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Biomedical subjects

G Baier

Publications and source records attributed to G Baier.

At least 19 recordsLinked to original sources
PubMed2002

Direct interaction of the extracellular matrix protein DANCE with apolipoprotein(a) mediated by the kringle IV-type 2 domain.

Lipoprotein(a) [Lp(a)] consists of LDL and apolipoprotein(a), and has been shown to be a major, independent, risk factor for arteriosclerosis and thrombosis in humans. To further elucidate the (patho)physiological function(s) of Lp(a)/apo(a), we searched for new protein ligands, using the yeast two-hybrid system and employing the highly repetitive kringle IV type 2 (KIV-2) sequence from apo(a) as bait. The extracellular matrix protein DANCE [developmental arteries and neural crest epidermal growth factor (EGF)-like] recently implicated in atherogenesis was identified as an interactor. A direct physical interaction between DANCE and apo(a) was confirmed by co-purification of both recombinant proteins derived from culture supernatants of transiently transfected COS-1 cells. Furthermore, binding of human plasma-derived Lp(a) to recombinant DANCE was also observed. Finally, when monoclonal anti-apo(a) and polyclonal anti-DANCE antibodies were applied to tissue slices of atherosclerotic carotid artery, the two proteins were found to be co-localized in endothelial and smooth muscle cells, suggesting that they occur together in the arterial wall. However, as yet, the in vivo relevance and the possible functional role of this newly identified DANCE:Lp(a)/apo(a) interaction remains speculative.

Animals↗
PubMed2002

[Cylindrocarcinoma in a patient with Brooke-Spiegler syndrome].

BACKGROUND: Cutaneous cylindromas are benign adnexal tumors that may occur as a solitary lesion or in a multiple familiar pattern. Malignant change is rare. The association of multiple trichoepitheliomas and cylindromas, the so called Brooke-Spiegler Syndrome, is supposed to be inherited in an autosomal dominant manner. PATIENTS: A 55 year old woman presented with multiple skin tumors on the scalp, as well as the nasolabial and periauricular area since the age of 20 years. Her daughter and her nephew were also affected. Tumors were surgically removed for cosmetic reasons and showed histological signs of benign cylindromas and trichoepitheliomas. 35 years after diagnosis patient presented with a large exulceration on the right occipital area with intracranial invasion. Staging revealed multiple metastases in both lungs. Patient died 1 month later. RESULTS: Histological examination showed beside zones of massive necrosis multiple mitosis. The jigsaw puzzle pattern and the thick PAS positive basal layer, the striking characteristics of benign cylindromas, were lost. These histological findings and the clinical presentation led to the diagnosis of cylindrocarcinoma. CONCLUSIONS: Cylindrocarcinoma is an aggressive tumor with tendency to a local destructive growth and metastases. As malignant transformation of a benign cylindroma occurs more often in the multiple form a close follow-up of patients with multiple cylindromas is necessary. A family study is indicated.

Carcinoma, Adenoid Cystic↗
PubMed2002

[Respiratory diseases and genotoxicity in tobacco smoke exposed children].

BACKGROUND: Tobacco smoke, containing more than 4800 chemical substances with a large number of mutagenic and carcinogenic compounds, is the most important indoor pollution. Aim of the study was to analyse the relationship between exposure of children (2-15 years) to environmental tobacco smoke (ETS) with the amount of respiratory diseases, the occurrence of atopic diseases and the risk for genotoxic damage. PATIENTS AND METHODS: Within the last 1.5 years 216 children were included in the study. Smoking habits of the family, environmental settings, housing, nutrition, social and economic factors were assessed by a detailed questionnaire. Two different effect markers were used to assess molecular and genetic damage. Biochemical effect of ETS was quantified by 4-aminobiphenyl-hemoglobin (4-ABP-Hb) adducts and the genotoxic damage was determined by chromosomal damage as seen in the micro nucleus test in lymphocytes. RESULTS: Chronic rhinosinusitis and allergic rhinitis are accumulated in the ETS-exposed children. In the ETS-group atopic diseases (allergic rhinitis, extrinsic asthma or neurodermatitis) were significantly more frequent (39.5 %, p = 0.01) than in the non-exposed group (23 %). In addition the genetic predisposition was significantly decreased in the ETS-group (20.8 %, p = 0.048) compared to the non-exposed group (45 %). Until now, blood samples of 63 individuals were analysed for Hb adducts and 92 for micro nuclei. Hemoglobin adducts of 4-ABP, a human carcinogenic aromatic amine, were significantly elevated in children with smoking parents (mean: 82.2pg/g Hb, p = 0.003) compared to children with non-smoking parents (mean: 60.6 pg/g Hb). ETS-exposed children showed significantly higher micro nucleus frequencies (mean ETS: 8.0/1000 binucleate (BN) cells, p = 0.001) than non-ETS exposed children (mean: 6.2/1000 BN cells). CONCLUSION: Our data underline the thesis, that ETS plays an important role for the development of atopic diseases. The significantly increased effect markers of tobacco smoke in exposed children give evidence, that ETS causes elevated molecular and genotoxic damage in children.

