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Results for “factorization”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,675 records · Page 93
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DOE OSTI2015

Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SUMOylation of the KRAB zinc-finger transcription factor PARIS/ZNF746 regulates its transcriptional activity

Parkin-interacting substrate (PARIS), a member of the family of Krüppel-associated box (KRAB)-containing zinc-finger transcription factors, is a substrate of the ubiquitin E3 ligase parkin. PARIS represses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), although the underlying mechanisms remain largely unknown. In the present study, we demonstrate that PARIS can be SUMOylated, and its SUMOylation plays a role in the repression of PGC-1a promoter activity. Protein inhibitor of activated STAT y (PIASy) was identified as an interacting protein of PARIS and shown to enhance its SUMOylation. PIASy repressed PGC-1a promoter activity, and this effect was attenuated by PARIS in a manner dependent on its SUMOylation status. Co-expression of SUMO-1 with PIASy completely repressed PGC-1a promoter activity independently of PARIS expression. PARIS-mediated PGC-1a promoter repression depended on the activity of histone deacetylases (HDAC), whereas PIASy repressed the PGC-1a promoter in an HDAC-independent manner. Taken together, these results suggest that PARIS and PIASy modulate PGC-1a gene transcription through distinct molecular mechanisms. -- Highlights: •PARIS can be SUMOylated in vivo and in vitro. •SUMOylation of PARIS functions in the repression of PGC-1a promoter activity. •PIASy interacts with PARIS and enhances its SUMOylation. •PIASy influences PARIS-mediated repression of PGC-1a promoter activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3

Aberrant expression of microRNAs (miRNAs) is implicated in cancer development and progression. While miR-320a is reported to be deregulated in many malignancy types, its biological role in multiple myeloma (MM) remains unclear. Here, we observed reduced expression of miR-320a in MM samples and cell lines. Ectopic expression of miR-320a dramatically suppressed cell viability and clonogenicity and induced apoptosis in vitro. Mechanistic investigation led to the identification of Pre-B-cellleukemia transcription factor 3 (PBX3) as a novel and direct downstream target of miR-320a. Interestingly, reintroduction of PBX3 abrogated miR-320a-induced MM cell growth inhibition and apoptosis. In a mouse xenograft model, miR-320a overexpression inhibited tumorigenicity and promoted apoptosis. Our findings collectively indicate that miR-320a inhibits cell proliferation and induces apoptosis in MM cells by directly targeting PBX3, supporting its utility as a novel and potential therapeutic agent for miRNA-based MM therapy. -- Highlights: •Expression of miR-320a in MM cell induces apoptosis in vitro. •miR-320a represses PBX3 via targeting specific sequences in the 3′UTR region. •Exogenous expression of PBX3 reverses the effects of miR-320a in inhibiting MM cell growth and promoting apoptosis. •Overexpression of miR-320a inhibits tumor growth and increases apoptosis in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

GOLDEN2-LIKE transcription factors coordinate the tolerance to Cucumber mosaic virus in Arabidopsis

Arabidopsis thaliana GOLDEN2-LIKE (GLKs) transcription factors play important roles in regulation of photosynthesis-associated nuclear genes, as well as participate in chloroplast development. However, the involvement of GLKs in plants resistance to virus remains largely unknown. Here, the relationship between GLKs and Cucumber mosaic virus (CMV) stress response was investigated. Our results showed that the Arabidopsis glk1glk2 double-mutant was more susceptible to CMV infection and suffered more serious damages (such as higher oxidative damages, more compromised in PSII photochemistry and more reactive oxygen species accumulation) when compared with the wild-type plants. Interestingly, there was little difference between single mutant (glk1 or glk2) and wild-type plants in response to CMV infection, suggesting GLK1 and GLK2 might function redundant in virus resistance in Arabidopsis. Furthermore, the induction of antioxidant system and defense-associated genes expression in the double mutant were inhibited when compared with single mutant or wild-type plants after CMV infection. Further evidences showed that salicylic acid (SA) and jasmonic acid (JA) might be involved in GLKs-mediated virus resistance, as SA or JA level and synthesis-related genes transcription were impaired in glk1glk2 mutant. Taken together, our results indicated that GLKs played a positively role in virus resistance in Arabidopsis. - Highlights: • GLKs play a positive role in CMV resistance in Arabidopsis. • Defective of GLKs suffered more ROS accumulation. • Arabidopsis lacking GLKs have damaged photosynthesis. • Arabidopsis lacking GLKs show low SA and JA accumulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation

