Biomedical subjects

H Yamazaki

Publications and source records attributed to H Yamazaki.

At least 91 records · Page 5Linked to original sources

PubMed2001

High-risk and multiple human papillomavirus infections associated with cervical abnormalities in Japanese women.

To estimate the risk of human papillomavirus (HPV) infection for cervical malignancies, we conducted a case-control study in Japan. Abnormal cervical cell (366) and normal cell samples (1562) were tested for the presence of HPV DNA using a new PCR-based test (LCR-E7 PCR). When single HPV infections were considered, 26 different HPV types were identified in normal cervices and in low-grade squamous intraepithelial lesions (LSIL); whereas HPV-16, -18, -31, -33, -35, -45, -51, -52, -56, -58 and -67 were detected in high-grade squamous intraepithelial lesions (HSIL) and in squamous cell carcinoma (SCC) of the cervix, and HPV-16 and -18 were detected in cervical adenocarcinoma. HPV-6 and -11 were detected in condyloma acuminatum tissue. In HSIL and SCC, HPV-16 was the most prevalent type and HPV-51, -52, and -58 were the next most prevalent; whereas HPV-39, -59, and -68 were not detected. Analysis by odds ratio (OR) revealed that HPV-11, -39, -42, -44, -53, -59, -62, and -66 (HPV-66: OR,139; 95% confidence interval (CI) = 6.7-168) were associated with LSIL; HPV-16, -18, -31, -51, -52 and -58 (HPV-16: OR, 69; 95%CI = 36-131) were associated with SCC; and HPV-16 and -18 (OR, 94; 95% CI = 28-317) were associated with adenocarcinoma. Multiple HPV infection was associated with LSIL (OR, 24; 95%CI = 13-44), HSIL (OR, 16; 95%CI = 8.4-32), and SCC (OR, 8.3; 95%CI = 3.2-22), although the prevalence decreased with the grade of the lesions. All results suggest that HPV-6 and -11 are condyloma types, HPV-16, -18, -31, -51, -52, -58, and perhaps -33, -35, -45, -56, and -67, are the high-risk HPV types, and many other types are LSIL-associated types in Japan. HPV typing and detection of multiple HPV infections in clinical samples may be useful as surrogate markers for cervical cell abnormalities.

Adenocarcinoma↗

PubMed2001

Ideomotor apraxia in patients with Alzheimer disease: why do they use their body parts as objects?

OBJECTIVE: Difficulty in pantomiming the use of tools is observed in patients with Alzheimer disease. Patients with Alzheimer disease tend to use their body parts as objects when they try to pantomime the use of tools. The body-parts-as-objects phenomenon was thought to consist of appropriate gross movement of patients' arms despite inappropriate patterns of handling tools with their hands. However, the mechanism has not been investigated fully. METHODS: The authors examined 11 healthy individuals and 24 patients with Alzheimer disease for ability to recognize tools, to pantomime the use of tools, to use actual tools, and to select an appropriate photograph of a handling pattern of the tool. RESULTS: In comparison with the patients with Alzheimer disease, the healthy individuals had higher scores for all tasks. The authors classified the patients into group A (patients with higher pantomime scores), group B (patients with middle level scores), and group C (patients with lower scores). Frequency of use of body parts as objects for patients in group B was higher than that of patients in group A and in group C. The mean Mini-Mental State Examination score for patients in group A was higher than that of patients in group B and in group C. In comparison with patients in group A, patients in group B showed lower scores on the hand-posture discrimination task without a tool, even after controlling the Mini-Mental State Examination score. CONCLUSIONS: The authors conclude that body-parts-as-objects responses in patients with Alzheimer disease occur because general cognition is lowered or because retrieval ability of the appropriate holding posture for tools is impaired.

Aged↗

PubMed2001

Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats.

