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Y Kato

Publications and source records attributed to Y Kato.

At least 181 records · Page 10Linked to original sources
PubMed2001

Cisplatin-loaded polymer-metal complex micelle with time-modulated decaying property as a novel drug delivery system.

PURPOSE: The pharmacological activity and pharmacokinetics of cisplatin (CDDP)-loaded polymeric micelles were examined to reveal their usefulness as a novel tumor-directed drug carrier system of CDDP. METHODS: In biodistribution assay, free CDDP or CDDP-loaded micelles were administered intravenously to Lewis lung carcinoma-bearing mice. Antitumor activity and nephrotoxicity were respectively evaluated by the measurement of tumor size and plasma blood urea nitrogen (BUN) after single bolus i.v. administration of each drug. RESULTS: The time profile of the plasma Pt level after the injection of the micelles exhibited a time-modulated disappearance as observed in saline in vitro. The micelles exhibited 5.2- and 4.6-fold higher AUC of Pt in the plasma and tumor, respectively, with minimal change in the kidney, in comparison with free CDDP, suggesting that prolonged circulation of Pt in circulation and specific accumulation in the tumor were achieved utilizing the micellar drug carrier system. Administration of the micelles at the dose exhibiting antitumor activity similar to free CDDP did not increase the plasma BUN, whereas free CDDP induced its remarkable increase. CONCLUSION: CDDP-loaded micelles restrained nephrotoxicity, which is the dose-limiting factor of CDDP, while exhibiting tumor-specific accumulation. Thus, CDDP-loaded micelles are expected to be a novel formulation of CDDP for clinical use.

Animals↗
PubMed2001

A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans: the mechanism for tumor-selective accumulation of 5-FU.

PURPOSE: To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. METHOD: The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations. RESULTS: The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges. CONCLUSIONS: It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.

Antimetabolites, Antineoplastic↗
PubMed2001

Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers.

PURPOSE: Insulin-like growth factor 1 (IGF-1) is predominantly bound to its specific binding proteins (IGFBPs) in circulating plasma. In the present study, pharmacokinetic analysis of IGF-1 was performed in healthy volunteers to characterize the effect of interactions with IGFBPs on IGF-1 disposition. METHODS: Plasma concentration profiles of both free and bound IGF-1 were examined at several doses. An in vitro plasma protein binding was also analyzed. RESULTS: The total body clearance (CLtotal) for the free IGF-1 was much higher than the creatinine clearance, suggesting that the major elimination pathway is by a route other than renal glomerular filtration. The CLtotal for the free IGF-1 exhibited a dose-dependent reduction whereas that for the sum of unbound and bound IGF-1 increased on increasing the dose. The data obtained fitted closely a one-compartment model that involved the binding and dissociation of IGF-1, as well as its biosynthesis and elimination. The estimated parameters suggest that IGF-1 exhibits high affinity binding to IGFBPs. the rate-limiting step in the overall elimination being the dissociation from IGFBPs. CONCLUSIONS: The saturation of both the plasma protein binding and elimination accounts for the nonlinear pharmacokinetic profile. The binding to IGFBPs markedly limits both the distribution and elimination of IGF-1.

Adult↗
PubMed2001

Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2).

PURPOSE: Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. METHODS: We examined the inhibitory effect of MTX and 24 analogs on the transport of [3H]-S-(2,4-dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The primary active transport of several compounds was also confirmed. RESULTS: The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. CONCLUSIONS: Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so-called "molecular weight threshold" for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.

Adenosine Triphosphate↗
PubMed2001

Enamel matrix derivative (EMDOGAIN) rapidly stimulates phosphorylation of the MAP kinase family and nuclear accumulation of smad2 in both oral epithelial and fibroblastic human cells.

In our previous study, we demonstrated that porcine enamel matrix derivative (EMD) induces p21WAF1/cip1 within 8 hours and subsequently arrests the cell cycle of human oral epithelial cells in G1 phase. In contrast, EMD markedly stimulates the proliferation of gingival fibroblasts without inducing p21WAF1/cip1. To investigate the mechanism of how EMD produces these differential effects, we have focused on the initial response of these two cell types to EMD. In epithelial cell cultures, EMD stimulated cytoskeletal actin polymerization within 30 min and promoted cell adhesion in our experimental system. EMD failed to stimulate either intracellular Ca2+ mobilization or cAMP production in either cell type. In both epithelial and fibroblastic cells, EMD (25-100 microgram/ml) rapidly produced dose-dependent phosphorylation of the mitogen-activated protein kinase (MAPK) family: extracellular signal response kinase (ERK), p38-MAPK (p38-K), and c-Jun-terminal kinase/stress-activated protein kinase (JNK). However, neither inhibitors of MEK (ERK kinase) nor p38-K could block EMD's anti-proliferative action on epithelial cells. On the other hand, EMD rapidly stimulated translocation of smad2 into the nucleus in both cell types. Spurred by this finding, we assayed for TGF-beta1, a ligand for one receptor associated with smad2 activation, and detected significant levels in EMD preparations. The sum of these pharmacological findings indicates that EMD contains at least one bioactive factor, which is most probably TGF-beta1 (or TGF-beta-like substances). In conjunction with the similarities in the differential growth-modulating actions between EMD and what is known for TGF-beta, we suggest that TGF-beta might act as the principal growth regulating agent of oral fibroblastic and epithelial cell types in EMD despite being present in only low levels.

