• BMB Reports
• /
• v.50 no.12
• /
• pp.601-609
• /
• 2017

Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrientrich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.

• BMB Reports
• /
• v.32 no.4
• /
• pp.385-392
• /
• 1999

The $NAD^+$-specific activity of a dual coenzyme-specific isocitrate dehydrogenase (IDH; EC 1.1.1.41) from the primitive fungus Pythium ultimum was investigated to elucidate the regulatory factors that may influence the intracellular distribution of carbon and the availability of intermediates, e.g. citrate, for fatty acid synthesis. Inhibition of $NAD^+$-IDH activity by diphospho- and triphosphonucleotides (ATP, ADP, and GTP) reflected the sensitivity of this enzyme to cellular energy charge even though monophosphonucleotides (AMP and GMP) had little effect on activity. NADPH, but not NADH, substantially inhibited $NAD^+$-IDH activity, showing noncompetitive inhibition with isocitrate. Oxalacetate and ${\alpha}$-ketoglutarate showed competitive inhibition with isocitrate, while citrate and cis-aconitate showed mixed-noncompetitive inhibition with isocitrate. Inhibition by these substances ranged from 29 to 46% at 10 mM. The inhibitory effect of oxalacetate was increased synergistically by glyoxylate, which alone caused 31% uncompetitive inhibition at 10 mM, and a mixture of the two substances at 1 mM each showed 98% inhibition of $NAD^+$-IDH activity. The regulation of $NAD^+$-IDH in Pythium ultimum seems to be a complex process involving mitochondrial metabolites. The addition of glyoxylate (3 mM) and oxalacetate (3 mM) to the culture medium resulted in the production of 49% more lipid by P. ultimum.

• Korean Journal of Poultry Science
• /
• v.19 no.3
• /
• pp.161-176
• /
• 1992

Coccidiosis is caused by Eimeria infecting primarily the intestine of the susceptible host, thereby seriously impairing the growth and feed utilization of livestock and poultry. The genus Eimeria contains a number of obligate intracellular protozoan parasites with a complicated life-cycle involving both asexual and sexual stages of development. The desire to develop a vaccine against Eimeria has Promoted active research to elucidate the mechanisms of protective immunity and identification of candidate vaccine antigens. Protozoa are unique in their modes of transmission and nature of disease manifestations, the significance of which should be considered in the development of a control strategy. An intricate and complex interplay of different cell populations and cytokines is involved not only in the pathogenesis of coccidiosis but also in the development of protective immunity Thus, comprehensive understanding of the events leading to protection following Eimeria infection will be crucial for the development of an effective vaccine.

• Journal of Microbiology and Biotechnology
• /
• v.16 no.8
• /
• pp.1174-1179
• /
• 2006

The wild-type Corynebacterium glutamicum ATIC 13032 and Corynebacterium glutamicum ATTC 13032 lysC S301Y, exhibiting a deregulated aspartokinase, were compared concerning growth, lysine production, and intracellular carbon fluxes. Both strains differ by only one single nucleotide over the whole genome. In comparison to the wild-type, the mutant showed significant production of lysine with a molar yield of 0.087 mol (mol glucose$^{-1}$) whereas the biomass yield was reduced. The deregulation of aspartokinase further led to a global rearrangement of carbon flux throughout the whole central metabolism. This involved an increased flux through the pentose phosphate pathway (PPP) and an increased flux through anaplerosis. Because of this, the mutant revealed an enhanced supply of NADPH and oxaloacetate required for lysine biosynthesis. Additionally, the lumped flux through phosphoenolpyruvate carboxykinase and malic enzyme, withdrawing oxaloacetate back to the glycolysis and therefore detrimental for lysine production, was increased. The reason for this might be a contribution of malic enzyme to NADPH supply in the mutant in the mutant. The observed complex changes are remarkable, because they are due to the minimum genetic modification possible, the exchange of only one single nucleotide.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.6
• /
• pp.2575-2580
• /
• 2015

Cancer is a multifaceted and genomically complex disease and rapidly accumulating high impact research is deepening our understanding related to the mechanisms underlying cancer development, progression and resistance to therapeutics. Increasingly it is being realized that genetic/epigenetic mutations, inactivation of tumor suppressor genes, overexpression of oncogenes, deregulation of intracellular signaling cascades and loss of apoptosis are some of the extensively studied aspects. Confluence of information suggested that rapidly developing resistance to therapeutics is adding another layer of complexity and overwhelmingly increasing preclinical studies are identifying different natural agents with efficacy and minimal off-target effects. We partition this multi-component review into citrus fruits and their bioactive ingredients mediating rebalancing of pro- and anti-apoptotic proteins to induce apoptosis in resistant cancer cells. We also discuss how oncogenic protein networks are targeted in cancer cells and how these findings may be verified in preclinical studies.