Phenytoin, 5,5-diphenylhydantoin, is a widely used anticonvulsant agent with a variety of toxicities, including drug interactions. The formation of four oxidative metabolites, 4'-hydroxylated (4'-HPPH), 3'-hydroxylated (3'-HPPH), a catechol (3',4'-diHPPH), and the 3',4'-dihydrodiol form of phenytoin was examined in rat liver microsomes. In 11 cDNA-expressed rat P450 enzymes tested, CYP2C6 had the highest activities in 4'- and 3'-HPPH formation from phenytoin, followed only by CYP2C11. In contrast, CYP2C11 had high activity for 3',4'-diHPPH formation from 4'-HPPH, followed by CYP2C6. The rates of 4'-HPPH and 3',4'-diHPPH formation from phenytoin in liver microsomes in the presence of NADPH were significantly decreased by oral administration of phenytoin (300 mg/kg for 20 days) to rats, despite the increase in P450 contents. However, the cumene hydroperoxide-supported formation of 3',4'-dihydrodiol and 4'-HPPH from phenytoin was induced by phenytoin administration. Hydrogen peroxide formation in reaction mixtures with NADPH was induced by the administration of phenytoin; however, the coupling ratio of phenytoin oxidation was decreased in phenytoin-induced liver microsomal P450 systems. These results suggested that phenytoin could not stimulate its own apparent oxidative metabolism by liver P450s induced with phenytoin administration. The increase of unmetabolized phenytoin and byproducts of oxygen generated in the phenytoin-induced liver microsomal P450 system may be involved in phenytoin-related drug toxicity.

Animals↗

PubMed2001

[A randomized comparative study assessing once versus twice a day treatment of benign prostatic hyperplasia with terazosin].

We compared the efficacy of once a day administration of terazosin hydrochloride with that of twice a day administration for benign prostatic hyperplasia (BPH) patients. Forty-two patients with BPH were randomly assigned to receive a maximum dose of 2 mg terazosin either once (n = 21) or twice (n = 21) a day. International prostate symptom score (IPSS), uroflowmetry and side effect profile were determined before and 4 weeks after randomization. Both groups were similar with respect to patient age, baseline IPSS and prostate volume. After 4 weeks of treatment with terazosin, significant improvement in IPSS, maximum flow rate and mean flow rate were observed in both groups. However, these improvements did not differ significantly between them. In addition, there were no differences in side effects between the groups. In conclusion, once a day administration of terazosin hydrochloride is as effective and safe as twice a day administration in patients with BPH.

Adrenergic alpha-Antagonists↗

PubMed2001

Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver.

Recently, we have reported that tegafur, an anticancer agent, is biotransformed into active drug 5-fluorouracil (5-FU) by cytochromes P450 1A2, 2A6, and 2C8 in human liver microsomes (T. Komatsu et al., Drug Metab. Dispos, 28: 1457-1463, 2000). Because the conversion of tegafur into 5-FU has also been reported to be catalyzed by cytosolic thymidine phosphorylase (dThdPase), the involvement of human liver microsomes and cytosol and individual differences in 5-FU formation from tegafur were investigated. In 14 human samples, the mean rates of 5-FU formation in liver microsomes were 5-fold and 2-fold higher than those in liver cytosol at substrate concentrations of 100 microM and 1 mM tegafur, respectively. In the presence of 5-chloro-2,4-dihydroxypyridine, a dihydropyrimidine dehydrogenase inhibitor, the rates of 5-FU formation by the combination of liver microsomes and cytosol showed 5- and 3-fold interindividual differences at 100 microM and 1 mM tegafur, respectively. Kinetic analysis of human liver cytosolic 5-FU formation indicated an apparent higher Km value (16 +/- 4 mM) than that of liver microsomes (1.8 +/- 0.3 mM) with similar Vmax values. Human liver cytosolic 5-FU formation was confirmed to be catalyzed by dThdPase with correlation and chemical inhibition studies. These results suggested that 5-FU formation from tegafur in human liver was mainly catalyzed by microsomal P450 at low concentrations of tegafur, but the contribution of cytosolic 5-FU formation by dThdPase would be important at high concentrations.

Antimetabolites, Antineoplastic↗

PubMed2001

Significant correlation between interleukin 10 expression and vascularization through angiopoietin/TIE2 networks in non-small cell lung cancer.

