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PubMedDate not supplied

Overexpression of CXC-chemokines and CXC-chemokine receptor type II constitute an autocrine growth mechanism in the epidermoid carcinoma cells KB and A431.

The CXC-chemokines Groalpha and interleukin-8 (IL-8) are well characterized growth factors for melanoma cells. Here the constitutive expression of Groalpha, IL-8 and their receptors (CXCR1 and CXCR2) as well as their functional involvement in the proliferation response were analyzed in normal keratinocytes and epidermoid carcinoma cell lines A431 and KB. Flow cytometric measurements, ELISA and semi-quantitative RT-PCR revealed low constitutive protein secretion and mRNA expression of both CXC-chemokines as well as CXCR1 and 2 in normal keratinocytes, whereas significant higher levels of CXC-chemokines and CXCR2 were deteced in epidermoid carcinoma cells. Proliferation of epidermoid carcinoma cells could be induced by CXC-chemokines and constitutive proliferation could be inhibited by neutralizing antibodies against CXC-chemokines and CXCR2. These studies indicate that constitutive Groalpha, IL-8 and CXCR2 protein expression enable an autocrine growth mechanism in epidermoid carcinoma cells.

Antigens, CD↗
PubMed2001

Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells.

The intracellular Src homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP-1) is a negative regulator of cell signaling and contributes to the establishment of TCR signaling thresholds in both developing and mature T lymphocytes. Although there is much functional data implicating SHP-1 as a regulator of TCR signaling, the molecular basis for SHP-1 activation in T lymphocytes is poorly defined. A modification of the yeast two-hybrid system was employed to identify in T cells phosphotyrosine-containing proteins capable of binding the SH2 domains of SHP-1. From this yeast tri-hybrid screen, the p85beta subunit of phosphatidylinositol 3-kinase and the immunoreceptor tyrosine-based inhibitory motif-containing receptors, leukocyte-associated Ig-like receptor-1 (LAIR-1) and programmed death-1 (PD-1), were identified. Coimmunoprecipitation studies demonstrated that the exclusive phosphotyrosine-containing protein associated with SHP-1 in Jurkat T cells under physiological conditions is LAIR-1. Significantly, this interaction is constitutive and was detected only in the membrane-enriched fraction of cell lysates. Ligand engagement of the SH2 domains of SHP-1 is a prerequisite to activation of the enzyme, and, consistent with an association with LAIR-1, SHP-1 was found to be constitutively active in unstimulated Jurkat T cells. Importantly, a constitutive interaction between LAIR-1 and SHP-1 was also detected in human primary T cells. These results illustrate the sustained recruitment and activation of SHP-1 at the plasma membrane of resting human T cells by an inhibitory receptor. We propose that this mechanism may exert a constitutive negative regulatory role upon T cell signaling.

Amino Acid Motifs↗
PubMed2001

Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter.

In melanoma cell lines, two different patterns of MHC class II expression have been described, either an IFN gamma-inducible expression of HLA-DR and HLA-DP, with a faint or null expression of HLA-DQ, resembling that described for melanocytes, or a constitutive expression, i.e., IFN-gamma independent, of all three HLA-D isotypes. As this latter phenotype has been associated with a more rapid progression of melanoma tumors, we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression. In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines, we have shown the constitutive expression of CIITA (class II transactivator) transcripts, CIITA being known as the master switch of MHC class II expression. Unexpectedly, these transcripts initiate from promoter III of the CIITA gene, a promoter that is mainly used constitutively in B lymphocytes. This expression was further shown to occur through factor(s) acting on the enhancer located upstream of CIITA promoter III, which was previously described in epithelioid cells as an IFN-gamma-response sequence. The hypothesis of a general abnormality of the IFN-gamma transduction pathway was dismissed. Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines, we propose the hypothesis that this phenomenon might not be a random event, but could be linked to the neoplasic state of the melanoma cells.

5' Untranslated Regions↗
PubMed2003

Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis.

