[Ectopic insulin secretion].
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Fatty Acids, Nonesterified↗
Biomedical subjects
Koji Murao
Publications and source records attributed to Koji Murao.
Platelet derived growth factor regulates ABCA1 expression in vascular smooth muscle cells.
The ATP-binding cassette transporter A1 (ABCA1) regulates lipid efflux from peripheral cells to High-density lipoprotein. The platelet-derived growth factor (PDGF) is a potent mitogen that enables vascular smooth muscle cells to participate in atherosclerosis. In this report, we showed that PDGF suppressed endogenous expression of ABCA1 in cultured vascular smooth muscle cells. Exposure of CRL-208 cells to PDGF elicited a rapid phosphorylation of a kinase downstream from PI3-K, Akt. The constitutively active form of both p110, a subunit of PI3-K, and Akt inhibited activity of the ABCA1 promoter. In conclusion, PI3-K-Akt pathways participate in PDGF-suppression of ABCA1 expression.
ATP Binding Cassette Transporter 1↗
High-density lipoprotein is a potential growth factor for adrenocortical cells.
The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [(3)H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor.
Adrenal Cortex↗
[Panhypopituitalism induced by xanthogranuloma of the sellar region].
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Humans↗
Neuropeptide W as a stress mediator in the hypothalamus.
Neuropeptide W (NPW) was isolated and found to be an endogenous peptide ligand for the orphan receptors GPR7 and GPR8. Centrally administered NPW caused a dose-dependent increase in corticosterone levels in rats. This observation indicates that NPW may play an important role in the hypothalamic organization of the endocrine response to stress. We examined the effects of immobilization stress and cold exposure on NPW-containing neurons in the hypothalamus of the rat, using dual immunostaining for NPW and Fos. In addition, to analyze the function of NPW, we studied the effect of intracerebroventricular (icv) NPW administration on Fos protein accumulation in the brain. Double immunohistochemistry for NPW and Fos showed that the percentage of Fos expression in the NPW-immunoreactive cells of the perifornical nucleus was significantly increased by immobilization stress compared with that in nonstressed rats. Similarly, the results indicated that cold exposure activates NPW-immunoreactive neurons in the perifornical nucleus. An icv administration of NPW resulted in significant Fos expression in the paraventricular nucleus, as compared with saline-infused controls. These results suggest that NPW is related to stress-responsive signal transduction, and that NPW may modulate the hypothalamus-pituitary-adrenal axis.
Animals↗
[Panhypopituitalism associated with HELLP syndrome].
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Adult↗
Lipid-altering drugs: decreasing cardiovascular disease at the expense of increasing cancer?
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Aged↗
Insulin-like growth factor-i regulation of hepatic scavenger receptor class BI.
High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. This process enables the transfer of cholesterol from peripheral tissues to the liver for further metabolism and eventual secretion in the form of bile. The scavenger receptor of the B class (SR-BI), human homolog of SR-BI, and CD36 and LIMPII analogous-1 (CLA-1) are different names for the same receptor that facilitates hepatocellular uptake of cholesterol from high-density lipoprotein. The pivotal role of this receptor in enterohepatic circulation of cholesterol and bile salts underlies our interest to study the regulation of hepatic SR-BI gene in response to the actions of IGF-I. The results of our studies showed that endogenous expression of SR-BI/CLA-1 was suppressed by exposure to GH or IGF-I in cultured HepG2 cells. This observation extended to a whole animal model of rats continuously infused with IGF-I. IGF-I decreased transcriptional activity of the SR-BI promoter. However, the inhibitory effect of IGF-I on SR-BI/CLA-1 promoter activity was abrogated by wortmannin, a specific inhibitor of phosphoinositide 3-kinase (PI3-K). Exposure of HepG2 cells to IGF-I elicited a rapid phosphorylation of Akt. We also demonstrated that the constitutively active form of both p110, a subunit of PI3-K, and Akt inhibited activity of the human SR-BI/CLA-1 promoter. Furthermore, the dominant-negative mutant of Akt abolished the ability of IGF-I to suppress activity of the SR-BI/CLA-1 promoter. In conclusion, PI3-K/Akt pathways participate in IGF-I-suppression of SR-BI/CLA-1 expression, which suggests that the activation of Akt plays an important role in cholesterol metabolism in liver.