Actins↗
PubMed2001

Correlation of sodium-related factors with insulin sensitivity in young, lean, male offspring of hypertensive and normotensive subjects.

Pioneer studies have proposed that multiple metabolic abnormalities, such as insulin resistance, increased Na(+)-H(+) exchanger activity and abnormal intracellular calcium homeostasis, are frequently associated with a subset of essential hypertensive patients with low plasma renin activity (PRA). However, it is unclear whether insulin resistance is related to the low renin status in the very early phase of genetical hypertension. Besides, there is controversy on the subject of the in vivo effect of acute hyperinsulinaemia on sodium-related factors. We investigated the relationship between sodium-related parameters and insulin sensitivity, and the effects of euglycaemic hyperinsulinaemia on cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) levels in 17 young, lean, normotensive male subjects, who displayed extreme predispositions for the development of hypertension. PRA was significantly lower in the positive than in the negative family history group (P < 0.05). Insulin sensitivity (M-value) was correlated with PRA before euglycaemic hyperinsulinaemic clamping (r = 0.577, P < 0.05), and was also inversely correlated with fractional excretion of sodium (FE(Na)) before clamping (r = -0.51, P < 0.05). Euglycaemic hyperinsulinaemia significantly decreased PRA (P < 0.0001) and increased cGMP (P < 0.05) and ANP levels (P < 0.01). In conclusion, insulin sensitivity may be partially determined by PRA levels and FE(Na) before clamping in young, lean, normotensive male subjects. Acute euglycaemic hyperinsulinaemia decreases PRA, and increases cGMP and ANP levels from the fasting condition.

Adult↗
PubMed2001

Spontaneous regression of multiple seborrheic keratoses associated with nasal carcinoma.

Seborrheic keratoses are very common epidermal neoplasms. We describe a patient with seborrheic keratoses presenting multifocal spontaneous regression. The patient had a concurrent nasal adenoid cystic carcinoma. The simultaneous regression of seborrheic keratoses ceased after total resection of the nasal carcinoma. Histological examination revealed marked infiltration of mononuclear cells, including CD4+, CD8+, CD68+ and cutaneous lymphocyte-associated antigen-positive cells, with profound accumulation of CD1a+ dendritic cells. Although apoptotic keratinocytes were not found in the lesional epidermis by histology, the majority of keratinocytes in the regressing seborrheic keratosis were positively stained by the TUNEL method. We postulate that the internal malignancy may induce spontaneous regression of seborrheic keratoses.

Aged↗
PubMed2001

Serum antibodies to human pituitary membrane antigens in patients with autoimmune lymphocytic hypophysitis and infundibuloneurohypophysitis.

OBJECTIVE: Serum antipituitary antibodies were investigated by the immunoblotting method using human anterior pituitary membrane preparation as the antigen. PATIENTS: Thirteen patients with autoimmune lymphocytic hypophysitis, two patients with infundibuloneurohypophysitis, four patients with isolated ACTH deficiency, 21 patients with diabetes mellitus (type 1 and type 2) and 38 healthy subjects were studied. METHODS: Human pituitary membrane antigens were electrophoresed by sodium dodecylsulphate-polyacrimide gel electrophoresis (SDS-PAGE). The antigens were transferred to polyvinylidene difluoride membrane and reacted with the sera followed by incubation with biotinylated anti-human IgG goat serum. RESULTS: Serum antibodies to 68, 49, 43 kD human pituitary membrane antigens were detected in five of 13, one of 12 patients with infundibuloneurohypophysitis and none of four patients with isolated ACTH deficiency. These antibodies were not detectable when human thyroid, liver or rat pituitary preparations were used as the antigen. CONCLUSION: These findings suggest that serum antibodies to 68, 49, 43 kD human anterior pituitary antigen are specific but not so frequently detected in autoimmune lymphocytic hypophysitis.