Constitutive activation of the NF-kappaB has been documented to be involved in the pathogenesis of many human malignancies, including hemopoietic neoplasms. In this study, we examined the status of NF-kappaB in two non-Hodgkin's lymphoma cell lines derived from mantle cell lymphoma (MCL) samples and in patient MCL biopsy specimens by EMSA and confocal microscopic analysis. We observed that NF-kappaB is constitutively activated in both the MCL cell lines and in the MCL patient biopsy cells. Since NF-kappaB has been shown to play an important role in a variety of cellular processes, including cell cycle regulation and apoptosis, targeting the NF-kappaB pathways for therapy may represent a rational approach in this malignancy. In the MCL cell lines, inhibition of constitutive NF-kappaB by the proteasome inhibitor PS-341 or a specific pIkappaBalpha inhibitor, BAY 11-7082, led to cell cycle arrest in G(1) and rapid induction of apoptosis. Apoptosis was associated with the down-regulation of bcl-2 family members bcl-x(L) and bfl/A1, and the activation of caspase 3, that mediates bcl-2 cleavage, resulting in the release of cytochrome c from the mitochondria. PS-341or BAY 11-induced G(1) cell cycle arrest was associated with the inhibition of cyclin D1 expression, a molecular genetic marker of MCL. These studies suggest that constitutive NF-kappaB expression plays a key role in the growth and survival of MCL cells, and that PS-341 and BAY 11 may be useful therapeutic agents for MCL, a lymphoma that is refractory to most current chemotherapy regimens.

Antineoplastic Agents↗
PubMed2005

A distal regulatory region is required for constitutive and IFN-beta-induced expression of murine TLR9 gene.

TLR9 is critical for the recognition of unmethylated CpG DNA in innate immunity. Accumulating evidence suggests distinct patterns of TLR9 expression in various types of cells. However, the molecular mechanism of TLR9 expression has received little attention. In the present study, we demonstrate that transcription of murine TLR9 is induced by IFN-beta in peritoneal macrophages and a murine macrophage cell line RAW264.7. TLR9 is regulated through two cis-acting regions, a distal regulatory region (DRR) and a proximal promoter region (PPR), which are separated by approximately 2.3 kbp of DNA. Two IFN-stimulated response element/IFN regulatory factor-element (ISRE/IRF-E) sites, ISRE/IRF-E1 and ISRE/IRF-E2, at the DRR and one AP-1 site at the PPR are required for constitutive expression of TLR9, while only the ISRE/IRF-E1 motif is essential for IFN-beta induction. In vivo genomic footprint assays revealed constitutive factor occupancy at the DRR and the PPR and an IFN-beta-induced occupancy only at the DRR. IRF-2 constitutively binds to the two ISRE/IRF-E sites at the DRR, while IRF-1 and STAT1 are induced to bind to the two ISRE/IRF-E sites and the ISRE/IRF-E1, respectively, only after IFN-beta treatment. AP-1 subunits, c-Jun and c-Fos, were responsible for the constitutive occupancy at the proximal region. Induction of TLR9 by IFN-beta was absent in STAT1-/- macrophages, while the level of TLR9 induction was decreased in IRF-1-/- cells. This study illustrates the crucial roles for AP-1, IRF-1, IRF-2, and STAT1 in the regulation of murine TLR9 expression.

Amino Acid Sequence↗
PubMed2001

Comparison of constitutive and inducible maize kernel proteins of genotypes resistant or susceptible to aflatoxin production.

Maize genotypes resistant or susceptible to aflatoxin production or contamination were compared for differences in both constitutive and inducible proteins. Five additional constitutive proteins were found to be associated with resistance in over 8 of the 10 genotypes examined. Among these, the 58- and 46-kDa proteins were identified as globulin-1 and globulin-2, respectively. Differences in the ability to induce specific antifungal proteins, such as the higher synthesis of the 22-kDa zeamatin in resistant genotypes, were also observed between resistant and susceptible kernels incubated under germinating conditions (31 degrees C, 100% humidity). Both constitutive and inducible proteins appear to be necessary for kernel resistance. Embryo-killed kernels (unable to synthesize new proteins) supported the highest level of aflatoxins, whereas imbibed kernels (to hasten protein induction) supported the lowest among all treatments. This suggests that the synthesis of new proteins by the embryo plays an important role in conferring resistance. However, significantly lower levels of aflatoxin production in embryo-killed resistant kernels than in susceptible ones suggest that, in reality, high levels of constitutive antifungal proteins are indispensable to kernel resistance.