Acromegaly↗
Thyrotropin-releasing hormone-stimulated thyrotropin expression involves islet-brain-1/c-Jun N-terminal kinase interacting protein-1.
Islet-brain-1 (IB1)/c-Jun N-terminal kinase interacting protein 1 (JIP-1) is a scaffold protein that is expressed at high levels in neurons and the endocrine pancreas. IB1/JIP-1 interacts with the c-Jun N-terminal kinase and mediates the specific physiological stimuli (such as cytokines). However, the potential role of the protein in the pituitary has not been evaluated. Herein, we examined expression of the gene encoding IB1/JIP-1 and its translated product in the anterior pituitary gland and a pituitary cell line, GH3. We then examined the potential role of IB1/JIP-1 in controlling TSH-beta gene expression. Exposure of GH3 cells to TRH stimulated the expression of IB1/JIP-1 protein levels, mRNA, and transcription of the promoter. The increase of IB1/JIP-1 content by transient transfection study of a vector encoding IB1/JIP-1 or by the stimulation of TRH stimulates TSH-beta promoter activity. This effect is not found in the presence of a mutated nonfunctional (IB1S59N) IB1/JIP-1 protein. Together, these facts point to a central role of the IB1/JIP-1 protein in the control of TRH-mediated TSH-beta stimulation.
Adaptor Proteins, Signal Transducing↗
Role of calcium-calmodulin-dependent protein kinase cascade in thyrotropin (TSH)-releasing hormone induction of TSH and prolactin gene expression.
TRH binds to a membrane receptor that activates several intracellular signaling pathways and increases transcription of the TSH and prolactin (PRL) genes. Although TRH induces TSH and PRL gene expression, the underlying mechanism is not clear. In this report we examined the role of the Ca(2+)/calmodulin-dependent protein (CaM) kinase cascade in mediating TRH-stimulated transcription of TSH and PRL. RT-PCR and Western blot analysis were used to show that CaM kinase kinase (CaM-KK) and CaM IV (CaM-KIV) were present in rat anterior pituitary and its cell line GH(3). Next, the effects of constitutively active CaM-KIV (CaM-KIVc) or its dominant negative mutant (CaM-KIVdn) on TSH and PRL promoter activity were tested in GH(3) cells. The results showed that either CaM-KIVc alone or an upstream kinase, CaM-KK, induced the activity of both TSH and PRL promoters. Exposure of GH(3) cells to 100 microm TRH induced CaM-KIV activity within 5 min and, as expected, also increased both TSH and PRL promoter activity. In contrast, cells carrying the CaM-KIVdn isoform had suppressed TRH induction of both TSH and PRL promoter activity. These results indicate that the CaM-KK-CaM-KIV cascade probably plays an important role in TRH induction of TSH and PRL transcriptional activity in pituitary cells.
Animals↗
A mutant high-density lipoprotein receptor inhibits proliferation of human breast cancer cells.
High-density lipoprotein (HDL) stimulates the growth of many types of cells, including those of breast cancer. High levels of HDL are associated with an increased risk of breast cancer development. A scavenger receptor of the B class (SR-BI)/human homolog of SR-BI, CD36, and LIMPII analogous-1 (CLA-1) facilitates the cellular uptake of cholesterol from HDL and thus augments cell growth. Furthermore, HDL is also believed to have antiapoptotic effects on various cell types, and this feature adds to its ability to promote cell growth. These collaborative roles of HDL and CLA-1 prompted us to assess the function of these components on human breast cancer cells. In this study, we created a mutant CLA-1 (mCLA) that lacked the COOH-terminal tail to determine its potential role in breast cancer cell growth. Expression of mCLA inhibited the proliferation of breast cancer cell line MCF-7. This inhibitory action of mCLA required the transcriptional factor activator protein-1 (AP-1), and the mutant receptor also affected the antiapoptotic features of HDL. The effect of HDL on AP-1 activation and [(3)H]thymidine incorporation was abrogated by wortmannin, a specific inhibitor of phosphoinositide 3-kinase. Furthermore, the dominant negative mutant of Akt abolished the ability of HDL to activate AP-1. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for breast cancer.
