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PubMed1993

p62cdc23 of Saccharomyces cerevisiae: a nuclear tetratricopeptide repeat protein with two mutable domains.

CDC23 is required in Saccharomyces cerevisiae for cell cycle progression through the G2/M transition. The CDC23 gene product contains tandem, imperfect repeats, termed tetratricopeptide repeats, (TPR) units common to a protein family that includes several other nuclear division CDC genes. In this report we have used mutagenesis to probe the functional significance of the TPR units within CDC23. Analysis of truncated derivatives indicates that the TPR block of CDC23 is necessary for the function or stability of the polypeptide. In-frame deletion of a single TPR unit within the repeat block proved sufficient to inactivate CDC23 in vivo, though this allele could rescue the temperature-sensitive defect of a cdc23 point mutant by intragenic complementation. By both in vitro and in vivo mutagenesis techniques, 17 thermolabile cdc23 alleles were produced and examined. Fourteen alleles contained single amino acid changes that were found to cluster within two distinct mutable domains, one of which encompasses the most canonical TPR unit found in CDC23. In addition, we have characterized CDC23 as a 62-kDa protein (p62cdc23) that is localized to the yeast nucleus. Our mutagenesis results suggest that TPR blocks form an essential domain within members of the TPR family.

Alleles↗

PubMed1989

Hemodynamic effects of endothelin in conscious rats.

The hemodynamic responses to endothelin, a recently isolated vasoconstrictor peptide, were determined in conscious rats with and without the three major known neurohumoral control systems. Rats (n = 6) were instrumented with arterial and venous catheters and an electromagnetic flow probe around the ascending aorta. Neurohumoral blockade was achieved with 10 mg/kg chlorisondamine, 0.5 mg/kg methscopolamine, 1 mg/kg captopril, and 10 micrograms/kg d(CH2)Tyr5(Me)AVP. Resting mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) in areflexic rats were restored to normal levels with a constant norepinephrine infusion. Endothelin was infused intravenously for 25 min in doses ranging from 0.01 to 1,000 ng.kg-1.min-1. Rats with intact reflexes did not respond significantly until a dose of 100 ng.kg-1.min-1 that increased MAP 20%, decreased CO 22% and increased TPR 58%. At a dose of 1,000 ng.kg-1.min-1 of endothelin (infused for 10 min), MAP increased 35%, CO decreased 66%, and TPR increased 303%. In areflexic rats, 1 ng.kg-1.min-1 of endothelin caused significant increases in MAP (14%), small decreases in CO (-5%), and a 20% increase in TPR. At a dose of 10 ng.kg-1.min-1, MAP increased 17%, CO decreased 3%, and TPR increased 21%; at 100 ng.kg-1.min-1, MAP increased 40%, CO decreased 13%, and TPR increased 67%; at 1,000 ng.kg-1.min-1, MAP increased 48%, CO decreased 61%, and TPR increased 319%. The pressor effects of endothelin were therefore significantly buffered by neurohumoral systems; however, the decreases in CO caused by high doses of endothelin were independent of neurohumoral control.

Animals↗

PubMedDate not supplied

Hemodynamic response: decrease in cardiac output vs reduction in vascular resistance.

From a hemodynamic point of view, an adequate response to antihypertensive therapy would be restoration of a normal circulatory system. In most patients with mild to moderate essential hypertension considered to need drug therapy, the cardinal hemodynamic disturbance is an increased total peripheral resistance (TPR) and a normal or reduced cardiac output (CO). During a 10- to 17-year follow-up of untreated hypertensives, a gradual increase in TPR, increase in MAP, and a decrease in CO and stroke volume (SV) were seen. Hemodynamic responses to chronic drug therapy were studied at rest and during exercise in 250 men with mild to moderate essential hypertension in WHO Stage I. A significant reduction in TPR was seen on thiazide diuretics, nifedipine and verapamil, but there was no increase of subnormal CO or SV. A greater normalization of central hemodynamics was achieved by prazosin, which induced a reduction in TPR and an increase in CO and SV, particularly during exercise. In contrast, beta-blocker therapy was associated with a chronic reduction in CO and heart rate (HR) and usually no reduction in TPRI below pretreatment values. The chronic CO reduction was associated with an increase in arteriovenous oxygen difference. In 14 patients with therapy-resistant hypertension, a marked increase in TPR was found. Captopril induced a reduction in TPR with rest and exercise, and also a reduction in cardiac output. Prolonged therapy for 5 years with beta-blockers did maintain blood pressure control, but with no further decrease in TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗

PubMedDate not supplied

A meta-analytic method for summarizing diagnostic test performances: receiver-operating-characteristic-summary point estimates.

The authors have devised a meta-analytic method to summarize diagnostic test performances, which they describe along with a clinical example wherein they analyze the performances of real-time ultrasonography in eight studies of the detection of proximal deep venous thrombosis of the lower extremity, selected on the basis of specific inclusion criteria. To evaluate the evidence for fitting a summary receiver operating characteristic (ROC) curve, a test of correlation between the estimates of true-positive rate (TPR) and false-positive rate (FPR) is performed. A high positive correlation argues for summarizing the studies with an ROC curve. In the absence of such correlation, a test of homogeneity is applied separately to the estimates of sensitivity (TPR) and specificity (TNR) to evaluate whether differences among studies are due to chance alone. If the estimates are homogeneous, a summary point estimate and confidence intervals (CIs) are calculated. As a final step, subgroup analyses can be performed to assess alternative explanations of variability in TPR and FPR. Within groups defined by the presence or absence of symptoms of venous thrombosis, a negative correlation between TPR and FPR and homogeneity among studies were found. For symptomatic patients, the summary TPR was 0.97 with a 95% CI of (0.94, 0.99) and the summary TNR was 0.97 (0.95, 0.99). For asymptomatic patients, the summary TPR was 0.66 (0.50, 0.81), and the summary TNR was 0.96 (0.90, 0.99). The difference in TPR between symptomatic and asymptomatic patients was statistically significant. There was no evidence that test referral bias or lack of independent interpretation of test results influenced these findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Confidence Intervals↗

PubMed2006

[A novel method of the genome-wide prediction for the target genes and its application].

Based on the protein databases of several model species, this study developed a new method of the Genome-wide prediction for the target genes, using Hidden Markov model by Perl programming. The advantages of this method are high throughput, high quality and easy prediction, especially in the case of multi-domains proteins families. By this method, we predicted the PPR and TPR proteins families in whole genome of several model species. There were 536 PPR proteins and 199 TPR proteins in Oryza sativa ssp. japonica, 519 PPR proteins and 177 TPR proteins in Oryza sativa L. ssp. indica, 735 PPR proteins and 292 TPR proteins in Arabidopsis thaliana, 6 PPR proteins and 32 TPR proteins in Cyanidioschyzon merolae. Synechococcus and Thermophilic archaebacterium did not have PPR proteins. By contrast, 10 TPR proteins were found in Synechococcus and 4 TPR proteins were found in Thermophilic archaebacterium. Moreover, of these results, some further bioinformatics analyses were conducted.