Adrenocorticotropic Hormone↗
PubMed2001

Effect of long-term administration of recombinant human growth hormone (rhGH) on plasma erythropoietin (EPO) and haemoglobin levels in anaemic patients with adult GH deficiency.

OBJECTIVE: We investigated the effect of recombinant human GH (rhGH) on erythropoietin (EPO) and haemoglobin (Hb) concentrations in anaemic patients with adult GH deficiency. PATIENTS AND DESIGN: rhGH was administrated in 8 patients with adult GH deficiency, three males and five females, aged from 24 to 69 years, mean (+/- SD) of 48.8 +/- 16.4 years, for 1 year by means of continuous subcutaneous infusion (CSI) at a flow rate of 0.036 U/kg/day using a portable syringe pump. Blood samples were obtained in the morning after an overnight fast every week for 1 month, followed by each month before and after the start of rhGH administration. RESULTS: Mean (+/- SE) plasma GH levels increased from 0.24 +/- 0.09 microg/l to 2.32 +/- 0.23 microg/l 1 week after the start of rhGH administration to maintain a steady state. Plasma IGF-I levels increased from 70.1 +/- 13.8 microg/l to 282.8 +/- 70.6 microg/l 1 week after the start of rhGH administration to maintain the steady state. Plasma EPO levels increased from 25.9 +/- 2.6 IU/l to 37.6 +/- 4.2 IU/l and 34.3 +/- 3.6 IU/l at 1 week and 2 weeks after the start of rhGH administration, respectively, and then decreased gradually to 14-9 +/- 2.1 IU/l at 10 months after the start of rhGH administration. Reticulocyte counts increased from 0.88 +/- 0.06% to 1.49 +/- 0.21% at 1 week. Hb concentrations increased from 103 +/- 5 g/l to 106 +/- 5 g/l at 2 weeks after the start of rhGH administration, and then increased gradually to reach the normal range. CONCLUSIONS: We conclude that EPO secretion was stimulated in the initial 2 weeks after the start of CSI of rhGH in anaemic patients with adult GH deficiency. Increased Hb concentrations after long-term administration of rhGH might be explained by direct stimulatory effects of rhGH and IGF-I on erythroid cells, which was accompanied by suppressed EPO secretion, in combination with a more generalized indirect impact of rhGH on physical activety. These findings suggest a beneficial effect of rhGH replacement in anaemic patients with adult GH deficiency.

Adult↗
PubMed2001

Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling.

BACKGROUND: Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-alpha/beta signalling complex, generated by spontaneously produced IFN-alpha/beta, in efficient IFN-gamma signalling. RESULTS: In the present study, we have demonstrated that the IFN-alpha/beta signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-alpha/beta signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-alpha/beta stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. CONCLUSIONS: The constitutive weak IFN-alpha/beta signal provides a foundation for strong cellular responses to IL-6, IFN-gamma, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a 'receptosome'-like structure, allowing the unique signalling cross talks to occur.

Animals↗
PubMed2001

Structure and promoter analysis of the mouse membrane-bound transferrin-like protein (MTf) gene.

Recently, we purified membrane-bound transferrin-like protein (MTf) from the plasma membrane of rabbit chondrocytes and showed that the expression levels of MTf protein and mRNA were much higher in cartilage than in other tissues [Kawamoto T, Pan, H., Yan, W., Ishida, H., Usui, E., Oda, R., Nakamasu, K., Noshiro, M., Kawashima-Ohya, Y., Fujii, M., Shintani, H., Okada, Y. & Kato, Y. (1998) Eur. J. Biochem. 256, 503--509]. In this study, we isolated the MTf gene from a constructed mouse genomic library. The mouse MTf gene was encoded by a single-copy gene spanning approximately 26 kb and consisting of 16 exons. The transcription-initiation site was located 157 bp upstream from the translation-start codon, and a TATA box was not found in the 5' flanking region. The mouse MTf gene was mapped on the B3 band of chromosome 16 by fluorescence in situ hybridization. Using primary chondrocytes, SK-MEL-28 (melanoma cell line), ATDC5 (chondrogenic cell line) and NIH3T3 (fibroblast cell line) cells, we carried out transient expression studies on various lengths of the 5' flanking region of the MTf gene fused to the luciferase reporter gene. Luciferase activity in SK-MEL-28 cells was higher than in primary chondrocytes. Although no luciferase activity was detectable in NIH3T3 cells, it was higher in chondrocytes than in ATDC5 chondrogenic cells. These findings were consistent with the levels of expression of MTf mRNA in these cells cultured under similar conditions. The patterns of increase and decrease in the luciferase activity in chondrocytes transfected with various 5' deleted constructs of the MTf promoter were similar to that in ATDC5 cells, but differed from that in SK-MEL-28 cells. The findings obtained with primary chondrocytes suggest that the regions between -693 and -444 and between -1635 and -1213 contain positive and negative cis-acting elements, respectively. The chondrocyte-specific expression of the MTf gene could be regulated via these regulatory elements in the promoter region.