Apoptosis↗
Effect of thimerosal, a preservative in vaccines, on intracellular Ca2+ concentration of rat cerebellar neurons.
The effect of thimerosal, an organomercurial preservative in vaccines, on cerebellar neurons dissociated from 2-week-old rats was compared with those of methylmercury using a flow cytometer with appropriate fluorescent dyes. Thimerosal and methylmercury at concentrations ranging from 0.3 to 10 microM increased the intracellular concentration of Ca2+ ([Ca2+]i) in a concentration-dependent manner. The potency of 10 microM thimerosal to increase the [Ca2+]i was less than that of 10 microM methylmercury. Their effects on the [Ca2+]i were greatly attenuated, but not completely suppressed, under external Ca(2+)-free condition, suggesting a possibility that both agents increase membrane Ca2+ permeability and release Ca2+ from intracellular calcium stores. The effect of 10 microM thimerosal was not affected by simultaneous application of 30 microM L-cysteine whereas that of 10 microM methylmercury was significantly suppressed. The potency of thimerosal was similar to that of methylmercury in the presence of L-cysteine. Both agents at 1 microM or more similarly decreased the cellular content of glutathione in a concentration-dependent manner, suggesting an increase in oxidative stress. Results indicate that thimerosal exerts some cytotoxic actions on cerebellar granule neurons dissociated from 2-week-old rats and its potency is almost similar to that of methylmercury.
Animals↗
The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression.
A number of factors have been reported to affect insulin synthesis in beta-cells. Although glucose is the most important regulator of insulin gene expression in pancreatic beta-cells, the mechanisms whereby glucose stimulates insulin gene transcription in response to changes in glucose concentration have not been clarified yet. In this study, we examined the role of the Ca(2+)/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of insulin. RT-PCR, Western blotting, and immunohistochemical staining analysis revealed that CaM-K kinase-alpha (CaM-KKalpha) and CaM-KIV were localized in rat pancreatic beta-cells and their cell line, INS-1. Exposure of INS-1 cells to 11.2 mmol/l glucose elicited an increase of insulin promoter activity as well as upregulation of CaM-KIV activity within 2 min after stimulation. We investigated the influence on insulin promoter activity of the constitutively active form (CaM-KIVc) or dominant-negative mutant (CaM-KIVdn) of CaM-KIV in transfected INS-1 cells. CaM-KIVc alone was sufficient, and the upstream kinase, CaM-KK, was enhanced to upregulate the insulin promoter activity in INS-1 cells. Furthermore, cotransfection of CaM-KIVdn suppressed to a significant degree the glucose-upregulated activity of the insulin promoter. Taken together, these results indicated that the CaM-KK/CaM-KIV cascade might play an important role in glucose-upregulated transcriptional activation of the insulin gene.
Animals↗
Activation of mu-calpain in developing cortical neurons following methylmercury treatment.