Adolescent↗
PubMed2001

Protein kinase C isoforms involved in the transcriptional activation of cyclin D1 by transforming Ha-Ras.

Transcriptional activation of the cyclin D1 by oncogenic Ras appears to be mediated by several pathways leading to the activation of multiple transcription factors which interact with distinct elements of the cyclin D1 promoter. The present investigations revealed that cyclin D1 induction by transforming Ha-Ras is MEK- and Rac-dependent and requires the PKC isotypes epsilon, lambda, and zeta, but not cPKC-alpha. This conclusion is based on observations indicating that cyclin D1 induction by transforming Ha-Ras was depressed in a dose-dependent manner by PD98059, a selective inhibitor of the mitogen-activated kinase kinase MEK-1, demonstrating that Ha-Ras employs extracellular signal-regulated kinases (ERKs) for signal transmission to the cyclin D1 promoter. Evidence is presented that PKC isotypes epsilon and zeta, but not lambda are required for the Ras-mediated activation of ERKs. Expression of kinase-defective, dominant negative (DN) mutants of nPKC-epsilon or aPKC-zeta inhibit ERK activation by constitutively active Raf-1. Phosphorylation within the TEY motif and subsequent activation of ERKs by constitutively active MEK-1 was significantly inhibited by DN aPKC-zeta, indicating that aPKC-zeta functions downstream of MEK-1 in the pathway leading to cyclin D1 induction. In contrast, TEY phosphorylation induced by constitutively active MEK-1 was not effected by nPKC-epsilon, suggesting another position for this kinase within the cascade investigated. Transformation by oncogenic Ras requires activation of several Ras effector pathways which may be PKC-dependent and converge on the cyclin D1 promoter. Therefore, we investigated a role for PKC isotypes in the Ras-Rac-mediated transcriptional regulation of cyclin D1. We have been able to reveal that cyclin D1 induction by oncogenic Ha-Ras is Rac-dependent and requires the PKC isotypes epsilon, lambda, and zeta, but not cPKC-alpha. Evidence is presented that aPKC-lambda acts upstream of Rac, between Ras and Rac, whereas the PKC isotypes epsilon and zeta act downstream of Rac and are required for the activation of ERKs.

Animals↗
PubMed2001

Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells.

Protein kinase C theta (PKC theta) is known to induce NF-kappa B, an essential transcriptional element in T cell receptor/CD28-mediated interleukin-2 production but also T cell survival. Here we provide evidence that PKC theta is physically and functionally coupled to Akt1 in this signaling pathway. First, T cell receptor/CD3 ligation was sufficient to induce activation as well as plasma membrane recruitment of PKC theta. Second, PKC theta selectively cooperated with Akt1, known to act downstream of CD28 co-receptor signaling, in activating a NF-kappa B reporter in T cells. Third, Akt1 function was shown to be required for PKC theta-mediated NF-kappa B transactivation. Fourth, PKC theta co-immunoprecipitated with Akt1; however, neither Akt1 nor PKC theta served as a prominent substrate for each other in vitro as well as in intact T cells. Finally, plasma membrane targeting of PKC theta and Akt1 exerted synergistic transactivation of the I-kappa B kinase beta/inhibitor of NF-kappa B/NF-kappa B signaling cascade independent of T cell activation. Taken together, these findings suggest a direct cross-talk between PKC theta and Akt1 in Jurkat T cells.

Base Sequence↗
PubMed2001

Differential requirements for ERK1/2 and P38 MAPK activation by thrombin in T cells. Role of P59Fyn and PKCepsilon.