The epidermal growth factor receptor (EGFR) is activated through binding to specific ligands and generates signals for proliferation, differentiation, migration, and cell survival. Recent data show the role of nuclear EGFR in tumors. Although many EGFR ligands are upregulated in cancers, little is known about their effects on EGFR nuclear translocation. We have compared the effects of six EGFR ligands (EGF, HB-EGF, TGF-α, β-Cellulin, amphiregulin, and epiregulin) on nuclear translocation of EGFR, receptor phosphorylation, migration, and proliferation. Cell fractionation and confocal immunofluorescence detected EGFR in the nucleus after EGF, HB-EGF, TGF-α and β-Cellulin stimulation in a dose-dependent manner. In contrast, amphiregulin and epiregulin did not generate nuclear translocation of EGFR. EGF, HB-EGF, TGF-α and β-Cellulin showed correlations between a higher rate of wound closure and increased phosphorylation of residues in the carboxy-terminus of EGFR, compared to amphiregulin and epiregulin. The data indicate that EGFR is translocated to the nucleus after stimulation with EGF, HB-EGF, TGF-α and β-Cellulin, and that these ligands are related to increased phosphorylation of EGFR tyrosine residues, inducing migration of SkHep-1 cells. - Highlights: • EGF, HB-EGF, TGF-α, β-Cellulin are involved in the EGFR nuclear translocation. • Amphiregulin and epiregulin did not promote nuclear translocation of EGFR. • EGF, HB-EGF, TGF-α and β-Cellulin have a role in SkHep-1 cells migration. • EGFR ligands associated with better prognosis don't stimulate EGFR translocation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Inactivation of the FoxO3a transcription factor is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated senescence in human colon cancer and breast cancer cells

We previously showed that protein kinase CK2 downregulation mediates senescence through the reactive oxygen species (ROS)–p53–p21{sup Cip1/WAF1} pathway in various human cells. In the present study, we investigated whether the FoxO3a transcription factor is associated with ROS production during CK2 downregulation-induced senescence in human colon cancer HCT116 and breast cancer MCF-7 cells. FoxO3a overexpression suppressed ROS production and p53 stabilization induced by a CK2α knockdown. CK2α downregulation induced nuclear export of FoxO3a through stimulation of AKT-mediated phosphorylation of FoxO3a and decreased transcription of its target genes (Cu/ZnSOD, MnSOD, and catalase). In contrast, CK2α overexpression inhibited AKT-mediated FoxO3a phosphorylation. This resulted in nuclear accumulation of FoxO3a, and elevated expression of its target genes. Therefore, these data indicate for the first time that CK2 downregulation stimulates ROS generation by inhibiting FoxO3a during premature senescence in human colon and breast cancer cells. - Highlights: • FoxO3a overexpression inhibited ROS production mediated by CK2α knockdown. • CK2α downregulation induced nuclear export of FoxO3a via AKT activation. • CK2α downregulation reduced transcription of FoxO3a target genes including SOD. • CK2α upregulation elevated nuclear import and target gene expression of FoxO3a. • This study indicates that CK2 can modulate the intracellular ROS level via FoxO3a.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The ascorbate peroxidase APX1 is a direct target of a zinc finger transcription factor ZFP36 and a late embryogenesis abundant protein OsLEA5 interacts with ZFP36 to co-regulate OsAPX1 in seed germination in rice

Highlights: • Yeast two-hybrid screening confirmed that ZFP36 interacted with OsLEA5 firstly. • OsAPX1 is a direct target of ZFP36. • OsLEA5 participates in regulating the OsAPX1 expression and the activity of APX. • The ZFP36 overexpression plants seeds germination is inhibited with ABA. • Silencing OsLEA5 could relieve the inhibition of ABA to the seed germination. Seed germination is a vital developmental process. Abscisic acid (ABA) is an essential repressor of seed germination, while ROS (reactive oxygen species) also plays a vital role in regulating seed germination. ABA could inhibit the production of ROS in seed germination, but the mechanism of ABA reduced ROS production in seed germination was hitherto unknown. Here, by ChIP (chromatin immunoprecipitation)-seq, we found that ZFP36, a rice zinc finger transcription factor, could directly bind to the promoter of OsAPX1, coding an ascorbate peroxidase (APX) which has the most affinity for H{sub 2}O{sub 2} (substrate; a type of ROS), and act as a transcriptional activator of OsAPX1 promoter. Moreover, ZFP36 could interact with a late embryogenesis abundant protein OsLEA5 to co-regulate the promoter activity of OsAPX1. The seed germination is highly inhibited in ZFP36 overexpression plants under ABA treatment, while an RNA interference (RNAi) mutant of OsLEA5 rice seeds were less sensitive to ABA, and exogenous ASC (ascorbate acid) could alleviate the inhibition induced by ABA. Thus, our conclusion is that OsAPX1 is a direct target of ZFP36 and OsLEA5 could interact with ZFP36 to co-regulate ABA-inhibited seed germination by controlling the expression of OsAPX1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of connective tissue growth factor (CTGF/CCN2) on condylar chondrocyte proliferation, migration, maturation, differentiation and signalling pathway