The expression of interleukin 10 (IL-10) is correlated with clinical prognosis in non-small cell lung cancer [NSCLC (H. Hatanaka et al., ANN: ONCOL:, 11: 815--819, 2000)]. However, the effects of IL-10 expression on vascularization in NSCLC are not apparent. We examined the gene expression of IL-10/IL-10 receptor and various angiogenic/angioinhibitory factors in 95 NSCLC samples to determine the correlation between IL-10 production and vascularization. Vascular endothelial growth factor, angiopoietin [Ang (Ang-1 and Ang-2)], thrombospondin, brain-specific angiogenesis inhibitor 1, vascular endothelial growth factor receptors (KDR and flt-1), and Ang receptor (TIE2) gene expression were evaluated by reverse transcription-PCR. The cellular localization of these factors and vascularity in the cancer stroma were examined immunohistochemically. Seventy-eight (82.1%) and 93 (97.9%) of these 95 NSCLCs were positive for IL-10 and IL-10 receptor, respectively. Ang-1, Ang-2, and TIE2 gene expression was seen in 76 (97.4%), 73 (93.6%), and 78 (100%) of 78 IL-10-positive NSCLCs, respectively, and was significantly correlated with IL-10 gene expression (P < 0.0088, <0.0008, and 0.0305, respectively; Fisher's exact method). The localizations of Ang-1, Ang-2, and TIE2 were confirmed within tumor cells immunohistochemically. Vascular number and measurement area were significantly higher in the IL-10-positive NSCLCs (33.500 +/- 9.299/microm(2) and 4.742 +/- 1.287%) as compared with IL-10-negative NSCLCs (10.611 +/- 2.839/microm(2) and 0.718 +/- 0.331%; Mann-Whitney U test, P = 0.0039). The IL-10 expression did not show any significant correlation with the expression of other factors. These results suggested that tumor-produced IL-10 promotes stromal vascularization through expression of Ang-1, Ang-2, and TIE2.

Angiogenesis Inhibitors↗

PubMed2001

Rat cytochrome p450 1A and 3A enzymes involved in bioactivation of tegafur to 5-fluorouracil and autoinduced by tegafur in liver microsomes.

Tegafur, an anticancer prodrug, is reported to be bioactivated to 5-fluorouracil (5-FU) by cytochrome P450 (P450) enzymes. Liver microsomal P450 enzymes involved in the biotransformation of tegafur into 5-FU in rats and the effect of tegafur in vivo on P450 levels in rats were investigated. Of 12 cDNA-expressed rat P450 enzymes tested, CYP1A2, CYP3A1, and CYP2C11 had high 5-FU formation rates from 100 microM and 1.0 mM tegafur concentrations. The contributions of CYP1A, CYP2C, and CYP3A enzymes to 5-FU formation in male rat liver microsomes were supported by immunoinhibition studies. 5-FU formation from tegafur, at substrate concentrations of 100 microM and 1.0 mM, was increased by intraperitoneal treatment of tegafur (50 mg/kg for 5 days) as well as by beta-naphthoflavone, phenobarbital, and dexamethasone. Orally administered tegafur (100 mg/kg daily for 20 days) caused the induction of CYP2B (5-fold) and of CYP1A and CYP3A (approximately 2-fold) and of 5-FU formation (approximately 2-fold) in rat liver microsomes. These results suggest that CYP1A and CYP3A enzymes, autoinduced by tegafur, have important roles in 5-FU formation from tegafur in rat liver microsomes. Coadministration of tegafur and P450-inducing drugs could markedly enhance the biotransformation of tegafur into 5-FU via P450 induction.

Animals↗

PubMed2001

Fortuitously discovered persistent left superior vena cava in young competitive athletes. Clinical implications of sports physicians.

This report describes two athletes with persistent left superior vena cava (PLSVC) accidentally identified during preparticipation medical evaluation. The clinical implications of PLSVC for sports physicians are also discussed. A 16-year-old male ice hockey player and an 18-year-old male high-level field hockey player visited our institute for medical evaluation prior to participating in competition. Neither complained of palpitation, faintness or syncope, which would have suggested a possible cardiac rhythm disturbance, or had been informed of any abnormalities in previous physical examinations. Nonetheless, echocardiography revealed dilated coronary sinuses, and venography confirmed PLSVC and, in one case, showed the absence of the right superior vena cava. Electrocardiograms showed the field hockey player to have an ectopic atrial rhythm with left axis deviation of the frontal plane P-wave and the ice hockey player to have normal sinus rhythm. Symptom-limited treadmill testing revealed nothing abnormal, and after explaining the possible rhythm instability and the potential risk associated with cardiac surgery, the subjects were permitted full participation in competitive sports. Although information is scarce, available data on PLSVC suggest it is benign for competitive athletes. Nevertheless, complications arising from other cardiovascular anomalies, from potential cardiac rhythm disturbances, and from cardiac surgery necessitated by major injuries should be considered prior to participation in competitive sports.

Adolescent↗

PubMed2001

Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate.