Aflatoxins↗
PubMed1976

[The epistemological obstacle in the constitution of social sciences].

I. General conception. The author contends that the constitution of science requires the completion of two different tasks: a) a negative-critical one, i.e. the clearing of the theoretical field through expurgating all pre-scientific ideologies jeopardizing the growth of scientific concepts; and b) a positive-constructive one, or the actual building up of a science through the production of the formal-abstract object, using ontically indeterminate raw material. Those tasks have characteristics that differ from the formal and factic-natural sciences to the social sciences. The reasons for the differences are: a) the former two have established objects, whereas the latter ones have their objects in the process of undergoing constitution, and thus possessing and oscillating ambiguity; b) the former two sciences have specific methods related to their specific objects, whereas the latter ones have a host of methods, all of them advocating scientific status; c) the former two sciences integrate their concepts into systems so as to constitute the unity of their meaning, whereas the latter ones lack a systematic integration. The consequence is that sciences already constituted (formal and factic-natural sciences) have, by the same token, established the co-implication of both moments (negative-critical and positive-constructive), to the extent that they are in the midst of universes admitting some law-system. Social sciences, on the contrary, set a double register of problems: a) "in-themselves", as they suppose the opening of a new way to approach the object; and b) "for-themselves", as long as that opening is performed at the expense of pre-scientific ideologies that bar the developments to be done "in-themselves". Furthermore, the double task is not accomplished in the same fashion in logic-formal sciences and factic-natural ones, both groups having an apodictic adequation (absolute in the first group, relative in the second one) between the context of discovery and the context of justification, be it formal or experimental, whereas in social sciences there is no such adequation, as they are still searching and trying to establish the mutually foundating relationship between both contexts. II. The epistemological obstacle in Psychology. Psychology, belonging to the general class of social sciences, is subject to two kinds of epistemological obstacles: a) those stemming from "common sense", born and nourished in the naïve, day-to-day experience, and being used as a general canon for usual as well as entirely new situations; they reach the status of a pre-critical "knowing", based solely on beliefs, and advocating to provide the grounds for our opinion on singular and general subjects; and b) those stemming from the "speculative discourse", understood as a system of notions encircling themselves and pretending to have an analogical reference to real objects, when analogy only actualizes objects that are absent...

Humans↗
PubMed1999

Protein kinase B (c-Akt), phosphatidylinositol 3-kinase, and STAT5 are activated by erythropoietin (EPO) in HCD57 erythroid cells but are constitutively active in an EPO-independent, apoptosis-resistant subclone (HCD57-SREI cells).

We found that erythropoietin (EPO) and stem cell factor (SCF) activated protein kinase B (PKB/Akt) in EPO-dependent HCD57 erythroid cells. To better understand signals controlling proliferation and viability, erythroid cells that resist apoptosis in the absence of EPO were subcloned and characterized (HCD57-SREI cells). Constitutive activations of PKB/Akt, STAT5a, and STAT5b were noted in these EPO-independent cells. PI3-kinase activity was an upstream activator of PKB/Akt because the PI3-kinase inhibitor LY294002 blocked both constitutive PKB/Akt and factor-dependent PKB/Akt activity. The LY294002 study showed that proliferation and viability of both HCD57-SREI and HCD57 cells correlated with the activity of PKB/Akt; however, PKB/Akt activity alone did not protect these cells from apoptosis. Treatment of HCD57 cells with SCF also activated PKB/Akt, but did not protect from apoptosis. This result suggested that PKB/PI3-kinase activity is necessary but not sufficient to promote viability and/or proliferation. Constitutive STAT5 activity, activated through an unknown pathway not including JAK2 or EPOR, may act in concert with the constitutive PI3-kinase/PKB/Akt pathway to protect the EPO-independent HCD57-SREI cells from apoptosis and promote limited proliferation.

Apoptosis↗
PubMed1999

Association of heparin with basic fibroblast growth factor, epidermal growth factor, and constitutive nitric oxide synthase on healing of gastric ulcer in rats.