Highlights: • It is the first discovery of CCN2 expression in the whole layers of condylar cartilage. • CCN2 promotes condylar chondrocyte migration, maturation and differentiation. • Blocking PI3K/Akt pathway impairs the stimulatory effect of CCN2 on the proliferation of condylar chondrocyte. CCN2, also known as connective tissue growth factor (CTGF), is a 38 kDa cysteine-rich extracellular matrix protein that regulates a sequence of cellular functions and participates in multiple complex biological processes, such as chondrogenesis and osteogenesis. In the present study, we provided the first evidence describing the physiological role of CCN2 in condylar chondrocyte proliferation, migration, maturation and differentiation. CCN2 was widely expressed throughout the whole layers of condylar cartilage and predominantly distributed in the proliferative zone. Recombinant CCN2 promoted the proliferation, migration, proteoglycan synthesis and differentiation capacity of isolated condylar chondrocytes. The stimulatory effect of CCN2 on chondrocyte proliferation was associated with the activation of phosphatidylinositol 3-kinase/Akt signalling pathway. The blocking of this pathway by its inhibitor LY294002 impaired the proliferative effect of CCN2 on chondrocytes. These results suggested a novel physiological role of CCN2 in the development of condylar cartilage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Heme oxygenase-1/carbon monoxide axis suppresses transforming growth factor-β1-induced growth inhibition by increasing ERK1/2-mediated phosphorylation of Smad3 at Thr-179 in human hepatocellular carcinoma cell lines

Highlights: • HO-1/CO axis inhibits TGF-β1-induced growth inhibition in human HCC cell lines. • HO-1/CO axis inhibits TGF-β1-induced Smad3 activation. • HO-1/CO axis selectively induces Smad3 phosphorylation at Thr179. • Smad3 Thr179 phosphorylation mediates the inhibition of TGF-β responses by HO-1. • ERK1/2 mediates HO-1 or CO-induced Smad3 phosphorylation at Thr179. Heme oxygenase-1 (HO-1) has been implicated in tumor progression, but the underlying molecular mechanisms remain largely unknown. Transforming growth factor-β1 (TGF-β1) exhibits cytostatic and apoptotic effects in hepatocytes and several types of hepatocellular carcinoma (HCC) cell lines, and deregulation of its signaling pathway is linked to hepatic tumorigenesis. In the present study, we observed that HO-1 is expressed at higher levels in HCC tissues than in paired normal tissues. Moreover, TGF-β1-induced cell cycle arrest and up-regulation of cyclin-dependent kinase inhibitors in HCC cell lines were significantly attenuated by overexpression of HO-1 or treatment with tricarbonyldichlororuthenium(II) dimer ([Ru(CO){sub 3}Cl{sub 2}]{sub 2}, suggesting an inhibitory role of the HO-1/CO axis in TGF-β signaling to growth inhibition in HCC cell lines. Interestingly, we observed that [Ru(CO){sub 3}Cl{sub 2}]{sub 2} inhibits TGF-β1-induced Smad3-dependent reporter activity without affecting its C-terminus phosphorylation, complex formation with Smad4, and nuclear translocation. Additional experiments revealed that HO-1/CO axis selectively induces phosphorylation of Smad3 at Thr-179 residue in the linker region through activation of extracellular signal-activated kinase (ERK) 1/2. Transfection with a phospho-deficient Smad3 (T179A) mutant or treatment with FR180204, a specific inhibitor for ERK1/2, significantly reversed the inhibitory effects of HO-1 and [Ru(CO){sub 3}Cl{sub 2}]{sub 2} on cell cycle arrest induced by TGF-β1. These findings for the first time demonstrate that HO-1/CO axis confer resistance of HCC cells to TGF-β growth inhibitory signal by increasing Smad3 phosphorylation at Thr-179 via ERK1/2 pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The transcriptional factor Apt regulates neuroblast differentiation through activating CycE expression

Highlights: • Apt exclusively expresses in NB6-4T cells. • Apt controls NB6-4T differentiation. • Apt activates the expression of Cyc E in neuronal cells. • Gcm represses the expression of CycE through Apt in glial cells. In Drosophila, the thoracic neuroblast 6-4 (NB6-4T) divides asymmetrically into a glial precursor and a neuronal precursor, while the abdominal neuroblast 6-4 (NB6-4A) divides symmetrically to produce two glial cells. The underlying mechanism by which NB6-4T and NB6-4A undergo distinct differentiation is still elusive. Here, we find that the transcription factor Apontic (Apt) exclusively expresses in NB6-4T cells and is involved in regulating NB6-4T differentiation. Loss of Apt results in neuronal precursor loss. Epistasis analysis shows that Apt controls NB6-4T differentiation through activating CycE expression. On the other hand, Gcm suppresses Apt expression in the NB6-4A cell, thus inhibiting CycE expression. Taken together, our findings reveal a Gcm-Apt-CycE axis that regulates neuroblast and glia cell differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Respective roles of the mitogen-activated protein kinase (MAPK) family members in pancreatic stellate cell activation induced by transforming growth factor-β1 (TGF-β1)