The inhibition and mechanism-based inactivation potencies of phenethyl isothiocyanate (PEITC) for human cytochrome P450 (CYP) activities were investigated using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. PEITC competitively inhibited phenacetin O-deethylase activity catalyzed by CYP1A2 (K(i) = 4.5 +/- 1.0 microM) and coumarin 7-hydroxylase activity catalyzed by CYP2A6 (K(i) = 18.2 +/- 2.5 microM). Benzyloxyresorufin O-dealkylase activity catalyzed by CYP2B6 was most strongly and noncompetitively inhibited (K(i) = 1.5 +/- 0.0 microM). Paclitaxel 6alpha-hydroxylase activity catalyzed by CYP2C8 was not affected by PEITC up to 100 microM. PEITC noncompetitively inhibited S-warfarin 7-hydroxylase activity catalyzed by CYP2C9 (K(i) = 6.5 +/- 0.9 microM), S-mephenytoin 4'-hydroxylase activity catalyzed by CYP2C19 (K(i) = 12.0 +/- 3.2 microM), bufuralol 1'-hydroxylase activity catalyzed by CYP2D6 (K(i) = 28.4 +/- 7.9 microM), and chlorzoxazone 6-hydroxylase activity catalyzed by CYP2E1 (K(i) = 21.5 +/- 3.4 microM). The inhibition for testosterone 6beta-hydroxylase activity catalyzed by CYP3A4 was a mixed-type of competitive (K(i) = 34.0 +/- 6.5 microM) and noncompetitive (K(i) = 63.8 +/- 12.5 microM) inhibition. Furthermore, PEITC is a mechanism-based inactivator of human CYP2E1. The k(inact) value was 0.339 min(-1) and K(i) was 9.98 microM. Human CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4 were not inactivated. The present study directly proved that the chemopreventive effects of PEITC for nitrosamine-induced carcinogenesis are due to the inhibition of CYP by an in vitro study. The possibility that PEITC would affect the pharmacokinetics of clinically used drugs that are metabolized by these CYP isoforms was also suggested.

Binding, Competitive↗

PubMed2001

[Assessment of exhaled NO concentration in monitoring radiation pneumonitis in patient who underwent thoracic radiotherapy for lung cancer].

To monitor radiation pneumonitis, we assessed the exhaled nitrogen oxide (NO) level in patient with lung cancer. A 73-year-old man with idiopathic interstitial pneumonitis underwent thoracic radiotherapy without chemotherapy for squamous cell lung cancer (T2N1M0). He showed elevation of exhaled NO level at 30 Gy-50 Gy, after a decrease at 10-20 Gy. He also showed an abnormal shadow on CT examination at 50 Gy. Although exhaled NO may have had the benefit of predicting radiation pneumonitis before severe clinical symptom appeared, he died three months after radiotherapy because of worsening of the radiation pneumonitis.

Aged↗

PubMed2001

[Breast cancer].

Neoadjuvant chemotherapy (NAC) represents a new approach based on sound theoretical, pharmacokinetic, and experimental principles. The purpose of NAC is to improve control of the primary site by downstaging and to improve control of micrometastatic disease. NAC has been standard therapy in the management of locally advanced breast cancer. Patients with earlier stage breast cancer may also benefit from treatment with NAC. Recently some investigators have mentioned that NAC can be used instead of adjuvant chemotherapy and would be most appropriate for patients who wish to preserve their breast but who have tumors too large for breast conserving surgery. In this article, we reviewed the present status of NAC (indication, clinical response, pathologic response, survival, possibility of breast conservation, prognostic/predictive factors, neoadjuvant endocrine therapy) and discussed several unanswered questions on NAC (survival benefit, optimal number of treatment cycles, optimal regimens) and future direction. Combined modality therapy including NAC appears to provide excellent local control, the possibility of breast conservation, and, probably, an increased survival rate, at least for some subsets of patients. Furthermore, through sequential sampling, NAC provides indeed the opportunity to identify molecular mechanisms associated with pathologic response and to study the possibility to guide the choice for induction treatment and patient populations submitted to neoadjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

A secure method of nasal endotracheal tube stabilization with suture and rubber tube.

A new method of stabilizing the nasal endotrascheal tube was described. The tube was secured to the anterior portion of the nasal septum with braided silk thread, which was tightened over the rubber tube to keep air route of the cuff open. There found no complications such as unplanned extubation, necrosis and infections of the nasal septum.

Adult↗

PubMed2001

Acinic cell carcinoma of the sublingual gland accompanied by bone formation.