Amino Acid Sequence↗
PubMed2001

An autopsy case of giant cell myocarditis probably due to a non-steroidal anti-inflammatory drug.

An autopsy case of giant cell myocarditis (GCM) in a 74-year-old woman is presented. She suffered from hepatic dysfunction, skin eruption and disseminated intravascular coagulation due to the side-effects of a non-steroidal anti-inflammatory drug. After admission, heart failure progressed rapidly, and the patient died suddenly. At autopsy, her heart was slightly enlarged and the heart muscle was thickened with many small whitish nodules. She was diagnosed with GCM because of the infiltration of multinuclear giant cells, histiocytes, eosinophils and lymphocytes into the heart. We did not find any similar lesions in any other organs. Giant cell myocarditis, the etiology of which is not defined, is a rare disease with unfavorable prognosis. This case suggests the possibility of drug-induced GCM.

Aged↗
PubMed2001

Ewing's sarcoma family of tumor arising in the adrenal gland--possible diagnostic pitfall in pediatric pathology: histologic, immunohistochemical, ultrastructural, and molecular study.

We present an adrenal Ewing's sarcoma family of tumor (ESFT) arising in an 11-year-old Japanese boy. Although intensive chemoradiotherapy and radical surgery were performed, the patient died of obstinate disease 1 year and 3 months after the initial presentation. The primary site (adrenal gland) with radiologic findings (with foci of calcification), high titer of serum neuron specific enolase, and sheets of monotonous primitive rounded cells on histology mostly favored neuroblastoma. However, a diagnosis of ESFT was confirmed by immunohistochemical profile, including MIC2-positivity and molecular study disclosing EWS-FLI1 chimera gene verified by direct sequencing. Recognition of adrenal ESFT and use of newly developed diagnostic techniques are required for differential diagnosis of undifferentiated small round cell tumor of the adrenal gland.

12E7 Antigen↗
PubMed2001

SPARC expression in primary human renal cell carcinoma: upregulation of SPARC in sarcomatoid renal carcinoma.

SPARC (secreted protein acidic and rich in cysteine, also called osteonectin, BM-40, and 43K protein) is a matricellular protein and is associated with cell-matrix interactions during cell proliferation and extracellular remodeling. It is also implicated in the neovascularization, invasion, and metastasis of human malignancies. To investigate a potential role of the SPARC in renal tumorigenesis, we examined primary renal cell carcinomas (RCCs) for SPARC expression by Northern blot analysis and for protein distribution by immunohistochemistry. We found that 6 (100%) of 6 sarcomatoid and 25 (70%) of 36 clear-cell carcinomas had enhanced SPARC transcription compared with that of the corresponding normal kidney tissue. In contrast, papillary and chromophobe RCCs characterized by a hypovascular or avascular tumor phenotype had undetectable SPARC expression. Immunohistochemical analysis showed that SPARC was strongly stained in the cytoplasm of the sarcomatoid neoplastic cells in sarcomatoid RCCs, whereas it was expressed only in the vascular endothelial cells and fibroblasts in clear-cell RCCs. SPARC staining intensity in the stromal cells was increased in the invading portion in some clear-cell RCCs. These findings suggest that tumor development, including neovascularization and invasion in clear-cell RCCs, might be regulated by SPARC from stromal endothelial cells and fibroblasts and that sarcomatoid transformation from common-type RCCs is associated with upregulation of SPARC expression; SPARC may contribute to its aggressive tumor phenotype.

Blotting, Northern↗
PubMed2001

Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization.

