Psychological skills training impacts autonomic nervous system responses to stress during sport-specific imagery: An exploratory study in junior elite shooters.

This study investigated the effects of psychological skills training (PST) in shooters psychophysiologically using heart rate variability (HRV) in addition to psychological questionnaires and participant interviews. Five junior pistol shooters participated in an 8-week PST program consisting of a group session per week followed by individual counseling. Before and after PST, we collected electrocardiography data during rest, mental imagery of sport-related crisis situations, and successful performance, to analyze differences in HRV indices. Participants also responded to the Psychological Skills Inventory for Archery and Shooting (PSIAS), Intrinsic Motivation Inventory (IMI), Sports Anxiety Scale (SAS), and Trait Sport Confidence Inventory (TSCI). Results showed that the perceived competence (pre: 2.52 ± 0.95, post: 3.36 ± 0.73, p = 0.049) and trait sport confidence (pre: 4.94 ± 1.17, post: 6.60 ± 0.65, p = 0.049) significantly improved after PST. The analysis of HRV indicated that the ratio of low-frequency power to high-frequency power (LF/HF ratio) decreased significantly during imagery of crisis (pre: 3.4 ± 2.3, post: 1.014 ± 0.71, p = 0.038) and success (pre: 1.933 ± 0.917, post: 0.988 ± 0.572, p = 0.046), reflecting a strengthened autonomic nervous system's responsiveness to stress. Our findings illustrate that PST can help athletes better cope with psychologically disturbed situations during competition, by providing psychophysiological evidence through HRV changes.

Porcine Epidemic Diarrhea Virus Infection Induces Autophagosome Formation but Inhibits Autolysosome Formation during Replication.

In this study, we investigated the correlation between the mechanism involved in porcine epidemic diarrhea virus (PEDV) replication and autophagic flux. In this study, we found that as PEDV replicated, production of LC3-II was significantly induced up to 24 h post-infection (hpi). Interestingly, although there was significant production of LC3-II, greater p62 accumulation was simultaneously found. Pretreatment with rapamycin significantly induced PEDV replication, but autolysosome formation was reduced. These results were confirmed by the evaluation of ATG5/ATG12 and LAMP1/LAMP2. Taken together, we conclude that PEDV infection induces autophagosome formation but inhibits autolysosome formation during replication.

Reduction of Cell Fusion by Deletion in the Hypervariable Region of the Spike Protein of Mouse Hepatitis Virus.

Deletions in the spike gene of mouse hepatitis virus (MHV) produce several variants with diverse biological characteristics, highlighting the significance of the spike gene in viral pathogenesis. In this study, we characterized the JHM-X strain, which has a deletion in the hypervariable region (HVR) of the spike gene, compared with the cl-2 strain, which has a full spike gene. Cytopathic effects (CPEs) induced by the two strains revealed that the size of the CPE produced by cl-2 is much greater than that produced by JHM-X in delayed brain tumor (DBT) cells. Thus, this finding explains the greater fusion activity of cl-2 than JHM-X in cultured cells, and we speculate that the deletion region of the spike protein is involved in the fusion activity differences. In contrast with the fusion activity, a comparison of the virus growth kinetics revealed that the titer of JHM-X was approximately 100 times higher than that of cl-2. We found that the deletion region of the spike protein was involved in fusion activity differences, whereas cl-2 produced significantly higher luciferase activity than JHM-X upon similar expression levels of the spike protein. However, the reason behind the growth difference is still unknown. Overall, we discovered that deletion in the HVR of the spike gene could be involved in the fusion activity differences between the two strains.

Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells.