• BMB Reports
• /
• v.31 no.5
• /
• pp.468-474
• /
• 1998

Membrane depolarization in PC12 cells induces calcium influx via an L-type voltage-sensitive calcium channel (L-VSCC) and increases intracellular free calcium, which leads to tyrosine phosphorylation of epidermal growth factor (EGF) receptor and the associated adaptor protein, She. This activated EGF receptor complex then can activate mitogen-activated protein (MAP) kinase, as in nerve growth factor (NGF) receptor activation. In the present study, we investigated the role of EGF receptor in the signaling pathway initiated by membrane depolarization of PC12 cells. Prolonged membrane depolarization induced phosphorylation of extracellular signal-regulated kinase (ERK) within 1 min in undifferentiated PC12 cells. Pretreatment of PC12 cells with the calcium chelator EGTA abolished depolarization-stimulated ERK phosphorylation, but NGF-induced phosphorylation of ERK was not affected. The chronic treatment of phorbol ester, which down-regulated the activity of protein kinase C (PKC), did not affect the phosphorylation of ERK upon depolarization. In the presence of an inhibitor of EGF receptor, neither depolarization nor calcium ionophore increased the level of ERK phosphorylation. These data imply that the EGF receptor is functionally necessary to activate ERK and neurite outgrowth in response to the prolonged depolarization in PC12 cells, and also that PKC is apparently not involved in this signaling pathway.

• BMB Reports
• /
• v.48 no.8
• /
• pp.431-437
• /
• 2015

Notch signaling plays a pivotal role in cell fate determination, cellular development, cellular self-renewal, tumor progression, and has been linked to developmental disorders and carcinogenesis. Notch1 is activated through interactions with the ligands of neighboring cells, and acts as a transcriptional activator in the nucleus. The Notch1 intracellular domain (Notch1-IC) regulates the expression of target genes related to tumor development and progression. The Notch1 protein undergoes modification after translation by posttranslational modification enzymes. Phosphorylation modification is critical for enzymatic activation, complex formation, degradation, and subcellular localization. According to the nuclear cycle, Notch1-IC is degraded by E3 ligase, FBW7 in the nucleus via phosphorylation-dependent degradation. Here, we summarize the Notch signaling pathway, and resolve to understand the role of phosphorylation in the regulation of Notch signaling as well as to understand its relation to cancer. [BMB Reports 2015; 48(8): 431-437]

• Journal of Korean Academy of Oral and Maxillofacial Radiology
• /
• v.24 no.2
• /
• pp.403-410
• /
• 1994

The purpose of this study was to investigate the irradiation effects on the secretory granules of the rat submandibular gland acinar cell. For this study, Sprague-Dawley strain rats were irradiated to their neck region with the dose of 5Gy and l0Gy by 6MV X-radiation, and sacrificed on the experimental periods after irradiation. The authors observed the ultrastructural changes of the secretory granules of the rat submandibular gland acinar cell under a trasmission electron microscope. The results were as follows: In the transmission electron microscopic examination, secretory granules were blurred in limiting membrane on the 3hours groups after irradiation. And they showed decrease in number, irregularities in shape and distributional pattern, and inhomogeneous internal electron density on the Iday and 3days groups. After then, these changes were recovered in shape and distributional pattern on the 14days groups, and changes of internal electron density and limiting membrane were recovered on the 28days groups after irradiation. Among the intracellular organelles, rough endoplasmic reticulum was scattered, but golgi complex was not changed. And such pathologic changes were earlier and more prominent in 10Gy irradiated groups than in 5Gy irradiated groups.

• Molecules and Cells
• /
• v.22 no.2
• /
• pp.175-181
• /
• 2006

Delivery of DNA vaccines to airway mucosa would be an ideal method for mucosal immunization. However, there have been few reports of a suitable gene delivery system. In this study we used a cationic emulsion to immunize mice via the intranasal route with pCMV-S coding for Hepatitis B virus surface antigen (HBsAg). Complexing pCMV-S with a cationic emulsion dramatically enhanced HBsAg expression in both nasal tissue and lung, and was associated with increases in the levels of HBs-specific Abs in serum and mucosal fluids, of cytotoxic T lymphocytes (CTL) in the spleen and cervical and iliac lymph nodes, and of delayed-type hypersensitivity (DTH) against HBsAg. In contrast, very weak humoral and cellular immunities were observed following immunization with naked DNA. In support of these observations, a higher proliferative response of spleenocytes was detected in the group immunized with the emulsion/pCMV-S complex than in the group immunized with naked pCMV-S. These findings may facilitate development of an emulsion-mediated gene vaccination technique for use against intracellular pathogens that invade mucosal surfaces.

• Macromolecular Research
• /
• v.17 no.1
• /
• pp.19-25
• /
• 2009

In order to enhance the gene delivery efficiency and decrease the cytotoxicity of polyplexes, we synthesized Solutol-g-PEI by conjugating polyethyleneimine (PEI) to Solutol (polyoxyethylene (10) stearate), and evaluated its efficiency as a possible nonviral gene carrier candidate. Structural analysis of synthesized polymer was performed by using $^1H$-NMR. Gel retardation assay, particle sizes and zeta potential measurement confirmed that the new gene carrier formed a compact complex with plasmid DNA. The complexes were smaller than 150 nm, which implicated its potential for intracellular delivery. It showed lower cytotoxicity in three different cell lines (Hela, MCF-7, and HepG2) than PEI 25 kDa. pGL3-lus was used as a reporter gene, and the transfection efficiency was in vitro measured in Hela cells. Solutol-g-PEI showed much higher transfection efficiency than unmodified PEI 25 kDa.