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Biomedical subjects

Masayo Fujita

Publications and source records attributed to Masayo Fujita.

11 recordsLinked to original sources
PubMed2006

alpha-Synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity.

Because a limited study previously showed that alpha-synuclein (alpha-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether alpha-syn might be involved in the regulation of tumor differentiation. For this purpose, alpha-syn and its non-amyloidogenic homologue beta-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with beta-syn-overexpressing and vector-transfected cells, alpha-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in alpha-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In alpha-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in alpha-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of alpha-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of alpha-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of alpha-syn regulation of tumor differentiation and neuropathological effects of alpha-syn may considerably overlap with each other.

Autophagy↗
PubMed2006

Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson's disease.

DJ-1 is an antioxidant protein whose loss of function by gene mutations has been linked to familial Parkinson's disease (PD). The main objective of the present study was to determine if this molecule was also involved in the pathogenesis of sporadic PD. For this purpose, quantitative immunoblot assays were performed to evaluate DJ-1 in cerebrospinal fluids (CSF) collected from sporadic PD patients (n=40) and non-PD controls (n=38). The results showed that the CSF DJ-1 levels in PD were significantly higher than those in non-PD controls. Especially, upregulation of CSF DJ-1 in the early stage of PD (Yahr I-II) were distinct compared to those in the advanced stage of PD (Yahr III-IV) and non-PD controls (p<0.001 by ANOVA with post hoc Bonferroni's test), suggesting a protective role of DJ-1 against oxidative stress during the early stage. Thus, we propose that CSF DJ-1 could be a possible biomarker for early sporadic PD.

Aged↗
PubMed2006

Chaperone and anti-chaperone: two-faced synuclein as stimulator of synaptic evolution.

Previous studies have shown that beta-synuclein (beta-syn), the homologue of alpha-syn, inhibited alpha-syn aggregation and stabilized Akt cell survival signaling molecule, suggesting that beta-syn was protective against alpha-syn-related neurodegenerative disorders, such as Parkinson's disease and diffuse Lewy body disease. However, emerging evidence argues that the situation may be not so simple. Two missense mutations of beta-syn were identified in familial and sporadic diffuse Lewy body disease, and wild type beta-syn was induced to form fibril structures in vitro, while, alpha-syn was shown to be protective against neurodegeneration caused by deletion of cysteine-string protein-alpha, the presynaptic cochaperone to Hsc70 in mice. Collectively, alpha- and beta-syn are both, but in varying degrees, featured with two opposite properties, namely normal chaperone and anti-chaperone. By reviewing recent progress in syn biology with a particular focus on beta-syn, this manuscript refers to the intriguing possibility that the dual syn proteins might have acquired a driving force for synaptic evolution. Hypothetically, the anti-chaperone syn may provoke stress-induced diverse responses, whereas, the chaperone syn may provide buffering for them, allowing accumulation of nonlethal phenotypic variations in synapses. Consequently, dual syn proteins may cope with forthcoming stresses in the brain by stimulating adaptive evolution. In this context, failure to regulate this process due to various causes, such as gene mutations and environmental risk factors, may result in imperfect adaptability against stresses, leading to neurodegenerative disorders.

Animals↗
PubMed2005

The adrenal gland is a source of stress-induced circulating IL-18.

The present study compared plasma IL-18 levels between sham-operated and adrenalectomized mice following stress to investigate whether the adrenal gland contributes to the elevation of circulating IL-18 during stress. Two hours of stress provoked a robust, stressor-dependent, elevation of IL-18 mRNA and peptide in the adrenal gland in sham-operated mice. Consistently, levels of circulating mature IL-18 increased during stress and remained elevated for up to 6 h after stress. The stress-induced increase in circulating IL-18 was abolished by adrenalectomy. These findings demonstrate that the adrenal gland is required to achieve elevation of circulating IL-18 during stress.

Adrenal Glands↗
PubMed2005

Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5'-flanking region (-5229G/A) with bone mineral density.

The 12/15-lipoxygenase gene Alox15 has been identified as a susceptibility gene for bone mineral density (BMD) in mice through combined genetic and genomic analyses. Here we studied the association between bone mineral density and an ALOX15 gene single nucleotide polymorphism to assess the potential involvement of the human ALOX15 gene in postmenopausal osteoporosis. Specifically, we examined the association between a single nucleotide polymorphism at -5299G/A in the ALOX15 5'-flanking region with BMD in 319 postmenopausal Japanese women (66.7 +/- 8.9 years, mean +/- SD). We found that subjects bearing at least one variant A allele (GA + AA; n = 273) had significantly lower Z scores for lumbar spine and total body bone mineral density than did subjects with no A allele (GG; n = 46) (lumbar spine, -0.25 +/- 1.34 versus 0.48 +/- 1.70; P = 0.0014; total body, 0.25 +/- 1.01 vs 0.62 +/- 1.11; P = 0.048). These findings suggest that the ALOX15 gene is one of the genetic determinants of BMD in postmenopausal women. Accordingly, this polymorphism could be useful as a genetic marker for predicting the risk of osteoporosis.