Bacterial Proteins↗

PubMed2026

Impact of spatial distribution of M2 macrophages on prognosis and neoadjuvant chemotherapy resistance in gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a crucial treatment for locally advanced gastric cancer; however, approximately 30-40% of patients experience primary resistance, the mechanisms of which urgently require elucidation. The tumor microenvironment exhibits a high degree of spatial heterogeneity. M2 macrophages, as critical immune cells within this environment, are typically associated with poor prognosis. Yet, whether their spatial distribution impacts chemotherapy efficacy remains unclear. This study aims to investigate the relationship between the in situ spatial distribution characteristics of M2 macrophages and chemoresistance in gastric cancer. METHODS: Based on The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort, the association between M2 markers (CD163, MRC1) and histological grade as well as overall survival (OS) was evaluated. Spearman correlation and functional enrichment analyses were conducted to explore the mechanistic link between M2 macrophages and stromal barrier construction. Multiplex immunofluorescence (mIF) and digital pathology image analysis were utilized to calculate the areal density of M2 macrophages in the intratumoral core and the peritumoral stroma, respectively. The tumor-to-peritumoral ratio (TPR) was constructed, followed by a rank correlation analysis between TPR and the tumor regression grade (TRG). RESULTS: TCGA-STAD results confirmed that patients with high expression of M2 markers had worse OS (P=0.03), and the expression levels of M2 markers increased with histological grade. MRC1 was highly significantly and positively correlated with the pro-fibrotic factor TGFB1 (rho=0.447, P<0.001), with the gene set significantly enriched in pathways such as positive regulation of cytokine production and myeloid leukocyte activation. Histological examination revealed that in chemoresistant patients (TRG 3), M2 macrophages were primarily retained in the peritumoral stroma, with a median TPR of 0.50; in chemosensitive patients (TRG 1-2), a massive influx of M2 macrophages into the tumor core was observed, with a median TPR of 6.67. TPR was negatively correlated with TRG (rs=-0.65, P=0.043). CONCLUSIONS: The clinical impact of M2 macrophages in the gastric cancer microenvironment is highly dependent on their spatial distribution. The peritumoral-enriched pattern (TPR <1) mediates primary chemoresistance, whereas high infiltration in the core objectively reflects the pathological footprint following effective chemotherapy. The TPR serves as a novel tool for assessing neoadjuvant chemosensitivity in gastric cancer.

Gastric cancer (GC)↗

PubMed1992

Terminal aortic response to sodium intake is the major determinant of total peripheral resistance in elderly hypertensives.

Thirty-four elderly patients were studied using a Doppler flowmeter during different sodium intakes. Salt increased mean blood pressure and cardiac output (CO), while total peripheral resistance (TPR) remained unchanged. Neither carotid nor terminal aortic resistance changed, while coeliac, superior mesenteric or renal resistance increased. There was a significant and direct correlation (r = 0.82) between the change in TPR and that in terminal aortic resistance. Salt-sensitive patients were divided into two subgroups; the SST group in which sodium loading increased TPR more than CO, and the SSC group in which salt loading increased CO more than TPR. Terminal aortic resistance increased in the SST, decreased in the SSC, and remained unchanged in the non-salt-sensitive group with salt loading. The terminal aortic vascular bed received much of the increase of CO in the SSC patients. In the SST group, the contribution of the individual vascular area to increased TPR was assessed, which revealed that terminal aortic response to sodium loading was the major determinant of increased TPR. We concluded that the responses of terminal aortic vascular bed to sodium loading contributed to the changes in TPR.

Aged↗

PubMed1999

The tetratricopeptide repeat: a structural motif mediating protein-protein interactions.

The tetratricopeptide repeat (TPR) motif is a protein-protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three-dimensional structural data have shown that a TPR motif contains two antiparallel alpha-helices such that tandem arrays of TPR motifs generate a right-handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, and there is extensive evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein-protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932-939.

Amino Acid Sequence↗

PubMed1993

A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers.

