[Association of pregnancy-induced hypertension with a molecular variant of angiotensinogen gene].
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Angiotensinogen↗
Biomedical subjects
A Hata
Publications and source records attributed to A Hata.
Activation of novel protein kinases C delta and C epsilon upon mitogenic stimulation of quiescent rat 3Y1 fibroblasts.
Rat fibroblast 3Y1 cells express at least three protein kinase C species, conventional PKC alpha (cPKC alpha), novel PKC delta (nPKC delta), and novel PKC epsilon (nPKC epsilon). The stimulation of quiescent 3Y1 cells by serum (or epidermal growth factor (EGF) but not 12-O-tetradecanoylphorbol-13-acetate (TPA) results in the induction of DNA synthesis. Upon stimulation by serum or EGF, endogenous PKC species showed no indication of activation such as translocation or down-regulation, whereas TPA or synthetic diacylglycerol caused activation of all these PKC species when judged by these criteria. The only indication of activation observed upon serum or EGF stimulation was an upward shift in the electrophoretic mobility of nPKC delta. The phosphorylation levels of endogenous PKC members determined by in vivo metabolic labeling experiments revealed increased phosphorylation of both nPKC delta and nPKC epsilon, but only a slight increase for cPKC alpha in response to serum or EGF. On the other hand, TPA caused increased phosphorylation of all three PKC species. Overexpression of these PKC members by introduction of the corresponding cDNA expression plasmids resulted in the enhancement of the cell response to TPA when monitored in terms of transcriptional activation through TPA- or serum-responsive elements. Such enhancement in transcriptional activation by overexpression of cPKC alpha, nPKC delta, or nPKC epsilon was also observed in response to diacylglycerol, indicating that all these PKC species are activated by diacylglycerol in cells. In contrast to these nonphysiological stimuli, serum (or EGF) stimulation of 3Y1 cells that overexpress the respective PKC members revealed a clear difference between cPKC and nPKC, in that overexpression of nPKC delta or nPKC epsilon resulted in a large increase in TPA- or serum-responsive element activation, whereas the overexpression of cPKC alpha increased activation only very slightly. These results indicate that the mitogenic stimulation of quiescent 3Y1 cells results in selective activation of endogenous nPKC members and that the modes of activation of cPKC and nPKC differ from each other.
Animals↗
Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src.
Csk (C-terminal Src kinase), a protein-tyrosine kinase, bearing the Src homology 2 and 3 (SH2 and SH3) domains, has been implicated in phosphorylation of c-Src Tyr-527, resulting in suppression of c-Src kinase activity. We found that mutations in the SH2 or SH3 domain of Csk, though they did not affect its kinase activity, resulted in a loss of suppression of c-Src activity in fibroblasts. In normal fibroblasts, tyrosine-phosphorylated paxillin and focal adhesion kinase pp125FAK, which colocalize at focal adhesion plaques, were the major proteins to which the Csk SH2 domain bound. Loss of binding to these proteins by the Csk SH2 mutants correlated with loss of the activity to suppress c-Src. Consistent with this observation, the levels of tyrosine phosphorylation of paxillin and pp125FAK were greatly reduced during mitosis, whereas the kinase activity of c-Src was elevated. We suggest that the SH2 domain is required for Csk to suppress c-Src, perhaps in combination with the SH3 domain, by anchoring Csk to a particular subcellular location where c-Src may exist. Our data also indicate that a certain fraction of the Csk and Src family kinases function at the focal adhesion plaques. The activity of the c-Src kinase localized at the focal adhesion plaques appears to be regulated by cell adhesion to the extracellular matrix.