BACKGROUND: One of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused coronavirus disease 2019 (COVID-19) pandemic and threatened worldwide. However, therapy for COVID-19 has rarely been proven to possess specific efficacy. As the virus relies on host metabolism for its survival, several studies have reported metabolic intervention by SARS-CoV-2. RESULTS: We investigated the coronavirus-metabolic hijacking using mouse hepatitis virus (MHV) as a surrogate for SARS-CoV-2. Based on the altered host metabolism by MHV infection, an increase of glycolysis with low mitochondrial metabolism, we tried to investigate possible therapeutic molecules which increase the TCA cycle. Endogenous metabolites and metabolic regulators were introduced to restrain viral replication by metabolic intervention. We observed that cells deprived of cellular energy nutrition with low glycolysis strongly suppress viral replication. Furthermore, viral replication was also significantly suppressed by electron transport chain inhibitors which exhaust cellular energy. Apart from glycolysis and ETC, pyruvate supplement suppressed viral replication by the TCA cycle induction. As the non-glucose metabolite, fatty acids supplement decreased viral replication via the TCA cycle. Additionally, as a highly possible therapeutic metabolite, nicotinamide riboside (NR) supplement, which activates the TCA cycle by supplying NAD+, substantially suppressed viral replication. CONCLUSIONS: This study suggests that metabolite-mediated TCA cycle activation suppresses replication of coronavirus and suggests that NR might play a role as a novel therapeutic metabolite for coronavirus.

Heat shock protein 70 could enhance porcine epidemic diarrhoea virus replication by interacting with membrane proteins.

In this study, we investigated the role of heat shock protein 70 (HSP70) in porcine epidemic diarrhoea virus (PEDV) replication. We found that PEDV infection induced strong HSP70 overexpression in the very early stage of infection. We also confirmed that HSP70 overexpression increased the speed of PEDV replication, resulting in the generation of more virions. In contrast, knockout of HSP70 in cells significantly downregulated PEDV protein expression, resulting in a significant reduction in PEDV replication. Most importantly, we confirmed that among the structural proteins of PEDV, membrane (M) proteins have this important role. We found that membrane proteins control cellular HSP70 expression in PEDV-infected cells. We confirmed HSP70/M complex formation by both immunoprecipitation and immunofluorescence assays. Additionally, PEDV M overexpression induced strong HSP70 expression. All our results clearly confirmed that in PEDV-infected cells, the M protein plays a very important role in PEDV replication in collaboration with HSP70.

Differential Diagnosis for Highly Pathogenic Avian Influenza Virus Using Nanoparticles Expressing Chemiluminescence.

Highly pathogenic avian influenza (HPAI) virus is a causative agent of systemic disease in poultry, characterized by high mortality. Rapid diagnosis is crucial for the control of HPAI. In this study, we aimed to develop a differential diagnostic method that can distinguish HPAI from low pathogenic avian influenza (LPAI) viruses using dual split proteins (DSPs). DSPs are chimeras of an enzymatic split, Renilla luciferase (RL), and a non-enzymatic split green fluorescent protein (GFP). Nanoparticles expressing DSPs, sialic acid, and/or transmembrane serine protease 2 (TMPRSS2) were generated, and RL activity was determined in the presence of HPAI or LPAI pseudotyped viruses. The RL activity of nanoparticles containing both DSPs was approximately 2 × 106 RLU, indicating that DSPs can be successfully incorporated into nanoparticles. The RL activity of nanoparticles containing half of the DSPs was around 5 × 101 RLU. When nanoparticles containing half of the DSPs were incubated with HPAI pseudotyped viruses at low pH, RL activity was increased up to 1 × 103 RLU. However, LPAI pseudotyped viruses produced RL activity only in the presence of proteases (trypsin or TMPRSS2), and the average RL activity was around 7 × 102 RLU. We confirmed that nanoparticle fusion assay also diagnoses authentic viruses with specificity of 100% and sensitivity of 91.67%. The data indicated that the developed method distinguished HPAI and LPAI, and suggested that the diagnosis using DSPs could be used for the development of differential diagnostic kits for HPAI after further optimization.

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses.

Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment.

Transplacental Transmission of Porcine Epidemic Diarrhea Virus.

