximal up-regulation about 50% of the naloxone effect, indicating that naloxone acts extracellularly and intracellularly. Expression of the mutant was enhanced by inverse agonists, a neutral antagonist, and agonists, with inverse agonists being most effective. In membranes, the mutant was structurally less stable than the wild type upon incubation at 37 degrees C, and naloxone and [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin stabilized the mutant. Coexpression of the dominant-negative mutants GRK2-K220R, arrestin-2(319-418), dynamin I-K44A, rab5A-N133I or rab7-N125I partially prevented the decline in binding of the mutant after naloxone removal. Chloroquine or proteasome inhibitor I reduced the down-regulation of the mutant. These results indicate that the D3.49(164)Q mutant is constitutively internalized via G protein coupled-receptor kinase-, arrestin-2-, dynamin-, rab5-, and rab7-dependent pathways and probably trafficked through early and late endosomes into lysosomes and degraded by lysosomes and proteasomes. Naloxone up-regulates the D3.49(164)Q mutant by stabilizing the mutant protein and blocking its constitutive internalization and down-regulation. To the best of our knowledge, this represents the first comprehensive analysis of the mechanisms involved in up-regulation of constitutively active mutants by an inverse agonist.

Animals↗
PubMed1976

[Operon for riboflavin synthesis in Bacillus subtilis. XI. Determination of the type of regulation using a test for dominance of operator-constitutive and regulator-constitutive mutations].

The strain GSY 468 of Bacillus subtilis, giving persistent unstable merozogotes was used as recipient in transformation. Diploid cells bearing a regulator constitutive or operator constitutive mutation were obtained, and their phenotype was studied. The operator constitutive mutation behaves as a dominant one, but the regulator constitutive is recessive. Hence the regulation type in riboflavin operon is negative. The product of the regulator gene is obviously a repressor protein.

Bacillus subtilis↗
PubMed1998

Bilateral multiple renal oncocytomas and cysts associated with a constitutional translocation (8;9)(q24.1;q34.3) and a rare constitutional VHL missense substitution.

We report here on a patient with bilateral multifocal renal oncocytomas and cysts. Cytogenetic analysis of the patient's lymphocytes revealed a constitutional 46,XY,add (9)(q34.3) karyotype. The rearrangement was further resolved as a constitutional reciprocal t(8;9)(q24.1;q34.3) by microdissection and FISH. Because the 9q breakpoint was located in the same region as the tuberous sclerosis type I locus (TSC1), which is associated with renal tumors, we performed FISH with two TSC1 flanking cosmids that were mapped proximal to the 9q breakpoint, thus excluding its involvement. Loss of heterozygosity (LOH) studies of the tumors revealed LOH in chromosome I, further strengthening the molecular diagnosis of oncocytoma. A previously unreported germline missense substitution, Pro40Arg, in exon I of the VHL gene was also found in the patient's constitutional DNA, adding to the complexity of the genetic profile.

Adenoma, Oxyphilic↗
PubMed2001

Mutations in the mouse TSH receptor equivalent to human constitutively activating TSH receptor mutations also cause constitutive activity.

Constitutively activating mutations in the human thyroid-stimulating hormone (TSH) receptor (TSHr) have been identified as the most prevalent molecular cause of non-autoimmune hyperthyroidism. To investigate the feasibility of an animal model for non-autoimmune hyperthyroidism, we introduced two mutations in the mouse TSHr which had previously been identified in the human TSHr. The two human mutations showed strong differences in TSH binding, basal cAMP and IP accumulation. In the human TSHr, the Ile 486 Phe mutation causes a high increase of basal cAMP accumulation and also basal stimulation of the inositol phosphate pathway, whereas the Val 509 Ala mutation results in a low increase of basal cAMP accumulation without affecting IP signaling. RNA was isolated from mouse thyroid tissue and reverse transcribed. A 2.4 kb PCR product from the mouse TSHr was cloned into the pGEM-T vector system. Ile was substituted with Phe at codon 486 and Val with Ala at codon 509. These mutated mouse TSHrs were subcloned in the pSVL expression vector. After transient expression in COS-7 cells, basal and TSH-stimulated cAMP and IP accumulation, cell surface expression and TSH binding were determined and directly compared to the human TSHr. Whereas constitutively activating mutations of the human parathyroid hormone (PTH)/PTH-related peptide receptor showed little or no change in basal cAMP accumulation when introduced into the rat PTH/PTHrP receptor, these two mouse TSHr mutations resulted in constitutive activity similar to the homologous mutations in the human TSHr. Therefore, it should be possible to establish a mouse model for non-autoimmune hyperthyroidism by homologous recombination to study the pathogenetic mechanisms of non-autoimmune hyperthyroidism.