Animals↗
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
Stimulation of B lymphocytes through their antigen receptor (BCR) results in rapid increases in tyrosine phosphorylation on a number of proteins and induces both an increase of phosphatidylinositol and mobilization of cytoplasmic free calcium. The BCR associates with two classes of tyrosine kinase: Src-family kinase (Lyn, Fyn, Blk or Lck) and Syk kinase. To dissect the functional roles of these two types of kinase in BCR signaling, lyn-negative and syk-negative B cell lines were established. Syk-deficient B cells abolished the tyrosine phosphorylation of phospholipase C-gamma 2, resulting in the loss of both inositol 1,4,5-trisphosphate (IP3) generation and calcium mobilization upon receptor stimulation. Crosslinking of BCR on Lyn-deficient cells evoked a delayed and slow Ca2+ mobilization, despite the normal kinetics of IP3 turnover. These results demonstrate that Syk mediates IP3 generation, whereas Lyn regulates Ca2+ mobilization through a process independent of IP3 generation.
Animals↗
Scaphoid megalourethra with multiple urogenital anomalies.
A male infant with scaphoid megalourethra, which is a rare congenital anomaly, is presented. At birth he exhibited a grossly swollen, malformed penis and cryptorchidism. The corpus spongiosum was not palpable. The infant had congenital renal failure. Retrograde urethrography revealed a crescent-shaped dilatation of the anterior urethra, and the diagnosis of scaphoid megalourethra was made. Subsequent uroradiological examinations showed that there were also severe urogenital anomalies, i.e. renal hypoplasia-dysplasia, hydronephrosis, hydroureter and vesicoureteral reflux. This disorder is frequently associated with other urogenital anomalies. Therefore, once the diagnosis is reached, a careful investigation for other associated abnormalities should be undertaken.
Abnormalities, Multiple↗
Functional analysis of Csk in signal transduction through the B-cell antigen receptor.
In B cells, two classes of protein tyrosine kinases (PTKs), the Src family of PTKs (Lyn, Fyn, Lck, and Blk) and non-Src family of PTKs (Syk), are known to be involved in signal transduction induced by the stimulation of the B-cell antigen receptor (BCR). Previous studies using Lyn-negative chicken B-cell clones revealed that Lyn is necessary for transduction of signals through the BCR. The kinase activity of the Src family of PTKs is negatively regulated by phosphorylation at the C-terminal tyrosine residue, and the PTK Csk has been demonstrated to phosphorylate this C-terminal residue of the Src family of PTKs. To investigate the role of Csk in BCR signaling, Csk-negative chicken B-cell clones were generated. In these Csk-negative cells, Lyn became constitutively active and highly phosphorylated at the autophosphorylation site, indicating that Csk is necessary to sustain Lyn in an inactive state. Since the C-terminal tyrosine phosphorylation of Lyn is barely detectable in the unstimulated, wild-type B cells, our data suggest that the activities of Csk and a certain protein tyrosine phosphatase(s) are balanced to maintain Lyn at a hypophosphorylated and inactive state. Moreover, we show that the kinase activity of Syk was also constitutively activated in Csk-negative cells. The degree of activation of both the Lyn and Syk kinases in Csk-negative cells was comparable to that observed in wild-type cells after BCR stimulation. However, BCR stimulation was still necessary in Csk-negative cells to elicit tyrosine phosphorylation of cellular proteins, as well as calcium mobilization and inositol 1,4,5-trisphosphate generation. These results suggest that not only activation of the Lyn and Syk kinases but also additional signals induced by the cross-linking of the BCR are required for full transduction of BCR signaling.
Animals↗
Angiotensinogen as a risk factor for essential hypertension in Japan.
A common molecular variant of angiotensinogen (AGT), the precursor of the potent vasoactive hormone angiotensin II, has been incriminated as a marker for a genetic predisposition to essential hypertension in Caucasians (Jeunemaitre, X., F. Soubrier, Y. V. Kotelevtsev, R. P. Lifton, C. S. Williams, A. Charru, S. C. Hunt, P. N. Hopkins, R. R. Williams, J. M. Lalouel, and P. Corvol. 1992. Cell. 71:169-180). We now show that the same variant, T235, is associated with essential hypertension in Japanese patients. The observation of this association in a distinct, ethnically homogeneous population further substantiates an involvement of angiotensinogen in the pathogenesis of essential hypertension and has physiological, epidemiological, and evolutionary implications.
Adolescent↗
[Assessment of social disability of patients suffering from chronic mental illness with the role play test].