Because the porcine epidemic diarrhea virus (PEDV) is a critical pathogen resulting in rapid spreading and high mortality rates in piglets, understanding of the transmission route of PEDV is required for its controlling. Until now, it is well known that PEDV transmission routes are various, such as fecal-oral route, contaminated feed, farmworkers, and transport vehicles. However, unlike several swine-infected viruses, there were no reports of vertical transmission with PEDV. In our study, we confirmed possible vertical transmission of PEDV. We confirmed PEDV in piglet testicles and umbilical cords from PEDV-positive sow. These findings are direct evidence that PEDV is transmitted vertically through placenta. This is the first report on transplacental transmission of PEDV and will be very important information for controlling PED.

Real-time monitoring of toxic components from fine dust air pollutant samples by utilizing spark-induced plasma spectroscopy.

A growing modern-day concern is fine dust air pollution that contains heavy metals and ammonium ions (NH4+) from industrial and agricultural waste sources, respectively. In the current study, the development of an innovative and effective technique for real-time, quantitative monitoring of toxic fine dust components using plasma emission spectroscopy is presented as a complement to emergency preparedness plans aimed at reducing dust pollution. A novel spark-induced plasma spectroscopic (SIPS) device that can control the frequency and magnitude of plasma was developed for the toxic pollutants in this work. SIPS utilizes an electrical discharge from a high voltage at a low current to produce plasma when the applied voltage is higher than the ambient voltage surrounding the electrodes. The detection limit of this setup was enhanced by a factor of 4.3 over laser-induced plasma spectroscopy (LIPS). This compact sensing device was used in combination with a new quantitative analytical method to measure the concentration of heavy metals and ammonia molecules in fine dust air pollution. By integrating the time-resolved plasma emission signals that were based on the plasma continuum decay time of each element, quantitative measurements of the minute changes in composition of 0.1 µg/m3 were conducted. The findings of this study could inspire future research on the use of SIPS for monitoring airborne fine dust pollutants with better sensitivity in real-time via a new quantitative analytical method.

A non-calorimetric approach for investigating the moisture-induced ageing of a pyrotechnic delay material using spectroscopies.

The degradation of thermal properties due to ageing such as burning rate and exothermic heat release are unsolved issues faced during a long-term storage of the pyrotechnic substances. Accordingly, we employed various non-calorimetric methods to investigate the thermal performance of pyrotechnic delay, which is exposed to various moisture-rich conditions at extended durations. The chemical and physical changes in the compositions of a pyrotechnic delay comprised of metal fuel (Zr-Ni alloy) and oxidants (KClO4, BaCrO4) are analysed for four different relative humidity levels using X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscope and laser-induced breakdown spectroscopy. The calculations using the NASA Chemical Equilibrium with Applications (CEA) software indicated that the heat of reaction for the components stored under the moisture-rich conditions is reduced by more than 50%. Unlike the conventional calorimetric analysis, the present non-calorimetric approach provided the compositional changes as well as the cause and effect of the relevant ageing process of pyrotechnic delay.

Molecular Insights Into Withaferin-A-Induced Senescence: Bioinformatics and Experimental Evidence to the Role of NFκB and CARF.

Withaferin-A (Wi-A) has been shown to possess anticancer activity. Molecular mechanism(s) of its action has not been fully resolved. We recruited low dose of Wi-A that caused slow growth arrest in cancer cells and was relatively safe for normal cells. Consistently, we detected nuclear translocation of nuclear factor kappa B (NFκB) and activation of p38MAPK selectively in cancer cells. Bioinformatics analyses revealed that Wi-A did not disrupt IKKα/IKKß-Nemo complex that regulates NFκB activity. However, it caused moderate change in the conformation of IKKß-Nemo interacting domain. Experimental data revealed increased level of phosphorylated IκBα in Wi-A-treated cells, suggesting an activation of IKK complex that was supported by nuclear translocation of NFκB. Molecular docking analysis showed that Wi-A did not disrupt; however, decreased the stability of the NFκB-DNA complex. It was supported by downregulation of DNA-binding and transcriptional activities of NFκB. Further analysis revealed that Wi-A caused upregulation of CARF (collaborator of ARF) demonstrating an activation of DNA damage oxidative stress response in both cancer and normal cells. In line with this, upregulation of p21WAF1, p16INK4A, and hypophosphorylated pRB and induction of senescence were observed demonstrating that Wi-A-induced senescence is mediated by multiple pathways in which CARF-mediated DNA damage and oxidative stress play a major role.