Activation of the mitogen-activated protein kinase (MAPK) cascade is a well documented mechanism for the G-protein-coupled receptors. Here, we have analysed the requirements for ERKs and p38 MAPK activation by thrombin in Jurkat T cells. We show that thrombin-mediated ERKs activation requires both PTK and PKC activities, whereas p38 MAPK activation is dependent only on PTKs. Thrombin-induced ERK and p38 MAPK activation was more pronounced in p56Lck deficient cells indicating that this PTK exerts a negative control on MAPK activity. Accordingly, overexpression of p50 Csk a kinase that inactivates p56Lck induced constitutive activation of ERKs. Requirement for a Src kinase was evidenced by expression of a constitutively active form of p59Fyn in Jurkat cells. Besides its effect on tyrosine phosphorylation events, thrombin also triggered a rapid and robust redistribution of PKCepsilon and delta from the cytosol to the membrane. Expression of constitutively active and dominant negative PKCepsilon demonstrates the pivotal role of this PKC isoform in ERKs activation by thrombin. These data are consistent with a model where thrombin induces ERK activation via both PKC-dependent and independent pathways, whereas p38 MAPK activation requires only PTKs. The PKC-independent pathway requires Src kinases other than p56Lck more likely p59Fyn, while the PKC-dependent mechanism depends on PKCepsilon

Benzoquinones↗
PubMed2001

Intracellular apolipoprotein E affects Amyloid Precursor Protein processing and amyloid Abeta production in COS-1 cells.

The apoE gene has been identified as a major susceptibility locus for late-onset Alzheimer's disease (LOAD). The epsilon4 allele greatly reduces age of onset of LOAD as compared to the wild-type 3 allele. The molecular mechanism(s) underlying the association has not yet been fully elucidated. The apoE protein has been shown to physically interact with the Abeta region of the Amyloid Precursor Protein (APP), but also with the ectodomain of the APP holoprotein itself. In this study we have used apoE fusion proteins containing either the ER retention sequence KDEL or trans-Golgi network (TGN) signal sequence in order to define potential apoE-mediated alterations in APP protein processing. Co-expression and pulse-chase experiments showed that a functional apoE:APP interaction occurs intracellularly which directly affects maturation and subsequently the secretion kinetics of APP. In addition, an epsilon4 allele-specific induction of Abeta production has been demonstrated. apoE3 resulted in increased Abeta production only when targeted to the ER, as observed in cells transfected with an apoE3KDEL fusion protein as well as following treatment with brefeldin A. The findings suggest that in cells that express both apoE and APP, such as astrocytes and microglia, a functional apoE:APP interaction may occur which modulates APP processing and Abeta production.

Alleles↗
PubMed2001

Induction of apoptosis by 7,8-dihydroneopterin: involvement of radical formation.

Interferon-gamma is a cytokine released in large amounts during cell-mediated immune response. It induces the expression of proinflammatory cytokines and enhances macrophage capacity to secrete reactive oxygen intermediates and the pteridines neopterin and 7,8-dihydroneopterin. To assay the role of these pteridines in the immune system several studies were performed. Thereby, 7,8-dihydroneopterin was found to induce apoptosis in T lymphocytes. In this study we report that caspases are involved in 7,8-dihydroneopterin-mediated apoptosis in Jurkat T cells. In connection with this result we found that 7,8-dihydroneopterin can increase Fas ligand expression detected in Western blot analysis and promoter reporter assays. Antioxidants potently reduced the effect of 7,8-dihydroneopterin on Fas ligand promoter activation suggesting an involvement of oxidative stress. In further investigations, ESR-measurements were performed to evaluate the role of 7,8-dihydroneopterin in the formation of radicals. We found that the pteridine in combination with the spin trap DMPO induces the production of DMPO-OH spin adducts. This reaction was sensitive to the presence of chelated metal ions and could completely be blocked by the addition of superoxide dismutase. These data suggest that 7,8-dihydroneopterin in aqueous solution leads to the formation of .OH radicals via generation of superoxide anion. We hypothesize that an overproduction of radicals caused by high levels of 7,8-dihydroneopterin is likely to be responsible for the pro-apoptotic effects observed in cell cultures and possibly contributes to the pathogenesis of diseases involving immune activation and elevated concentrations of neopterin-derivatives.

Apoptosis↗
PubMed2001

Protein kinase C isoenzyme: selective expression pattern of protein kinase C-θ during mouse development.

Protein kinase C (PKC)-θ, a serine/threonine protein kinase and novel PKC subfamily member, has been recently identified as an essential component of the T cell synapse which activates the NF-kB signaling cascade leading to expression of the IL-2 gene during T cell activation. By RNA in situ hybridization to whole-body embryo sections it is shown that the murine PKCθ is specifically expressed in tissues with hematopoietic and lymphopoietic activity. Expression is also evident in skeletal muscle. A further highly specific expression was observed in the peripheral and central nervous system which is described in detail. Expression in the brain persists up to adult stages.

Animals↗
PubMed2001

Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and bullous pemphigoid 230.