UNLABELLED: Among the chronic mentally ill patients, disabilities invade most parts of their social functioning, and influences their long term course profoundly. It is important clinical issue to improve disability. Social skills training is assumed to be effective method to improve disability, and it has been disseminated over Japan recently. The assessment system to evaluate disabilities objectively at the viewpoint of social skills must be required to verify effects of social skills training, and to develop further effective therapeutic method. A role play test is the assessment tool for social skills through role plays under specific social conditions. It was reported to be useful as the method of functional assessment before treatment, and as the tool to evaluate effects of treatment to improve disability. PURPOSE: We created the Role Play Test (RPT) which was adapted to Japanese cultural background, and we tried to verify feasibility, reliability, and validity of the RPT. SUBJECTS: Thirty out-patients attending in the Day Hospital attached to Tokyo University Hospital. Twenty-six were schizophrenia, and 4 were other diagnoses. METHOD: Subjects were assessed with the RPT, BPRS, SANS, four rating scales for social functioning, and self-efficacy rating scale. The RPT was designed to assess components of social skills--social perception, role play behavior, and self-efficacy. Role play behaviors were recorded with video tapes for analysis of interrater reliability. The RPT is consisted of 12 scenes to evaluate social skills which are required in daily life. Statistical analyses were done with SAS (Statistical Analysis System). RESULTS: (1) The RPT was presumed to be feasible clinically, because the RPT could be practiced easily and responsibilities of both subjects and testers were not so much. (2) Interrater reliabilities assessed with ANOVA-ICC on 12 items was sufficiently high except one item. (3) Construct validity was certified through factor analysis, and criterion-related validity was certified through correlation analysis with other rating scales of social functioning. (4) Individual profile of the RPT should be useful instrument for functional analysis before social skills training. We also discussed on some hypotheses on the causal relationship between positive and negative symptoms and social skills. The RPT could be used as a tool to research causes of disabilities, and to evaluate improvement of social functioning after psycho-social intervention including social skills training, because the RPT can assess social skills quantitatively according to the cognitive-behavioral model.
Adolescent↗
Binding of lipoprotein lipase to heparin. Identification of five critical residues in two distinct segments of the amino-terminal domain.
Binding to heparan sulfate governs many aspects of the physiological action and regulation of the lipolytic enzyme, lipoprotein lipase (LPL). In an attempt to identify the structural determinants which mediate this interaction, basic residues in three segments of the primary sequence of human LPL (residues 147-151, 279-282, and 292-304) were replaced with alanine, either singly or in various combinations, and variant proteins were subjected to affinity chromatography on heparin-Superose. Five basic residues in two distinct segments of the primary sequence were critical determinants of the high affinity for heparin manifested by the active enzyme (R279, K280, R282, K296, R297). By contrast, no such evidence could be detected for basic residues in the first cluster (K147, K148) or for other basic residues in the third cluster (K292, R294, K304), while the evidence for K300 was unresolved. The conformation of this heparin-binding domain can be inferred by reference to the three-dimensional structure of the homologous enzyme, pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Affinity of the active enzyme for heparin could not be reduced below a threshold, suggesting that other heparin-binding determinants exist elsewhere in the molecule, as supported by recently published evidence (Davis, R. C., Wong, H., Nikazy, J., Wang, K., Han, Q., and Schotz, M. C. (1992) J. Biol. Chem. 267, 21499-21504).
Amino Acid Sequence↗
Functional divergence of protein kinase C (PKC) family members. PKC gamma differs from PKC alpha and -beta II and nPKC epsilon in its competence to mediate-12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive transcriptional activation through a TPA-response element.