Porcine epidemic diarrhea vaccine evaluation using a newly isolated strain from Korea.

Porcine epidemic diarrhea virus (PEDV) infects pigs and causes an enteric disease that is characterized by vomiting and watery diarrhea. PEDV outbreaks have a tremendous financial impact on the worldwide pork industry. In South Korea, the incidence of PEDV has continued despite nationwide use of attenuated and inactivated vaccines, raising questions regarding the current vaccines' efficacy and the need for new vaccine development. In the present study, we isolated a new Korean PEDV epidemic strain, PED-CUP-B2014, in Vero cells. Phylogenetic analysis of the spike gene demonstrated that the PED-CUP-B2014 belongs in genogroup G2b and is close to PEDVs currently circulating in many countries including the United States, and is distinct from many current vaccine strains. Upon serial passages into Vero cells, PED-CUP-B2014 adapted to Vero cells, which was evidenced as higher virus growth in Vero cells and confirmed lower virulence in suckling piglets. The administration of the inactivated 65-passaged PED-CUP-B2014 to sows greatly increased the survival rate of their offspring and significantly reduced diarrhea severity after PEDV challenge. Higher serum/colostrum PEDV-specific antibodies and higher neutralizing titers were shown in sows vaccinated with PED-CUP-B2014 compared to unvaccinated sows or sows administered commercial PEDV vaccine. Altogether, our data demonstrated that the newly isolated PEDV strain conferred critical passive immune protection to pigs against epidemic PEDV infection.

Pectinase-treated Panax ginseng protects against chronic intermittent heat stress-induced testicular damage by modulating hormonal and spermatogenesis-related molecular expression in rats.

BACKGROUND: Elevated testicular temperature disrupts spermatogenesis and causes infertility. In the present study, the protective effect of enzymatically biotransformed Panax ginseng Meyer by pectinase (GINST) against chronic intermittent heat stress-induced testicular damage in rats was investigated. METHODS: Male Sprague-Dawley rats (4 wk old, 60-70 g) were divided into four groups: normal control (NC), heat-stress control (HC), heat-stress plus GINST-100 mg/kg (HG100), and heat-stress plus GINST-200 mg/kg (HG200) treatment groups. Each dose of GINST (100 mg/kg and 200 mg/kg) was mixed separately with a regular pellet diet and was administered orally for 24 wk. For inducing heat stress, rats in the NC group were maintained at 25°C, whereas rats in the HC, HG100, and HG200 groups were exposed to 32 ± 1°C for 2 h daily for 6 mo. At week 25, the testes and serum from each animal were analyzed for various parameters. RESULTS: Significant (p < 0.01) changes in the sperm kinematic values and blood chemistry panels were observed in the HC group. Furthermore, spermatogenesis-related molecules, sex hormone receptors, and selected antioxidant enzyme expression levels were also altered in the HC group compared to those in the NC group. GINST (HS100 and HS200) administration significantly (p < 0.05) restored these changes when compared with the HC group. For most of the parameters tested, the HG200 group exhibited potent effects compared with those exhibited by the HG100 group. CONCLUSION: GINST may be categorized as an important medicinal herb and a potential therapeutic for the treatment of male subfertility or infertility caused by hyperthermia.

Relevance of mortalin to cancer cell stemness and cancer therapy.

Mortalin/mtHsp70 is a member of Hsp70 family of proteins. Enriched in a large variety of cancers, it has been shown to contribute to the process of carcinogenesis by multiple ways including inactivation of tumor suppressor p53 protein, deregulation of apoptosis and activation of EMT signaling. In this study, we report that upregulation of mortalin contributes to cancer cell stemness. Several cancer cell stemness markers, such as ABCG2, OCT-4, CD133, ALDH1, CD9, MRP1 and connexin were upregulated in mortalin-overexpressing cells that showed higher ability to form spheroids. These cells also showed higher migration, and were less responsive to a variety of cancer chemotherapeutic drugs. Of note, knockdown of mortalin by specific shRNA sensitized these cells to all the drugs used in this study. We report that low doses of anti-mortalin molecules, MKT-077 and CAPE, also caused similar sensitization of cancer cells to chemotherapeutic drugs and hence are potential candidates for effective cancer chemotherapy.