Cicatricial pemphigoid is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to bullous pemphigoid (BP)180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the beta4 subunit of alpha6beta4 integrin. We describe a patient with extensive disease of ocular, oral, pharyngeal, laryngeal and genital mucous membranes that healed with scarring of conjunctivae. IgG autoantibodies bound to the dermal-epidermal junction on direct immunofluorescence (IF) microscopy and to the epidermal side of 1 mol L(-1) NaCl-split skin on indirect IF microscopy. Our patient's circulating IgG recognized a 205-kDa protein in extracts of 293T cells transfected with the beta4 subunit of alpha6beta4 integrin and in the cell extract of DJM-1 cells. Our patient's IgG and IgA autoantibodies also reacted with full-length BP180 derived from epidermal extracts and the ectodomain of BP180 (LAD-1) derived from culture supernatant of keratinocytes. In addition, a weak IgG reaction with BP230 was noted. The disease rapidly responded to dexamethasone-cyclophosphamide pulse therapy, and immunoblot reactivity to both beta4 integrin and BP180 decreased according to disease activity.

Aged↗
PubMed2001

[Carcinoma of the external ear canal and middle ear as interdisciplinary challenge for ear surgery and radiotherapy].

BACKGROUND: Carcinoma of the external auditory canal are tumours considered to have a poor prognosis. Improvement of the survival rate by surgical means alone is not possible. Individual therapy modalities as a result of an interdisciplinary approach between otosurgeon and radiotherapist are necessary. PATIENTS AND METHODS: A series of 30 patients (3 patients pretreated at other institutions) with carcinoma of the external auditory canal and middle ear treated between 1978 and 1997 in our institutions was analysed with particular reference to tumour size and its relation to surrounding tissues, patterns of neck node involvement, surgical procedures, and radiation techniques. Clinical endpoints were freedom from local failure, overall survival, disease-free survival. The mean follow-up was 4.7 years (range: 0.1 to 18.8 years), median 3 years. RESULTS: Treatment by surgery and radiotherapy resulted in an overall 5-year survival rate of 51%. According to Pittsburgh classification the 5-year survival rate for early disease (T1- and T2-tumours) was 89%, for stage III 67% and for stage IV 39%. Most important prognostic factors were dural infiltration (all patients with dural invasion died within 2.2 years) and the infiltration of surgical margins (the 5-year survival rate of patients with complete tumour resection was 100%, but 54% in patients with tumour beyond surgical margins). 192-iridium HDR afterloading brachytherapy based on 3D CT-treatment planning is an effective tool in the management of local recurrences following surgery and a full course of external beam radiotherapy. CONCLUSIONS: Surgical resection followed by radiotherapy adapted to the stage of disease and grade of resection is the preferred treatment of cancer of the external auditory canal and middle ear.

Adult↗
PubMed2001

[Diagnosis, treatment and results of malignant skull base tumours].

BACKGROUND: Malignant tumours of the cranial base are rare and present usually in advanced tumour stage due to the lack of early clinical symptoms. PATIENTS AND METHODS: Sixty patients with malignant tumours infiltrating the skull base were treated at the Department of Otorhinolaryngology Head and Neck Surgery, University of Würzburg between 1987 and 1999. Most of the tumours (n = 51) originated from the nose or paranasal sinuses, the epipharynx, the outer ear canal or the middle ear. Seven tumours were malignant brain tumours infiltrating the bony structures of the skull base or originated from the cranial base itself. Two patients suffered from metastases of an adenocarcinoma of the prostata. The histological diagnosis was confirmed in 53 patients preoperatively and in seven patients during tumour resection. Squamous cell carcinoma (n = 24), adenocarcinoma (n = 10) and sarcoma (n = 7) were the most common histologies found. RESULTS: A radical en bloc resection of the tumour was only possible in 26 out of 60 cases. A surgical tumour reduction with postoperative radiation therapy was performed in seven patients as a palliative approach. Eight patients underwent a combined radio- and chemotherapy according to the histological diagnosis. Primary radiotherapy was the treatment of choice in eleven patients, where the tumours were located in the central area of the cranial base. Palliative radiotherapy or solely medical pain control were applied to eight patients who presented either with distant metastases or an advanced tumour growth. The mean postoperative survival following radical surgery was 48 months and after primary radiotherapy 27 months. DISCUSSION: A statistical analysis of the results is not applicable due to the great variety of the disease concerning the histological diagnosis, the tumour size and the location as well as the small number of patients.

Adenocarcinoma↗
PubMed2001

Determination of protein-protein interactions of ICIn by the yeast two-hybrid system.