A physiologically based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intravenous (iv) dihydropyridine drugs in healthy volunteers. This model incorporates a limited number of hemodynamic variables, namely, mean arterial blood pressure (MAP), cardiac output (CO) or heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR), into a closed-loop system supposed to represent essential features of the cardiovascular regulation. We also defined an additional auxiliary control variable (U) which is thought to represent primarily the role of the baroreceptor reflex. It was assumed that the variable U was related to MAP changes through both deviation- and rate-sensitive mechanisms. Other model parameters are the baseline levels for MAP, CO (or HR), and TPR, as well as time constants to account for further temporal aspects of the regulation. Finally, TPR was assumed to be linked to the plasma concentrations of dihydropyridine drugs via a conventional pharmacokinetic/pharmacodynamic (PK/PD) model, relying upon an effect compartment and a linear, hyperbolic, or sigmoidal relationship between the reduction in TPR and the drug concentrations at the effect site. The model characteristics were explored by studying the influence of various parameters, including baseline levels and deviation- and rate-sensitive control parameters, on the hemodynamic responses to a fictive constant rate i.v. infusion of a vasodilator drug. Attempts were also made to mimic literature data with nifedipine, following i.v. administration under both constant and exponentially decreasing infusion rates. The applicability of the model was demonstrated by fitting hemodynamic data following i.v. infusion of nicardipine to healthy volunteers, under experimental conditions similar to those described above for nifedipine. The effect model for the action of nicardipine on TPR, combined with the physiological model including a feedback control loop, allowed an adequate quantitative description of time profiles for both cardiac output and mean arterial pressure. The suggested model is a useful tool for integrated data analysis of hemodynamic responses to vasodilator drugs in healthy volunteers. Computer simulations suggest that a graded variation of a few model parameters--including baseline levels of TPR and MAP and the deviation-sensitive parameter of the arterial pressure control--would also be able to account for the pattern of hemodynamic response observed in hypertensive patients, which is qualitatively different to that seen in normotensive subjects. Extrapolation of drug response from the healthy volunteer to the hypertensive patient is allowed by our model. Its usefulness for an early evaluation of drug efficacy during drug development is under current investigation.

Adult↗

PubMed2002

Haemodynamic responses during head-up tilt and tilt reversal in two groups with chronic autonomic failure: pure autonomic failure and multiple system atrophy.

Continuous haemodynamic responses to head-up tilt (HUT) and its reversal were studied in 21 subjects with sympathetic denervation due to primary chronic autonomic failure; 10 had pure autonomic failure (PAF; peripheral failure) and 11 had multiple system atrophy (MSA; central failure); 8 healthy subjects (controls) also were studied. Supine systolic, diastolic and mean arterial pressure (MAP) and total peripheral resistance (TPR) were highest in PAF. The MAP response to HUT and tilt reversal were different between groups. After HUT, MAP increased in controls (12+/-4 mmHg), but decreased in PAF and MSA (41+/-4 & 19+/-4 mmHg respectively); the fall in PAF was greater than in MSA. With tilt reversal, MAP returned promptly, but not entirely to pretilt levels in controls, with small (insignificant) overshoots in MSA and PAF. The TPR response to HUT and tilt reversal was different between groups. After HUT, TPR increased in controls (0.31+/-0.04 PRU), decreased in PAF (0.23+/-0.1 PRU) and was unchanged in MSA. With tilt reversal, TPR remained elevated (15 %) above baseline in the controls and rose in PAF (13 %) with no change in MSA. There were no differences in supine heart rate (HR), stroke volume (SV) or cardiac output (CO) between the three groups; HR, SV or CO responses to HUT or tilt reversal also did not differ between the groups. Thus, after HUT, MAP decreased, with greater hypotension induced in PAF than MSA. Since CO did not differ between groups, the decrease in TPR appears to account for the greater fall in BP in PAF than in MSA. The elevated TPR at rest pre-tilt and after tilt reversal probably contributed to supine hypertension in PAF. These haemodynamic observations may aid therapeutic strategies to reduce orthostatic hypotension and prevent supine hypertension.

Aged↗

PubMed2004

Subfamily I Treponema pallidum repeat protein family: sequence variation and immunity.

A 12-membered Treponema pallidum repeat (Tpr) protein family has been identified in T. pallidum subsp. pallidum, the causative agent of syphilis. The subfamily I Tpr proteins (C, D, F, and I) possess conserved sequence at the N- and C-termini and central regions that differentiate the members. These proteins may be important in the immune response during syphilis infection and in protective immunity. Strong antibody responses have been observed toward some of the subfamily I Tpr proteins during infection with different syphilis isolates. Some sequence variation has also been identified in one subfamily I Tpr member, TprD, among T. pallidum subsp. pallidum isolates. In this study, we examined sequences in the remaining subfamily I Tpr proteins among strains. Both TprF and TprI were conserved among T. pallidum subsp. pallidum isolates. While some heterogeneity was identified in TprC. We further examined the immune response and protective capacity of TprF protein in this paper. We demonstrate that the N-terminal conserved region of the subfamily I Tpr proteins elicits strong antibody and T-cell responses during infection, and immunization with this region attenuates syphilitic lesion development upon infectious challenge.