A rare case of acinic cell carcinoma of the sublingual gland accompanied by bone formation is reported. The patient is a 79-year-old male who was referred to Yokohama Minami Kyosai Hospital with sublingual swelling. A tumor mass, 20 x 10 mm in diameter, was detected on the right side of the floor of the mouth. Computed tomography (CT) revealed a mass lesion with calcification in the sublingual gland. The patient underwent total sialadenectomy of the sublingual gland with conservation of the lingual nerve. Histologically, the lesion showed amylase-positive atypical cells with thyroid gland-like arrangement, and mature bone tissue in the stroma. Based on these findings, the tumor was diagnosed as acinic cell carcinoma accompanied by bone formation. Postoperative recovery was uneventful, and two years after surgery, there are no signs of distant metastases or recurrence.

Aged↗

PubMed2000

Bioactivation of diesel exhaust particle extracts and their major nitrated polycyclic aromatic hydrocarbon components, 1-nitropyrene and dinitropyrenes, by human cytochromes P450 1A1, 1A2, and 1B1.

The genotoxicities of four samples of diesel exhaust particle (DEP) extracts (DEPE) and nine nitroarenes found in DEPE were investigated after activation catalyzed by human cytochrome P450 (P450) family 1 enzymes co-expressed with NADPH-cytochrome P450 reductase (NPR) in Escherichia coli membranes. The DEPE samples induced umu gene expression in Salmonella typhimurium TA1535/pSK1002 without any P450 system and were further activated by human P450 1B1/NPR membranes. Moderate activation of the DEPE sample by P450 1A2/NPR membranes was also observed, but not by either P450 1A1/NPR or NPR membranes. 1-Nitropyrene (1-NP) was strongly activated by human P450 1B1/NPR membranes. 1,8-Dinitropyrene (1,8-DNP) was most highly activated by P450 1A1 and 1B1 systems for the three DNPs tested. In contrast, 1, 3-DNP was inactivated by P450 1A1/NPR, 1A2/NPR, and 1B1/NPR systems and slightly activated by NPR membranes. 2-Nitrofluoranthene (2-NF) and 3-nitrofluoranthene (3-NF) showed activities similar to 1-NP after bioactivation by P450 1B1/NPR membranes. However, the genotoxicities of 6-nitrochrysene, 7-nitrobenz[a]anthracene, and 6-nitrobenzo[a]pyrene were all weak in the present assay system. Apparent genotoxic activities of DEPE were very low compared with standard nitroarenes in the presence of P450s, possibly because unknown component(s) of DEPE had inhibitory effects on the bioactivation of 1-NP and 1,8-DNP catalyzed by human P450 1B1. These results suggest that environmental chemicals existing in airborne DEP, in addition to 1-NP, 1,6-DNP, 1,8-DNP, 2-NF, and 3-NF, can be activated by human P450 1B1. Biological actions of air pollutants such as nitroarenes to human extrahepatic tissues may be of concern in tissues in which P450 1B1 is expressed.

Aryl Hydrocarbon Hydroxylases↗

PubMed2000

Accelerated growth of hepatocytes in association with Up-regulation of cyclin E in transgenic mice expressing the dominant negative form of retinoic acid receptor.

Retinoids play an important role in pathogenesis of liver diseases. To clarify the functional role of retinoic acid (RA) in liver, we developed transgenic mice (Tg) which express the dominant negative form of retinoic acid receptor (RARE) in liver. Here, we report that proliferation of hepatocytes in RARE Tg is greatly enhanced and that cyclin E is up-regulated in RARE Tg. Liver weight, liver/body weight, and proliferating cell nuclear antigen (PCNA) labeling index in RARE Tg were significantly increased, compared to those in wild-type mice (P < 0.01, each). Cell cycle analysis showed that 2N DNA content cells and aneuploid area between 2N and 4N DNA, reflecting S phase cells, were significantly increased in RARE Tg, compared to wild-type mice (P < 0.01, each). Of G1 phase-related proteins including cyclins, cyclin-dependent protein kinases (CDKs) and cyclin-dependent protein kinase inhibitors (CKIs), cyclin E mRNA and protein was up-regulated in liver from RARE Tg by reverse transcription polymerase chain reaction and Western blot analysis. Furthermore, the immunoprecipitation with anti-cdk2 antibody, followed by Western blot analysis with anti-cyclin E antibody indicated that cyclin E/cdk2 complex is increased in liver of RARE Tg. The results of the present study suggest that cyclin E in association with cdk2 governs cell cycle progression through G1 in hepatocytes where function of RA is inhibited.