ICln is a ubiquitously expressed eukaryotic protein. Expression of the protein in Xenopus laevis oocytes, the knocking-down of the protein in fibroblasts, or the reconstitution of the protein in lipid bilayer led to the assumption that this protein is an ionic channel or a significant part thereof. However, other possible roles for ICln in potential regulatory mechanisms have been postulated, as diverse as regulator of cell morphology by interacting with the Skb1 protein and/or interaction with core spliceosomal proteins. Here we show that ICln is able to interact with SnRNP core proteins SmD1, SmD2, SmD3, SmX5 and SmB/B'.

Amino Acid Sequence↗
PubMed2001

Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice.

Smooth muscle cell (SMC) accumulation is a key event in the development of atherosclerosis, including vein bypass graft arteriosclerosis. Because members of the protein kinase C (PKC) family signal cells to undergo proliferation, differentiation, or apoptosis, we generated PKCdelta knockout mice and performed vein bypass grafts on these animals. PKCdelta(-/-) mice developed normally and were fertile. Vein segments from PKCdelta(-/-) mice isografted to carotid arteries of recipient mice of either genotype led to a more severe arteriosclerosis than was seen with PKCdelta(+/+) vein grafts. Arteriosclerotic lesions in PKCdelta(-/-) mice showed a significantly higher number of SMCs than were found in wild-type animals; this was correlated with decreased SMC death in lesions of PKCdelta(-/-) mice. SMCs derived from PKCdelta(-/-) aortae were resistant to cell death induced by any of several stimuli, but they were similar to wild-type SMCs with respect to mitogen-stimulated cell proliferation in vitro. Furthermore, pro-apoptotic treatments led to diminished caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and cytochrome c release in PKCdelta(-/-) relative to wild-type SMCs, suggesting that their apoptotic resistance involves the loss of free radical generation and mitochondrial dysfunction in response to stress stimuli. Our data indicate that PKCdelta maintains SMC homeostasis and that its function in the vessel wall per se is crucial in the development of vein graft arteriosclerosis.

Animals↗
PubMed2000

Mapping of a minimal apolipoprotein(a) interaction motif conserved in fibrin(ogen) beta - and gamma -chains.

Lipoprotein(a) (Lp(a)) is a major independent risk factor for atherothrombotic disease in humans. The physiological function(s) of Lp(a) as well as the precise mechanism(s) by which high plasma levels of Lp(a) increase risk are unknown. Binding of apolipoprotein(a) (apo(a)) to fibrin(ogen) and other components of the blood clotting cascade has been demonstrated in vitro, but the domains in fibrin(ogen) critical for interaction are undefined. We used apo(a) kringle IV subtypes to screen a human liver cDNA library by the yeast GAL4 two-hybrid interaction trap system. Among positive clones that emerged from the screen, clones were identified as fibrinogen beta- and gamma-chains. Peptide-based pull-down experiments confirmed that the emerging peptide motif, conserved in the carboxyl-terminal globular domains of the fibrinogen beta and gamma modules specifically interacts with apo(a)/Lp(a) in human plasma as well as in cell culture supernatants of HepG2 and Chinese hamster ovary cells, ectopically expressing apo(a)/Lp(a). The influence of lysine in the fibrinogen peptides and of lysine binding sites in apo(a) for the interaction was evaluated by binding experiments with apo(a) mutants and a mutated fibrin(ogen) peptid. This confirmed the lysine binding sites in kringle IV type 10 of apo(a) as the major fibrin(ogen) binding site but also demonstrated lysine-independent interactions.

Amino Acid Sequence↗
PubMed2000

Protein kinase C theta and epsilon promote T-cell survival by a rsk-dependent phosphorylation and inactivation of BAD.

Both MAPK and protein kinase C (PKC) signaling pathways promote cell survival and protect against cell death. Here, we show that 12-O-tetradecanoylphorbol-13-acetate (TPA) prevents Fas-induced apoptosis in T lymphocytes. The effect of TPA was specifically abolished by the PKC inhibitor GF109203X and by dominant negative PKCtheta, PKCepsilon, and PKCalpha, suggesting that novel and conventional PKC isoforms mediate phorbol ester action. Moreover, TPA stimulated phosphorylation of BAD at serine 112, an effect abrogated by GF109203X but not by the MEK inhibitor PD98059. Expression of constitutively active PKC increased the phosphorylation of BAD at serine 112 but not at serine 136. Additionally, Fas-mediated cell death was enhanced by overexpression of a catalytically inactive form of p90Rsk (Rsk2-KN). Finally, Rsk2-KN abolished the protective effect of constitutively active PKC and totally blocked phosphorylation of BAD on serine 112. Thus, novel PKCtheta and PKCepsilon rescue T lymphocytes from Fas-mediated apoptosis via a p90Rsk-dependent phosphorylation and inactivation of BAD.

Carrier Proteins↗