Animals↗
PubMed1999

Constitutive activation of the prolactin receptor results in the induction of growth factor-independent proliferation and constitutive activation of signaling molecules.

The ability to induce the oncogenic activation of the human prolactin receptor (PRLR) was examined by deleting 178 amino acids of the extracellular ligand-binding domain. Expression of this deletion mutant in the interleukin-3 (IL-3)-dependent murine myeloid cell line 32Dcl3 resulted in the induction of growth factor-independent proliferation. Parental 32Dcl3 cells proliferated only in the presence of exogenous murine IL-3 (mIL-3), while 32Dcl3 cells transfected with the long form of the human PRLR were able to proliferate in response to mIL-3, ovine prolactin, or human PRL. Cells expressing the Delta178 deletion mutant contained numerous phosphotyrosine-containing proteins in the absence of stimulation with either mIL-3 or ovine prolactin. Growth factor stimulation increased the number of proteins phosphorylated and the intensity of phosphorylation. These proteins included constitutively phosphorylated Janus kinase 2, signal transducer and activator of transcription 5, and SHC. Activated extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) were observed in unstimulated 32Dcl3 cells expressing the Delta178 mutant. Likewise, transfection of Nb2 cells with the Delta178 deletion mutant induced growth factor-independent proliferation and constitutive activation of Janus kinase 2, ERK1, and ERK2. In addition to the induction of a growth factor-independent state, the expression of the Delta178 deletion mutant also suppressed the apoptosis that occurs when 32Dcl3 cells are cultured in the absence of growth factors such as IL-3. These data suggest that the constitutive activation of the PRLR can be achieved by deletion of the ligand binding domain and that this mutation leads to the oncogenic activation of the receptor as determined by the ability of the receptor to induce growth factor-independent proliferation of factor-dependent hematopoietic cells.

Caseins↗
PubMed1979

Inducible and constitutive kynureninases. Control of the inducible enzyme activity by transamination and inhibition of the constitutive enzyme by 3-hydroxyanthranilate.

The inducible kynureninase from Neurospora crassa is inactivated by incubation with L-alanine or L-ornithine. The inactivated enzyme is resolved to the apoenzyme by dialysis. Reactivation of the apoenzyme is achieved by incubation with pyridoxamine 5'-phosphate plus pyruvate, as well as with pyridoxal 5'-phosphate. The kynurenine hydrolysis proceeds linearly in the presence of added pyridoxal 5'-phosphate, or pyridoxamine 5'-phosphate plus pyruvate. These findings indicate that the fungal inducible kynureninase can act as an amino-transferase to control the enzyme activity, and that the control mechanism is similar to that reported for the bacterial kynureninase (Moriguchi, M. & Soda, K. (1973) Biochemistry 12, 2974-2980). The ratio of kynureninase activity to aminotransferase activity was determined with bacterial and fungal enzymes. All the inducible kynureninases from various fungal species examined are also controlled by the transamination. In contrast, the pig liver kynureninase and the fungal constitutive enzymes are little or not at all affected by preincubation with amino acids. Thus, the present regulatory mechanism does not operate in these constitutive-type enzymes. The rate of hydrolysis of L-3-hydroxykynurenine by the pig liver enzyme decreases with increase in the incubation time; the enzyme is inhibited by 3-hydroxyanthranilate produced from L-3-hydroxykynurenine. The inhibition is found in all the constitutive-type enzymes, suggesting that 3-hydroxyanthranilate plays a regulatory role in NAD biosynthesis from tryptophan.

3-Hydroxyanthranilic Acid↗
PubMed1999

[Body composition and constitution: a constitutional syndrome (1st of 2 parts)].

Constitutional syndrome alters body constitution modifying (usually decreasing) two of its dimensions--weight and perimeters--by changing the composition of one, several or every body levels. Apart of the cause, the basic physiopathological process that characterizes this new syndrome is the amino acid mobilization from the muscle (proteolysis). As soon as fat loss has no consequence to the organism, proteolysis reduces the muscle mass and life is in danger. Actually, there is no effective treatment to improve the nitrogen balance by medication or hormones in speed catabolic states but it can also approach us to more proper therapeutics for these so frequent processes in clinic.

Adult↗