The healing effect of heparin on gastric ulcer and its underlying mechanisms were studied. The influences of protamine on these effects were also investigated. Gastric ulcer was induced by acetic acid in rats. Heparin (100-1000 U/kg i.v.) was given once daily for 4 or 7 days. Ulcer area was measured; gastric mucosal regeneration, proliferation, and angiogenesis were determined by histological or immunohistochemical methods. Gastric mucosal basic fibroblast growth factor (bFGF) level was assessed by an enzyme-linked immunosorbent assay, and the mucosal epidermal growth factor (EGF) level and nitric oxide synthase (NOS) activity were measured by radioimmunoassay. The anticoagulant action of heparin was determined by the duration of bleeding time. The results showed that heparin given for 4 or 7 days significantly accelerated gastric ulcer healing in a dose-dependent manner. The three doses of heparin significantly stimulated mucosal regeneration and proliferation as well as angiogenesis but not the contraction of ulcer base. Similar effects were observed in gastric mucosal bFGF and EGF levels and constitutive NOS activity. Protamine not only abolished the anticoagulant action of heparin but also significantly potentiated its effects on ulcer healing, gastric mucosal proliferation, angiogenesis, and constitutive NOS activity. These findings indicate that heparin can accelerate gastric ulcer healing, which is associated with mucosal regeneration, proliferation, and angiogenesis. These actions are likely to be stimulated by bFGF, EGF, and constitutive NOS activity in the gastric mucosa. Protamine potentiates the ulcer-healing effect of heparin, which is probably acting through constitutive NOS activation.

Acetates↗
PubMed1999

Quantitative characterization and study of the relationship between constitutive-facultative skin color and phototype in Caucasians.

In this study constitutive and facultative colorimetric values were quantified to determine the physiologic changes in Caucasian skin color and to define the correlation between skin color and phototype assessed according to the Fitzpatrick method. Our population consisted of 401 subjects ranging in age from 24 to 28 years with similar life styles. Skin color was measured with a Minolta CR-200 colorimeter on the upper medial quarter of the buttock (constitutive color) and on the cheek (facultative color). Advanced multivariate statistical analysis allowed differentiation between constitutive and facultative skin color in relation to the phototype to be quantified. Moreover, Kullback divergence showed that the probability of correctly determining a subject's phototype is high when the variables of constitutive and facultative skin color are considered together. This interesting result makes it possible, in the future, to use colorimetric values of exposed and nonexposed skin, together with determination of Fitzpatrick phototype and of other phenotypic characters, to better predict cutaneous sun reactivity.

Adult↗
PubMed2000

Facilitation of constitutive alpha(2A)-adrenoceptor activity by both single amino acid mutation (Thr(373)Lys) and g(alphao) protein coexpression: evidence for inverse agonism.

The recombinant human alpha(2A)-adrenoceptor (alpha(2A)-AR, RC 2.1. ADR.A2A) can be transformed into a constitutively activated form in CHO-K1 cells by coexpression with a rat G(alphao) protein. Constitutive activity could be enhanced more by both mutation of Thr(373) of the alpha(2A)-AR to a Lys and Cys(351) of the G(alphao) protein by an Ile. The basal [(35)S]GTPgammaS binding response displayed a constitutive alpha(2A)-AR activity that amounted to 21% of the maximal receptor activation as obtained with 10 microM (-)-adrenaline. UK 14304, BHT 920, d-medetomidine, oxymetazoline, and clonidine acted as efficacious agonists. The enhancement of basal activity was entirely blocked (-50 +/- 3%) by ligands that thus appeared to act as inverse agonists (i.e., RX 811059 and its (+)-enantiomer, (+)-RX 821002, RS 15385, and yohimbine); the potencies of the ligands corresponded with their binding affinities for the alpha(2A)-AR. Fluparoxan and WB 4101 displayed partial inverse agonism. Atipamezole and dexefaroxan at 10 microM were virtually free of intrinsic activity and thus acted as neutral antagonists; idazoxan displayed potent partial agonist properties as observed with BRL 44408 and SKF 86466. The inverse agonist activity induced by (+)-RX 811059 could be reversed by atipamezole with a pK(B) value (8.73 +/- 0.07) that was similar to that required for blockade of the UK 14304-mediated response. Constitutive alpha(2A)-AR activation was mainly observed with the G(alphao) Cys(351)Ile protein compared with the pertussis toxin-resistant mutants of the G(alphai) protein subtypes. The observed spectrum of intrinsic activities for the various ligands suggests that pure, neutral antagonists are rather uncommon in this specified alpha(2A)-AR system.