Aged↗
PubMed2004

14-3-3sigma is down-regulated in human prostate cancer.

The 14-3-3sigma is a negative regulator of the cell cycle, which is induced by p53 in response to DNA damage. It has been characterized as an epithelium-specific marker and down-regulation of the protein has been shown in breast cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we demonstrate that 14-3-3sigma protein is down-regulated in human prostate cancer cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells. Immunohistochemical analysis of primary prostate cells shows that the expression of 14-3-3sigma protein is epithelial cell-specific. Among prostate pathological specimens, > 95% of benign hyperplasia samples show significant and diffuse immunostaining of 14-3-3sigma in the cytoplasm whereas < 20% of carcinoma samples show positive staining. In terms of mechanisms for the down-regulation of 14-3-3sigma in prostate cancer cells, hypermethylation of the gene promoter plays a causal role in LNCaP cells as 14-3-3sigma mRNA level was elevated by 5-aza-2'-deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated proteolysis is responsible for 14-3-3sigma reduction in DU145 and PC3 cells, as 14-3-3sigma protein expression was increased by treatment with a proteasome inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing ligand enhances 14-3-3sigma gene and protein expression in DU145 and PC3 cells. These data suggest that 14-3-3sigma expression is down-regulated during the neoplastic transition of prostate epithelial cells.

14-3-3 Proteins↗
PubMed2004

Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral density.

Low-density lipoprotein receptor-related protein 5 (LRP5) is an important regulator of osteoblast growth and differentiation, affecting peak bone mass in vertebrates. Here, we analyzed whether the LRP5 gene was involved in the etiology of postmenopausal osteoporosis, using association analysis between bone mineral density (BMD) and an LRP5 gene single-nucleotide polymorphism (SNP). Association of an SNP in the LRP5 gene at IVS17-1677C > A (intron 17) with BMD was examined in 308 postmenopausal Japanese women (65.2 +/- 9.6 years; mean +/- SD). The subjects bearing at least one variant A allele (CA + AA; n = 142) had significantly lower Z scores for total body and lumbar BMD than the subjects with no A allele (CC; n = 166) (total body, 0.08 +/- 1.09 versus 0.50 +/- 1.03; P = 0.0022; lumbar spine, -0.42 +/- 1.43 versus -0.02 +/- 1.42; P = 0.013). These findings suggest that the LRP5 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis.

Aged↗
PubMed2002

Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts.

Estrogen plays important roles in maintaining bone density and protecting against osteoporosis, but the underlying mechanisms of estrogen action via estrogen receptors (ERs) in bone remain to be clarified. In the present study, we isolated primary osteoblasts derived from transgenic rats harboring a dominant negative ER mutant, rat ERalpha (1-535) cDNA, and from their wild-type littermates. We observed that the rate of cell growth of osteoblasts from the transgenic rats was reduced compared to that of wild-type osteoblasts. Utilizing cDNA microarray analysis, we found that mRNA level of cyclin D2 was lower in the osteoblasts from the transgenic rats. D-type cyclins including cyclin D1, cyclin D2, and cyclin D3 are cell cycle regulators that promote progression through the early-to-mid G1 phase of the cell cycle. The protein levels of D-type cyclins including cyclin D2 and cyclin D3 but not cyclin D1 were elevated in wild-type osteoblasts with 17beta-estradiol treatment, resulting in the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6) activities and the promotion of cell growth. Moreover, an anti-estrogen ICI 182,780 abolished the induction of the expression of D-type cyclins by 17beta-estradiol. Our findings indicate that estrogen and its receptors enhance Cdk4/6 activities through the induction of D-type cyclins, leading to the growth promotion of osteoblasts.

Animals↗
PubMed2002

Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth.

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ER alpha, is a member of the RING-finger B-box coiled-coil (RBCC) motif family. Efp is predominantly expressed in various female organs as well as in breast cancers, and is thought to be essential for oestrogen-dependent cell proliferation and organ development Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3 sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3 sigma as a target for proteolysis by Efp, leading to cell proliferation.

14-3-3 Proteins↗
PubMed2002

Changes in mood status and neurotic levels during a 20-day bed rest.

This study evaluated changes of mood status and depressive and neurotic levels in nine young male subjects during a 20-day 6 degrees head-down tilting bed rest and examined whether exercise training modified these changes. Participants were asked to complete psychometrical inventories on before, during, and after the bed rest experiment. Depressive and neurotic levels were enhanced during bed rest period according to the Japanese version of Zung's Self-rating Depression Scale and the Japanese version of the General Health Questionnaire. Mood state "vigor" was impaired and "confusion" was increased during bed rest and recumbent control periods compared to pre-bed rest and ambulatory control periods according to the Japanese version of Profiles of Mood State, whereas the mood "tension-anxiety", "depression-dejection", "anger-hostility" and "fatigue" were relatively stable during experiment. Isometric exercise training did not modify these results. Microgravity, along with confinement to bed and isolation from familiar environments, induced impairment of mental status.

Adaptation, Psychological↗