Korean red ginseng improves testicular ineffectiveness in aging rats by modulating spermatogenesis-related molecules.

Korean red ginseng (Panax ginseng Meyer) is known to rejuvenate testicular effectiveness and the sperm maturation process by regulating redox proteins in aged rats. This study was performed to investigate the effect of Korean red ginseng water extract (KRG-WE) on the expression level of spermatogenesis-related key biomolecules and sex hormone receptors as well as enzymes regulating oxidation, histone deacetylation, and growth-related activities in aged rat testis. KRG-WE (200mg/kg) mixed with a regular pellet diet was administered to 12-month-old rats for 6months (KRG-AC), whereas the young (YC, 2months) and aged (AC, 12months) controls received the vehicle only. The results showed that the expression levels of spermatogenesis-related key biomolecules (inhibin-α, nectin-2, and cyclic adenosine monophosphate [cAMP] responsive element binding protein [CREB]-1), sex hormone receptors (androgen, luteinizing- and follicle-stimulating hormone receptors [AR, LHR, and FSHR, respectively]), and antioxidant enzymes (glutathione S-transferase mu [GSTm]-5, glutathione peroxidase [GPx]-4, peroxiredoxin [PRx]-3), as well as histone deactylation (silent mating type information regulation 2 homolog 1, SIRT1) and growth-related (mammalian target of rapamycin complex 1, mTORC1) molecules were significantly altered in the AC group rat testes compared with those of the YC group. However, KRG-WE treatment of the AC group significantly (p<0.05) attenuated these molecular changes. From these results, it can be concluded that long-term administration of KRG-WE significantly delayed the aging-induced testicular dysfunction.

Canola oil is an excellent vehicle for eliminating pesticide residues in aqueous ginseng extract.

BACKGROUND: We previously reported that two-phase partition chromatography between ginseng water extract and soybean oil efficiently eliminated pesticide residues. However, an undesirable odor and an unpalatable taste unique to soybean oil were two major disadvantages of the method. This study was carried out to find an alternative vegetable oil that is cost effective, labor effective, and efficient without leaving an undesirable taste and smell. METHODS: We employed six vegetable oils that were available at a grocery store. A 1-mL sample of the corresponding oil containing a total of 32 pesticides, representing four categories, was mixed with 10% aqueous ginseng extract (20 mL) and equivalent vegetable oil (7 mL) in Falcon tubes. The final concentration of the pesticides in the mixture (28 mL) was adjusted to approximately 2 ppm. In addition, pesticides for spiking were clustered depending on the analytical equipment (GC/HPLC), detection mode (electron capture detector/nitrogen-phosphorus detector), or retention time used. Samples were harvested and subjected to quantitative analysis of the pesticides. RESULTS: Soybean oil demonstrated the highest efficiency in partitioning pesticide residues in the ginseng extract to the oil phase. However, canola oil gave the best result in an organoleptic test due to the lack of undesirable odor and unpalatable taste. Furthermore, the qualitative and quantitative changes of ginsenosides evaluated by TLC and HPLC, respectively, revealed no notable change before or after canola oil treatment. CONCLUSION: We suggest that canola oil is an excellent vehicle with respect to its organoleptic property, cost-effectiveness and efficiency of eliminating pesticide residues in ginseng extract.

Stress chaperone mortalin contributes to epithelial-mesenchymal transition and cancer metastasis.

Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In the present study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), ß-catenin (CTNNB1), CK14 (KRT14) and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNA-mediated and pharmacological inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models.

Simple synthetic protein scaffolds can create adjustable artificial MAPK circuits in yeast and mammalian cells.