We have established an assay system where overexpression of a specific protein kinase C (PKC) type caused by introduction of the respective cDNA results in the enhancement of a cell response: the transcriptional activation of a set of genes in response to PKC activators such as 12-O-tetradecanoylphorbol 13-acetate (TPA). When monitored by the expression of a reporter gene containing the chloramphenicol acetyltransferase gene fused downstream of a synthetic TPA response element (TRE) or a serum response element (SRE), the overexpression of cPKC alpha and -beta II or nPKC epsilon all resulted in the enhancement of transcriptional activation through both TRE and SRE. On the other hand, PKC gamma activates TRE only very weakly, although it activates SRE in a similar manner to the other PKC members examined. The overexpression of cPKC alpha and -beta II or nPKC epsilon, but not cPKC gamma, resulted in the enhanced expression of the endogenous c-jun gene, which contains TRE in the 5'-upstream, promoter region. The gel mobility shift assay showed that the activation of PKC gamma, as well as PKC alpha and -beta II and nPKC epsilon, causes the increase in TRE-binding proteins, suggesting that transcriptional activation through TRE requires an additional step, which is not activated by PKC gamma, such as a qualitative change in TRE-binding or in TRE-associating proteins. This finding provides not only a rationale to explain the presence of multiple PKC family members, but also permits the dissection of the complex cellular signaling cascade involving PKC family members.
Amino Acid Sequence↗
Compensatory function of central dopaminergic system for suppressing psychic seizures--repeated plasma homovanillic acid measurement in refractory temporal lobe epilepsy.
Repeatedly measured plasma homovanillic acid concentration, as a clinically available index of central dopaminergic activity in a patient with temporal lobe epilepsy during a drug-free period, was significantly correlated with seizure frequency in the week immediately following, but not preceding, blood sampling days. This result suggests a compensatory function of the dopaminergic system in suppressing refractory psychic seizures.
Adult↗
A molecular variant of angiotensinogen associated with preeclampsia.
Pregnancy-induced hypertension (PIH) is a heterogeneous disorder which complicates 5-7% of all pregnancies and remains a leading cause of maternal, fetal and neonatal morbidity and mortality. Severe preeclampsia is the most distinctive and life-threatening form; a multi-system disorder more common in first pregnancies, it is characterized by high blood pressure and proteinuria. In a series of Caucasian women with pregnancy-induced hypertension, we have observed a significant association of preeclampsia with a molecular variant of angiotensinogen, T235, found previously to be associated with essential hypertension. This finding is corroborated in a sample ascertained in Japan. Together, these observations support a new pathophysiological interpretation of preeclampsia and of its relation to some forms of essential hypertension.
Angiotensinogen↗
Association of human herpesvirus 6 infection of the central nervous system with recurrence of febrile convulsions.
To determine the relationship of human herpesvirus-6 (HHV-6) infection to febrile convulsions, cerebrospinal fluid (CSF) from patients with a history of febrile convulsion were tested by polymerase chain reaction (PCR) amplification for HHV-6 DNA. HHV-6 DNA was detected in 9 of 10 samples from patients with exanthem subitum who showed neurologic symptoms. Also, 8 of 10 CSF samples from 8 patients who had three or more febrile convulsions and 1 of 7 CSF samples from patients who had a single febrile convulsion contained HHV-6 DNA. These data suggest that HHV-6 may invade the brain during the acute phase of exanthem subitum and that recurrence of febrile convulsions may be associated with reactivation of HHV-6.
Adolescent↗
Linkage analysis between familial myoclonus epilepsy and short arm of chromosome 6 using HLA phenotype as genetic marker.
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Adult↗
Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes.
A proband with chylomicronemia, pancreatitis, and non-insulin-dependent diabetes (NIDDM) bears two different mutations in exon 3 of the lipoprotein lipase (LPL) gene: a missense mutation, 75Arg-->Ser, inherited through the paternal line and a truncation, 73Tyr-->Ter, through the maternal line. NIDDM appeared to be independently segregating. The R75S mutant was studied in extracts and media from transfected COS-1 cells. Detectable amounts of catalytically competent R75S LPL suggested destabilization of the active homodimer as with exon 5 mutants (Hata et al. 1992. J. Biol. Chem. 267:20132-20139). Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II. Subjects with NIDDM and wild-type LPL, and nondiabetic middle-aged carriers of the 73Tyr-->Ter truncation had moderate hypertriglyceridemia (260-521 mg/dl) and reduced high density lipoprotein cholesterol. A maternal aunt with NIDDM carried the truncation. Her phenotype (triglycerides of 5,300 mg/dl, eruptive xanthomatosis, and recurrent pancreatitis) was as severe as that in homozygotes or compound heterozygotes. We conclude: (a) diabetic carriers of dysfunctional LPL alleles are at risk for severe lipemia; and (b) the physiologic defects in NIDDM may be additive or synergistic with heterozygous LPL deficiency.