Amino Acid Sequence↗

PubMed2001

Different combinations of the heat-shock cognate protein 70 (hsc70) C-terminal functional groups are utilized to interact with distinct tetratricopeptide repeat-containing proteins.

A group of tetratricopeptide repeat (TPR)-containing proteins has been shown to interact with the C-terminal domain of the 70 kDa heat-shock cognate protein (hsc70). In the present study, the effect of the TPR-containing proteins, including the C-terminus of hsc70-interacting protein (CHIP), TPR1 and human glutamine-rich TPR-containing protein (hSGT), on refolding of luciferase by DnaJ and hsc70 was investigated. These proteins inhibited the restoration of luciferase activity by the chaperones. The inhibitory effect exerted by TPR1 and hSGT depended upon their binding to hsc70. However, the interaction with hsc70 did not appear to be required for the inhibition of luciferase refolding by CHIP. We also demonstrate that the peptide, GPTIEEVD, corresponding to the C-terminal end of hsc70, abolished the association of [(3)H]hsc70 with CHIP, TPR1 and hSGT. This implied that the GPTIEEVD motif of hsc70 was responsible for interacting with these TPR-containing proteins. However, the GGXP-repeats (where X is any aliphatic residue), another C-terminal conserved motif of vertebrate hsc70s, were not essential for interacting with the TPR-containing proteins. On the basis of mutagenesis studies, it was clear that a unique combination of the functional groups in the GPTIEEVD motif were utilized to interact with each TPR-containing protein, suggesting that inhibitors can be designed and used to elucidate the functional role of these interactions.

Amino Acid Motifs↗

PubMed2006

Transanal coloanal anastomosis for Hirschsprung's disease: comparison between endorectal and perirectal pull-through procedures.

BACKGROUND/PURPOSE: The aim of this study was to compare the results of 2 procedures of transanal pull-through for the management of rectosigmoid Hirschsprung's disease. METHODS: Twenty-one consecutive children with rectal or rectosigmoid Hirschsprung's disease were operated on between November 1999 and April 2003, in two pediatric surgical departments (Dijon and Strasbourg). Twelve children underwent a transanal perirectal pull-through procedure (TPR) and 9 had a transanal endorectal (Soave) pull-through procedure (TER). The collected data in each group included demographic data, length of aganglionosis, age and weight at operation, operating time, duration of hospital stay, incidence of postoperative complications (sepsis, enterocolitis, stricture) and quality of fecal continence on long-term follow-up. RESULTS: No significant differences were observed between the TPR and TER groups with respect to mean age at presentation, length of aganglionosis (rectosigmoid in 10/12 and 8/9 patients respectively), age at operation, with seventeen children operated on before one year of age (mean 3.8 and 3.3 months, respectively) and duration of hospital stay (5.2 vs. 5.3 days), frequency of bowel movements at 3 months postoperatively (1 - 3 per day). Mild differences were observed between TPR and TER groups for gender (ratio M : F 5 : 1 vs. 2 : 1), gestational age at term (39 vs. 37.5 weeks), birth weight (3240 g vs. 2520 g) and operating time (116 min vs. 138 min). No iatrogenic injury of the surrounding pelvic structures occurred during surgery and no blood transfusion was required in either of the groups. A retrorectal pelvic abscess was found in one child of the TPR group. It resolved after an enterostomy had been performed with parenteral antibiotics. Anal dilatation for postoperative anorectal stricture was required in 3 and 2 patients, respectively, for the TPR and TER groups. A mild postoperative enterocolitis developed in one case in the TER group. The average follow-up period was 35.3 months, but ten children still wear diapers, making a functional evaluation difficult. Constipation was noted in 4 and 3 patients, respectively, for the TPR and TER groups. No permanent soiling has been noted at long-term follow-up. CONCLUSION: As an objective assessment of fecal continence could not yet be done for this short series, further follow-up is required. Up to now, no significant difference was observed between these two transanal pull-through procedures.