Aneuploidy↗

PubMed2000

Immunoreactivity for glutamic acid decarboxylase and N-methyl-D-aspartate receptors of intracellularly labeled respiratory neurons in the cat.

In adult cats, immunofluorescence images of glutamic acid decarboxylase (GAD) and N-methyl-D-aspartate (NMDA) receptors were achieved in the ventral respiratory group (VRG) neurons, which had been individually identified by in vivo intracellular recording and labeling with neurobiotin. Among augmenting inspiratory (aug-I), postinspiratory (post-I), and augmenting expiratory (aug-E) neurons labeled, GAD-immunoreactivity was demonstrated only in those neurons that were not antidromically activated (NAA) by stimulation of the vagus nerve and the C2-C3 spinal cord. Substantial immunoreactivity for NMDA receptors was presented in virtually all types of neurons, but lesser reactivity in aug-E bulbospinal neurons. These results suggest that the aug-I, post-I, and aug-E types of NAA neurons are gamma-aminobutyric acid (GABA)ergic and that NMDA receptors distribute in lesser degree in aug-E bulbospinal neurons than in other types of VRG neurons.

Animals↗

PubMed2000

High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial.

PURPOSE: To improve results for localized prostate cancer, a prospective clinical trial of hyperfractionated Iridium-192 high-dose-rate (HDR) brachytherapy as a monotherapy was initiated. METHODS AND MATERIALS: Between May 1995 and September 1998, 22 implants were performed on 22 patients with localized prostate cancer (T1:T2:T3:T4 = 4:6:9:3) at Osaka University Hospital. Nineteen patients, who had T3-T4 tumors or pretreatment PSA >/= 20.0 ng/mL, received hormone therapy. No patient had external beam radiation. Transperineal needle implants using real-time ultrasound guidance were performed, followed by dose optimization program. Patients were irradiated twice a day, with a time interval of more than 6 h. Total dose was 48 Gy/8 fractions/5 days or 54 Gy/9 fractions/5 days. Acute toxicity was scored using the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Median follow-up time was 31 months. RESULTS: HDR brachytherapy as a monotherapy was well-tolerated. No significant intra- or peri-operative complications occurred. No patient experienced acute toxicity of grade 3 or more. PSA levels normalized in 95% of patients within 20 months after irradiation. Four-year clinical and biochemical relapse-free rates were 95% and 55%, respectively. CONCLUSION: Acute toxicity with this method was acceptable. Further patient accrual and longer follow-up will allow comparison to other techniques.

Aged↗

PubMed2000

Differential expression of LR11 during proliferation and differentiation of cultured neuroblastoma cells.

An involvement of the low density lipoprotein receptor (LDLR) gene family in both intracellular signal pathways for neural organization and metabolic pathways for lipoprotein homeostasis is now well established. The discovery of LR11, a mosaic LDLR family member offers the opportunity to gain new insights into receptor multifunctionality. Here, we studied the proliferation-dependent expression of LR11 mRNA and protein using two cultured cell lines, IMR32 neuroblastoma and PC12 pheochromocytoma. Within 24 h, the LR11 protein rose 1.9-fold in proliferating IMR32 cells, and increased further to 5.3-fold at 72 h. This conformed with a transcript level increase of 4.7-fold at 72 h in the proliferating cells. On the other hand, under differentiation conditions, a 2.9-fold increase was observed within 24 h, but at 72 h thereafter the protein levels decreased to 60% of control. The transcript also increased to 1. 8-fold within 24 h, and then decreased to 1.1-fold at 72 h. In order to assess the transcriptional activities of the LR11 gene, we identified the 5'-flanking region of the murine LR11 gene. Transfection of IMR32 and PC12 cells with plasmids containing the whole or deleted fragments of 5'-flanking region showed that element(s) responsible for the above described different transcriptional activities are located in the upstream sequence between -861 and -396. Thus, the transcription of LR11 in these two cell systems is regulated differently during proliferation and differentiation, suggesting that the multifunctionality of LR11, as well as other LDLR family members, for rapid cell growth in malignant cells and neural outgrowth in cultured neurons, respectively. The possible involvement of LR11 in cellular proliferation and differentiation sheds new light on its functions in neurons, malignant, and vascular cells.

Animals↗