Adrenergic Agonists↗
PubMed2000

Selective expression and constitutive phosphorylation of SHC proteins [corrected] in the CD34+ fraction of chronic myelogenous leukemias.

The BCR/ABL fusion protein is a constitutively active tyrosine kinase that is responsible for the pathogenesis of chronic myelogenous leukemia (CML). Clinically, CML is characterized by a chronic phase (CP) that eventually terminates into a blast crisis (BC). BC transformation is associated with accumulation of CD34+ blasts. We investigated the expression and phosphorylation of Src-homology-2 and collagen-homology domains (SHC) [corrected] proteins in subpopulations of CML primary cells. Shc polypeptides are tyrosine kinase substrates that are constitutively tyrosine-phosphorylated in continuous cell lines of CML origin. High levels of Shc expression were found in the CD34+ cells from CML-BC, CML-CP and normal bone marrow. In contrast, CD34- fractions from CML-CP and normal bone marrow expressed low levels of p46Shc. Shc proteins were constitutively phosphorylated in the CD34+ fractions from CML cells (both CP and BC), but not in normal CD34+ cells. These data bear implications for the role of Shc in normal hemopoiesis and CML leukemogenesis: (a) dramatic changes of Shc expression during terminal differentiation of hemopoietic cells adds a further level of regulation to the signal transduction function of Shc; and (b) constitutive Shc tyrosine-phosphorylation in the rare CD34+ cells of CML-CP might contribute to the selection of this subpopulation during the blast crisis transformation of CMLs.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Constitutive activation of STAT3 is associated with the acquisition of an interleukin 6-independent phenotype by murine plasmacytomas and hybridomas.

Interleukin 6 (IL-6), the major growth factor for myeloma cells, signals through the activation of signal transducers and activators of transcription (STAT) proteins. An important step in the malignant progression of murine plasmacytomas is the transition from dependence on IL-6 to a state of IL-6 independence. To elucidate the mechanism whereby IL-6 independence occurs, intracellular signaling events elicited by IL-6 in both IL-6-dependent and -independent plasmacytomas and hybridomas were compared. It was found that STAT3, a key molecule involved in IL-6 signaling, was constitutively activated and phosphorylated in IL-6-independent cell lines compared to the IL-6-dependent cells. Further comparison of upstream signaling pathways revealed that JAK-1 was constitutively present in anti-phosphotyrosine immunoprecipitates of IL-6-independent cells; gp130 was constitutively phosphorylated in a subset of IL-6-independent plasmacytomas, whereas other IL-6-independent lines showed no detectable gp130 phosphorylation in the absence of exogenous IL-6. Secretion of a factor capable of supporting the growth of IL-6-dependent cells was observed in one of the IL-6-independent plasmacytomas, but not in others, making an autocrine mechanism an unlikely explanation for IL-6 independence. These findings provide evidence that the constitutive activation of STAT3, either in the absence of detectable receptor-proximal events or associated with the concomitant activation of gp130, can contribute to the process of IL-6 independence.

Animals↗
PubMed2001

Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells.