Anal Canal↗

PubMed2006

Rac GTPase signaling through the PP5 protein phosphatase.

We have investigated the Rac-dependent mechanism of KCNH2 channel stimulation by thyroid hormone in a rat pituitary cell line, GH(4)C(1), with the patch-clamp technique. Here we present physiological evidence for the protein serine/threonine phosphatase, PP5, as an effector of Rac GTPase signaling. We also propose and test a specific molecular mechanism for PP5 stimulation by Rac-GTP. Inhibition of PP5 with the microbial toxin, okadaic acid, blocked channel stimulation by thyroid hormone and by Rac, but signaling was restored by expression of a toxin-insensitive mutant of PP5, Y451A, which we engineered. PP5 is unique among protein phosphatases in that it contains an N-terminal regulatory domain with three tetratricopeptide repeats (TPR) that inhibit its activity. Expression of the TPR domain coupled to GFP blocked channel stimulation by the thyroid hormone. We also show that the published structures of the PP5 TPR domain and the TPR domain of p67, the Rac-binding subunit of NADPH oxidase, superimpose over 92 alpha carbons. Mutation of the PP5 TPR domain at two predicted contact points with Rac-GTP prevents the TPR domain from functioning as a dominant negative and blocks the ability of Y451A to rescue signaling in the presence of okadaic acid. PP5 stimulation by Rac provides a unique molecular mechanism for the antagonism of Rho-dependent signaling through protein kinases in many cellular processes, including metastasis, immune cell chemotaxis, and neuronal development.

Amino Acid Sequence↗

PubMed1998

Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90.

The molecular chaperone hsp90 in the eukaryotic cytosol interacts with a variety of protein cofactors. Several of these cofactors have protein domains containing tetratricopeptide repeat (TPR) motifs, which mediate binding to hsp90. Using a yeast two-hybrid screen, the 12-kDa C-terminal domain of human hsp90alpha (C90) was found to mediate the interaction of hsp90 with TPR-containing sequences from the hsp90 cofactors FKBP51/54 and FKBP52. In addition, the mitochondrial outer membrane protein hTOM34p was identified as a TPR-containing putative partner protein of hsp90. In experiments with purified proteins, the TPR-containing cofactor p60 (Hop) was shown to form stable complexes with hsp90. A deletion mutant of hsp90 lacking the C90 domain was unable to bind p60, whereas deletion of the approximately 25-kDa N-terminal domain of hsp90 did not affect complex formation. Both p60 and FKBP52 bound specifically to the C90 domain fused to glutathione S-transferase and competed with each other for binding. In reticulocyte lysate, the C90 fusion protein recognized the TPR proteins p60, FKBP52, and Cyp40. Thus, our results identify the C90 domain as the specific binding site for a set of hsp90 cofactors having TPR domains.

Animals↗

PubMed2002

A structure-based mutational analysis of cyclophilin 40 identifies key residues in the core tetratricopeptide repeat domain that mediate binding to Hsp90.