Adolescent↗
Concentric left ventricular hypertrophy in patients with Takayasu arteritis.
Although aortic regurgitation (AR) in patients with Takayasu arteritis (TA) is believed to be caused by dilatation of the aortic ring or thickening of the aortic cusps, the pattern of left ventricular hypertrophy (LVH) in these patients has not been described. To clarify the geometry of the LV in patients with TA that had been documented both echocardiographically and hemodynamically, the authors evaluated 22 patients with TA and severe AR (group 1), 10 with TA and systemic hypertension (group 2), and 17 with isolated severe AR of other etiologies (group 3). M-mode echocardiography showed that LV dimensions were smaller in groups 1 and 2 than in group 3 and that wall thickness was greater in group 1 than in group 3. The concentric hypertrophic ratio (CHR = wall thickness/LV end-diastolic dimension+wall thickness) was larger than group 1 (p < 0.001) and group 2 (p < 0.01) than in group 3. CHR was similar in groups 1 and 2. Systolic blood pressure was significantly increased in group 2 and showed a tendency to increase in group 1 as compared with group 3. The results confirmed the presence of concentric LVH related to a pressure overload in patients with TA, even when TA was complicated by severe AR.
Adult↗
Missense mutations in exon 5 of the human lipoprotein lipase gene. Inactivation correlates with loss of dimerization.
Most missense mutations of the lipoprotein lipase (LPL) gene identified among LPL-deficient subjects cluster in a segment of the sequence that encodes the catalytic triad as well as functional elements involved in the activation of the lipase at lipid-water interfaces. Consequently, loss of activity may result either from direct alterations of such functional elements or from less specific effects on protein folding and stability. This issue was addressed by examining biochemical properties of four such variants (A176T, G188E, G195E, and S244T) in a heterologous expression system (COS-1 cells). Variant G195E (GGA----GAA) was previously unreported. In all instances, inactive enzyme was recovered in medium, albeit at reduced levels. Cellular synthesis and extracellular degradation were similar to those for wild type, suggesting that reduced secretion resulted from increased intracellular degradation. When cell extracts were subjected to heparin-Superose affinity chromatography followed by elution on a linear salt gradient, all variants exhibited a single, inactive, low affinity immunoreactive peak. By contrast, wild-type enzyme presented an additional, high affinity, active species, which we interpret as homodimeric enzyme. Substitution of the active-site serine (S132A) led to loss of activity but maintenance of the high affinity species. When large amounts of the G188E variant were applied to the column, small but significant amounts of high affinity, active enzyme were recovered. Systematic substitutions at residue 188 showed that only glycine could accommodate structural constraints at this position. We conclude that the mutations examined did not impart lipase deficiency by affecting specific functional elements of the enzyme. Rather, they appear to affect protein folding and stability, and thereby formation and maintenance of subunit assembly.
Adult↗
Transcriptional activation of the gene for the large subunit of human m-calpain by 12-o-tetradecanoyl-phorbol-13-acetate.
The effect of the treatment of HeLa cells with a tumor-promoting phorbol ester, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) on the expression of the genes for the calpain family has been examined. Among the mRNAs for the calpain family, only the mRNA for the large subunit of human m-calpain (calpain mL) was specifically induced by treatment of cells with TPA, suggesting its specific function in response to cellular stimuli. The effect of TPA on the expression of the calpain mL gene was further examined using fusion genes containing the promoter/enhancer region of the calpain mL gene fused upstream of the bacterial chloramphenicol acetyltransferase (CAT) gene, showing that the promoter/enhancer sequence of the calpain mL gene contains a cis-acting element which responds to TPA and activates transcription of the downstream sequence.
Calcium-Binding Proteins↗