In order to examine the possible involvement of mu-calpain in methylmercury (MeHg)-induced neurotoxicity in developing cortical neurons, we performed biochemical and immunohistochemical studies utilizing two antibodies which specifically recognize the 150-kDa mu-calpain-specific alpha-spectrin breakdown product (SBDP) and the active form of mu-calpain in rats on postnatal day 16. Soluble fractions of the cerebral cortex from control rats exhibited slight immunoreactivity for SBDP. Although the amount of SBDP in the cerebral cortex was only slightly increased the day after the final treatment of MeHg (10 mg/kg) for 3 or 7 consecutive days, there was a prominent accumulation of SBDP 3 days after the final treatment of MeHg for 7 consecutive days. On the other hand, the 76-kDa isoform of mu-calpain gradually increased after chronic treatment of MeHg, but markedly decreased 3 days after the final treatment of MeHg for 7 consecutive days. At this stage, many cortical neurons were densely stained with anti-SBDP antibody. The delayed increase in SBDP corresponded well with the delayed nature of the MeHg-induced neurotoxicity. When MK-801 (0.1 mg/kg), a non-competitive antagonist of N-methyl-D-aspartate (NMDA), was administered intraperitoneally with MeHg for 7 consecutive days, both neuronal damage and accumulation of SBDP were markedly depressed in the cerebral cortex 3 days after the final treatment. Our results indicate that mu-calpain activation and mu-calpain-mediated proteolysis of alpha-spectrin preceded neuronal damage in the developing cerebral cortex induced by chronic treatment of MeHg.
Animals↗
Expression of human scavenger receptor B1 on and in human platelets.
OBJECTIVE: The abundance of HDL particles correlates inversely with the incidence of coronary heart disease. The human scavenger receptor B1 (hSR-B1/CLA-1) is a receptor for HDL. Expression of hSR-B1/CLA-1 mRNA and protein in human platelets was determined using reverse transcriptase-polymerase chain reaction and Western blot, respectively. Presence of the protein on the surface of platelets was shown using flow cytometry. METHODS AND RESULTS: Immunochemical staining for hSR-B1/CLA-1 showed that it was expressed in megakaryocytes, the platelet precursors of human bone marrow. These findings prompted us to ask whether hSR-B1/CLA-1 was differentially expressed on platelets obtained from patients with atherosclerotic disease compared with those in control subjects. Our findings showed that abundance of hSR-B1/CLA-1 was significantly reduced on the surface of platelets from patients with atherosclerotic disease. The reduced levels of hSR-B1/CLA-1 were associated with increased cholesterol ester content in platelets from patients with atherosclerotic disease compared with control subjects. A negative correlation existed between hSR-B1/CLA-1 expression and platelet aggregation. In summary, our studies show that the HDL receptor hSR-B1/CLA-1 is expressed in platelets and their precursor, the megakaryocyte. The levels of hSR-B1/CLA-1 expression correlate inversely with cholesterol ester content and platelet aggregation. CONCLUSIONS: These findings suggest that determining the level of hSR-B1/CLA-1 expression on the platelets may be a useful clinical marker for atherosclerotic diseases.
Adult↗
The multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells.
A mutant gene isolated from a patient with multiple endocrine neoplasia type 1, MEN1 encodes a protein, menin. Features of MEN1 include multiple endocrine tumors of the parathyroid glands, anterior pituitary and pancreatic islets. Insulinoma, arising from the pancreas is the most common MEN1-related tumor. Menin is a nuclear protein and interacts with the transcription factor, Jun D, but whether menin has a role in the pathogenesis of MEN1-related endocrine tumors including insulinoma remains unknown. In this study, we examined the effects of menin on production of human insulin. Insulinoma cells, INS-1 were co-transfected with a vector that expressed menin and a reporter template containing 235 bp of the rat insulin gene 5'-flanking region fused to the luciferase gene to yield pINS-LUC. Promoter activity of the insulin gene was significantly decreased in co-transfected cells as compared to mock-transfected controls. INS-1 cells stably transfected with a vector that expressed menin were used to examine the insulin secretion. In cells with a high level of menin expression, both insulin secretion and thymidine incorporation into DNA were inhibited when compared to mock-transfected cells. Additionally, the rate of apoptosis of menin-transfected cells was increased compared to mock-transfected cells. These observations suggest that menin inhibits insulin promoter activity and secretion, and also cell proliferation, raising the possibility that menin may play an important role in the pathogenesis of insulinoma.
Animals↗