Cyclophilin 40 (CyP40) is a tetratricopeptide repeat (TPR)-containing immunophilin and a modulator of steroid receptor function through its binding to heat shock protein 90 (Hsp90). Critical to this binding are the carboxyl-terminal MEEVD motif of Hsp90 and the TPR domain of CyP40. Two different models of the CyP40-MEEVD peptide interaction were used as the basis for a comprehensive mutational analysis of the Hsp90-interacting domain of CyP40. Using a carboxyl-terminal CyP40 construct as template, 24 amino acids from the TPR and flanking acidic and basic domains were individually mutated by site-directed mutagenesis, and the mutants were coexpressed in yeast with a carboxyl-terminal Hsp90beta construct and qualitatively assessed for binding using a beta-galactosidase filter assay. For quantitative assessment, mutants were expressed as glutathione S-transferase fusion proteins and assayed for binding to carboxyl-terminal Hsp90beta using conventional pulldown and enzyme-linked immunosorbent assay microtiter plate assays. Collectively, the models predict that the following TPR residues help define a binding groove for the MEEVD peptide: Lys-227, Asn-231, Phe-234, Ser-274, Asn-278, Lys-308, and Arg-312. Mutational analysis identified five of these residues (Lys-227, Asn-231, Asn-278, Lys-308, and Arg-312) as essential for Hsp90 binding. The other two residues (Phe-234 and Ser-274) and another three TPR domain residues not definitively associated with the binding groove (Leu-284, Lys-285, and Asp-329) are required for efficient Hsp90 binding. These data confirm the critical importance of the MEEVD binding groove in CyP40 for Hsp90 recognition and reveal that additional charged and hydrophobic residues within the CyP40 TPR domain are required for Hsp90 binding.

Amino Acid Motifs↗

PubMed1997

Activation of the JNK pathway is essential for transformation by the Met oncogene.

The Met/Hepatocyte Growth Factor (HGF) receptor tyrosine kinase is oncogenically activated through a rearrangement that creates a hybrid gene Tpr-Met. The resultant chimeric p65(Tpr-Met) protein is constitutively phosphorylated on tyrosine residues in vivo and associates with a number of SH2-containing signaling molecules including the p85 subunit of PI-3 kinase and the Grb2 adaptor protein, which couples receptor tyrosine kinases to the Ras signaling pathway. Mutation of the binding site for Grb2 impairs the ability of Tpr-Met oncoprotein to transform fibroblasts, suggesting that the activation of the Ras/MAP kinase signaling pathway through Grb2 may be essential for cellular transformation. To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts. Cells overexpressing the mutants were found to be morphologically reverted and exhibited reduced growth in soft agar. Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein. Additionally, cells expressing dominant-negative Grb2 mutants had reduced PI-3-kinase activity and dominant-negative mutants of Rac1 blocked both Tpr-Met-induced transformation and activation of JNK. These experiments reveal a novel link between Met and the JNK pathway, which is essential for transformation by this oncogene.

Adaptor Proteins, Signal Transducing↗

PubMed1983

Systemic and regional haemodynamic effects of renal denervation in spontaneously hypertensive rats.

Systemic and regional haemodynamic effects of renal denervation were evaluated in adult (six-month-old) male spontaneously hypertensive rats (SHR) using the Fick procedure and electromagnetic flowmetry technique. Renal denervation (bilateral, 10% phenol in ethanol), performed five to eight days before the experiment, resulted in a significant decrease (-12%) in arterial pressure in conscious SHR (denervated = 182 +/- 4 versus sham = 207 +/- 8 mmHg, P less than 0.05) that was associated with a reduction in total peripheral resistance (TPR: denervated = 1.83 +/- 0.19 versus sham = 2.78 +/- 0.29 mmHg/ml/min, P less than 0.05) and an increase in cardiac output (denervated = 106 +/- 10 versus sham = 80 +/- 9 ml/min, P less than 0.05). Heart rate was not different between the two groups. Renal, hindquarter and superior mesenteric blood flows, determined under pentobarbital anaesthesia, of denervated SHR were not significantly different from sham values. Renal vascular resistance (mmHg/ml/min) was substantially reduced (-39%) in the denervated SHR (denervated = 25.1 +/- 1.86 versus sham = 41.1 +/- 3.48, P less than 0.01), but vascular resistances in the hindquarter and superior mesenteric beds were not reduced significantly. In this preparation TPR was reduced 32% in denervated SHR. The data demonstrate that renal denervation in adult SHR proves an antihypertensive vasodilator-like effect related to a decrease in TPR with increased cardiac output. The reduction in renal vascular resistance in denervated SHR may produce a major contribution to decreased TPR. Other beds may also contribute to the decrease in TPR, although to a lesser extent, since the decrease in TPR cannot be fully accounted for by decreased renal vascular resistance.

Animals↗