Although hemihepatic portal vein embolization (PVE) has been used preoperatively to extend indications for hepatectomy in patients with colorectal metastases, the effects of this procedure on tumor growth and outcome remain controversial. To address this issue, we assessed the proliferative activity of intrahepatic metastases after PVE and the long-term outcome of this procedure. Eighteen patients with colorectal metastases underwent preoperative PVE between 1996 and 2000 (PVE group). Twenty-nine patients who underwent major hepatic resection without PVE served as control (non-PVE group). The hepatic parenchymal fraction of the left lobe had significantly increased from 38.1 +/- 3.2% to 45.9 +/- 2.9% 3 weeks after PVE (+20.5%, P <.0001). Tumor volume and percent tumor volume had also significantly increased from 223 +/- 89 mL to 270 +/- 97 mL (+20.8%, P =.016) and from 13.7 + 4.3% to 16.2 + 4.9% (+18.5%, P =.014), respectively. There was no apparent correlation between the increase in parenchymal volume and that in tumor volume. The Ki-67 labeling index of metastatic lesions was 46.6 +/- 7.2% in the PVE group and 35.4 +/- 12.6% in the non-PVE group (P =.013). Long-term survival was similar in the PVE and non-PVE groups, however, disease-free survival was significantly poorer in the PVE group than in the non-PVE group (P =.004). We conclude that PVE increases tumor growth and probably is associated with enhanced recurrence of disease. Although PVE is effective in extending indications for surgery, patient selection for PVE should be cautious.

Adult↗
PubMed2001

Change in plasma viral load, and viral DNA and mRNA burdens, in peripheral blood mononuclear cells from patients infected with HIV-1.

OBJECTIVES: To clarify the virological state of human immunodeficiency virus (HIV)-1-infected patients, we compared the plasma HIV-1 RNA copy number (plasma viral load (VL)), viral DNA and mRNA burdens in peripheral blood mononuclear cells (PBMCs), and the other clinical predictors. METHODS: One hundred and thirty-one samples of PBMCs and plasma from 26 patients infected with HIV-1 were obtained during 20 consecutive months for the measurement of VL, viral DNA and mRNA burdens, and CD4 positive (CD4+) cells count. The quantitative polymerase chain reaction (PCR) method with detection by solid phase DNA was utilized for the assay of VL, viral DNA and mRNA burdens. RESULTS: Eighty-six VL, 101 viral mRNA and 129 viral DNA out of 131 samples were detected. There was a significant positive correlation between VL and the viral mRNA burden (r = 0.600, P < or = 0.001), and between VL and the viral DNA burden (r = 0.368, P < or = 0.001). Focused on individuals, the viral mRNA burdens varied in a manner relatively dependent on VL when both values were detectable. However, viral DNA burdens varied relatively independently of VL and the viral mRNA burdens. In six patients the viral mRNA burden was detectable and changed even if the VL was undetectable throughout the observation period. CONCLUSIONS: Both viral DNA and viral mRNA burdens still showed detectable changes even when the VLs became undetectable in most patients. The measurement of viral mRNA or DNA burdens may be clinically available to identify viral replication when VL is undetectable.

Adolescent↗
PubMed2001

Chondrocyte-derived ezrin-like domain containing protein (CDEP), a rho guanine nucleotide exchange factor, is inducible in chondrocytes by parathyroid hormone and cyclic AMP and has transforming activity in NIH3T3 cells.

OBJECTIVE: The purpose of this study is to investigate stage- and hormone-dependent expression of chondrocyte-derived ezrin-like domain containing protein (CDEP), a putative guanine nucleotide exchange factor (GEF) for Rho in chondrocytes, and demonstrate the guanine nucleotide exchange activity of this protein in vitro, as well as the transforming activity in NIH3T3 cells. METHODS: The expression of CDEP mRNA in growth plate chondrocytes in vivo and in vitro was examined by RT-PCR Southern analysis. The guanine nucleotide exchange activity was determined using a recombinant CDEP peptide containing the DH and PH domains in Sf9 cell lysates. The transforming activity was examined using NIH3T3 cells transiently transfected with a truncated CDEP cDNA. RESULTS: CDEP mRNA was expressed at the highest level in the hypertrophic (terminal) stage of chondrocytes in vivoand in vitro. Parathyroid hormone (PTH) elicited a biphasic increase of CDEP mRNA in chondrocytes. The CDEP mRNA level increased within 1 h, then decreased nearly to the control level at 3 h. Thereafter the mRNA level started to increase at 6 h, reaching a plateau at 24 h. Dibutyryl cyclic AMP had a similar effect on CDEP expression in chondrocytes. The dissociation of [3H]GDP from RhoA was stimulated dose-dependently by Sf9 cell lysates containing the CDEP peptide. Furthermore, transfection of a truncated CDEP cDNA induced focus formation in NIH3T3 cultures. CONCLUSIONS: CDEP is a novel GEF for Rho family GTPases with the transforming activity. CDEP may play a role in mediating or modulating the action of cAMP-elevating hormones on maturing chondrocytes.

Animals↗