Constitutive IKK activity associated with increased IkappaBalpha phosphorylation and degradation contribute to the high level of endogenous nuclear factor-kappaB (NF-kappaB) activation in Hs294T melanoma cells as compared with RPE cells (R. L. Shattuck-Brandt and A. Richmond, Cancer Res., 57: 3032-3039, 1997; M. N. Devalaraja et al., Cancer Res., 59: 1372-1377, 1999). To determine whether this endogenous NF-kappaB activation was characteristic of melanoma, we examined the level of constitutive activation of NF-kappaB in a number of melanoma cell lines. We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha and p65, and enhanced nuclear localization of p65/p50 in comparison to normal human epidermal melanocytes. The chemokines, CXC ligand 1 (CXCL1) and CXCL8, but not CXCL5, are highly expressed in most of the melanoma cell lines, suggesting that the constitutive production of chemokines is highly correlated to endogenous NF-kappaB activity. Our failure to observe a direct relationship between the fold activation of IKK, CXCL1, or CXCL8 mRNA levels and secretion of these chemokines into the culture medium suggest that regulation of chemokine expression also occurs at the posttranscription level of mRNA stability and/or translational control. Moreover, recombinant CXCL1 can directly induce IKK activity in normal human epidermal melanocytes in a concentration-dependent manner after up-modulation of CXCL1 protein expression, whereas inhibition of IKKbeta activity results in down-modulation of CXCL1 protein expression. Finally, CXCL1 antibody blocks IKK activity and inhibits the proliferation of melanoma cells to further support the concept that the constitutive activation of NF-kappaB and autocrine effects of CXCL1 play an important role in the pathogenesis of melanoma.

Cell Division↗
PubMed2001

Unmasking different constitutive activity of four chemoattractant receptors using Na+ as universal stabilizer of the inactive (R) state.

Neutrophils express receptors for the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) complement C5a, leukotriene B4 (LTB4) and platelet-activating factor (PAF). The aim of this study was to analyze the constitutive activity of chemoattractant receptors by studying binding of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) to the G-protein Gi alpha 2 beta 1 gamma 2 expressed in Sf9 cells. We used Na+ as modulator of constitutive activity because there are no known inverse agonists for the C5a receptor (C5aR), LTB4 receptor (BLTR) and PAF receptor (PAFR). In the absence of NaCl, PAF and LTB4 exhibited larger relative stimulatory effects on GTP gamma S binding than fMLP and C5a. NaCl showed larger inhibitory effects on basal GTP gamma S binding in membranes expressing the formyl peptide receptor (FPR) and C5aR than in membranes expressing BLTR and PAFR. The order of potency of NaCl at inhibiting basal GTP gamma S binding was FPR > C5aR approximately BLTR > PAFR. As a result of the inhibitory effect of NaCl on basal GTP gamma S binding, the relative stimulatory effects of agonists were increased. By quantitatively analyzing the expression levels of chemoattractant receptors and Gi alpha 2 and the stoichiometry of receptor/G-protein coupling we obtained no evidence for structural instability of constitutively active receptors and catalytical G-protein activation. Taken together, the FPR and C5aR exhibit higher constitutive activity than the BLTR and PAFR. Na+ acts as a universal stabilizer of the inactive (R) state in chemoattractant receptors. The different potencies of NaCl at suppressing basal G-protein activity with different receptors indicate that chemoattractant receptors differ from each other in their Na(+)-affinity.

Antigens, CD↗
PubMed2003

Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation.

Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.

Enzyme Activation↗
PubMed2003

[Authorizing procedure and performing of ritual slaughter after the judgement of the German Constitutional Court in Karlsruhe].

The judgement of the German Constitutional Court from February the 15th in 2002 allows Moslems to perform ritual slaughter, provided that they can state compelling religious reasons. Animal protection was assessed just as a public interest in contrast to the constitutional rights of religious and professional freedom. However this can not be kept up any more as it is aimed to integrate animal protection into the German constitutional law. The authorities now have the duty to investigate each request for ritual slaughter carefully. This investigation must include a close look at the compelling religious reasons, the expert knowledge of the applicant (which includes stunning methods), the local facilities of the slaughterhouse and which is more for whom the meat is for. It is also important whether the animal is slaughtered for sacrificial or commercial reasons. Furthermore the consequences which threaten the religious community, if their members don't live according to the rules, have to be shown. Electric stunning and the fact that it is accepted by Islamic authorities has also to be pointed out. It seems to be possible to turn down a request for ritual slaughter referring that to the fact that animal protection is aimed to be part of the constitutional law.

Abattoirs↗
PubMed1992

Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma.

The "stromal" or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3-specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.

Animals↗