As hubs for eukaryotic cell signaling, scaffold proteins are attractive targets for engineering and manipulating signaling circuits. We designed synthetic scaffolds with a repeated PDZ domain that interacted with engineered kinases of the mitogen-activated protein kinase (MAPK) cascade involved in yeast mating to investigate how modular interactions mediate kinase cascades. The synthetic scaffolds functioned as logic gates of signaling circuits. We replaced the endogenous yeast scaffold Ste5 with designer scaffolds with a variable numbers of a PDZ domain that bound kinases or phosphatases engineered with a PDZ-binding motif. Although association with the membrane was necessary for pathway activity, surprisingly, mating responses occurred when the circuit contained a scaffold with only two PDZ domains, which could only bind two of the three kinases simultaneously. Additionally, the three tiers of the MAPK pathway exhibited decreasing positional plasticity from the top [MAPK kinase kinase (MAPKKK)] to the bottom (MAPK) tier such that binding of a MAPKKK, but not a MAPK, from the osmoregulatory pathway or protein kinase C pathway to the synthetic scaffold activated a reporter of the mating response. We also showed that the output duration and intensity could be altered by recruiting phosphatases or varying the affinity of the recruited proteins for the scaffold and that a designer MAPK scaffold functioned in mammalian cells. Thus, this synthetic approach with designer scaffolds should enable the rational manipulation or engineering of signaling pathways and provide insight into the functional roles of scaffold proteins.

Functional significance of point mutations in stress chaperone mortalin and their relevance to Parkinson disease.

Mortalin/mtHsp70/Grp75 (mot-2), a heat shock protein 70 family member, is an essential chaperone, enriched in cancers, and has been shown to possess pro-proliferative and anti-apoptosis functions. An allelic form of mouse mortalin (mot-1) that differs by two amino acids, M618V and G624R, in the C terminus substrate-binding domain has been reported. Furthermore, genome sequencing of mortalin from Parkinson disease patients identified two missense mutants, R126W and P509S. In the present study, we investigated the significance of these mutations in survival, proliferation, and oxidative stress tolerance in human cells. Using mot-1 and mot-2 recombinant proteins and specific antibodies, we performed screening to find their binding proteins and then identified ribosomal protein L-7 (RPL-7) and elongation factor-1 α (EF-1α), which differentially bind to mot-1 and mot-2, respectively. We demonstrate that mot-1, R126W, or P509S mutant (i) lacks mot-2 functions involved in carcinogenesis, such as p53 inactivation and hTERT/hnRNP-K (heterogeneous nuclear ribonucleoprotein K) activation; (ii) causes increased level of endogenous oxidative stress; (iii) results in decreased tolerance of cells to exogenous oxidative stress; and (iv) shows differential binding and impact on the RPL-7 and EF-1α proteins. These factors may mediate the transformation of longevity/pro-proliferative function of mot-2 to the premature aging/anti-proliferative effect of mutants, and hence may have significance in cellular aging, Parkinson disease pathology, and prognosis.

Identification and functional characterization of nuclear mortalin in human carcinogenesis.

The Hsp70 family protein mortalin is an essential chaperone that is frequently enriched in cancer cells and exists in various subcellular sites, including the mitochondrion, plasma membrane, endoplasmic reticulum, and cytosol. Although the molecular mechanisms underlying its multiple subcellular localizations are not yet clear, their functional significance has been revealed by several studies. In this study, we examined the nuclear fractions of human cells and found that the malignantly transformed cells have more mortalin than the normal cells. We then generated a mortalin mutant that lacked a mitochondrial targeting signal peptide. It was largely localized in the nucleus, and, hence, is called nuclear mortalin (mot-N). Functional characterization of mot-N revealed that it efficiently protects cancer cells against endogenous and exogenous oxidative stress. Furthermore, compared with the full-length mortalin overexpressing cancer cells, mot-N derivatives showed increased malignant properties, including higher proliferation rate, colony forming efficacy, motility, and tumor forming capacity both in in vitro and in vivo assays. We demonstrate that mot-N promotes carcinogenesis and cancer cell metastasis by inactivation of tumor suppressor protein p53 functions and by interaction and functional activation of telomerase and heterogeneous ribonucleoprotein K (hnRNP-K) proteins.