Activated pancreatic stellate cells (PSCs) play a crucial role in the progression of pancreatic fibrosis. Transforming growth factor-β (TGF-β) is one of the strongest stimulator inducing fibrosis. The mitogen-activated protein kinase (MAPK) proteins (including ERK, JNK and p38 MAPK) are known to contribute to PSC activation and pancreatic fibrosis. Previous studies have identified PSC activation induced by TGF-β1 is related to MAPK pathway, but the respective role of MAPK family members in PSC activation still unclear, and which family member may be the key mediator in mice PSC activation still controversial. In this study, we investigated the influence of different MAPK family member (JNK, ERK, and p38 MAPK) on mice PSC activation using an in vivo and in vitro model. The results showed p-JNK, p-ERK and p-p38 MAPK were all over-expressed in CP group, and p-JNK, p-ERK, and p-p38 MAPK were co-expressed with activated PSC. In vitro, TGF-β1 induced JNK and ERK over-expression in PSCs. In contrast, p38 MAPK expression in PSC showed only a very weak increase. JNK- and ERK-specific inhibitors inhibited FN and α-SMA mRNA expression in PSCs, and a p38 MAPK inhibitor had no effect on PSC activation. These findings indicate that JNK and ERK were directly involved in the PSCs activation induced by TGF-β1 and the development of pancreatic fibrosis. p38 MAPK participate in the progression of CP, but it does not respond to TGF-β1 directly and may not be regarded as the target of TGF-β1 induced PSC activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

BMP2/Smad signaling pathway is involved in the inhibition function of fibroblast growth factor 21 on vascular calcification

Vascular calcification is extremely common and associated with major adverse cardiovascular events. Fibroblast growth factor (FGF) 21 has been identified as a potent metabolic regulator and a protector of the cardiovascular system. In this study, we aimed to investigate the effect of FGF21 on calcification of vascular smooth muscle cell (VSMC) and its mechanism. FGF21 inhibited beta-glycerophosphate (BGP) induced mineralization in VSMCs as determined by calcium concentration and Alizarin Red S. FGF21 suppressed BGP-induced BMP2/Smad signaling pathway components as well as osteoblast differentiation markers. FGF21 and Noggin could synergistically inhibit BGP-induced BMP2/Smad pathway expressions and calcification. Taken together, FGF21 inhibits vascular calcification in vitro by modulating BMP2/Smad signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Insulin-like growth factor I receptor regulates the radiation-induced G2/M checkpoint in HeLa cells

Highlights: • Inhibition of IGF-IR elongated radiation-induced G2 arrest in HeLa cells. • Inhibition of PI3K or AKT, but not MEK, induced the same effect. • IGF-IR inhibition did not essentially affect DSB repair kinetics. • Radiation-induced CHK1 nuclear localization lasted longer in IGF-IR-inhibited cells. • IGF-IR may regulate G2/M checkpoint in part via CHK1 shuttling within the cell. Insulin-like growth factor I receptor (IGF-IR) plays pivotal roles in various biological events, including cell growth, transformation, survival, and DNA repair. In this study, we explored its possible involvement in cell cycle checkpoints, using HeLa cells expressing the fluorescent ubiquitination-based cell cycle indicator (Fucci). We found that IGF-IR inhibitor delayed release from radiation-induced G2 arrest, as demonstrated by FACS and pedigree analysis of Fucci fluorescence. Elongated G2 arrest was also induced by inhibitors of phosphatidylinositol-3 kinase (PI3K) and AKT, but not by inhibitor of MEK, which are two major IGF-IR downstream signaling pathways. Double-strand break (DSB) repair kinetics were not affected by IGF-IR inhibitor. CHK1 inhibitor abrogated radiation-induced G2 arrest, whereas radiation-induced phosphorylation of CHK1 at Ser 345 or Ser 296 was decreased by the IGF-IR inhibitor. However, radiation-induced nuclear localization of CHK1 was prolonged in IGF-IR inhibitor–treated cells in comparison with cells that received radiation alone; in the latter, CHK1 returned to the original diffuse distribution in conjunction with release from G2 arrest. We conclude that IGF-IR directly regulates the G2/M checkpoint via the PI3K/AKT pathway without influencing DSB repair, in part by controlling CHK1 localization between the nucleus and cytoplasm.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Fibroblast growth factor 19 improves cardiac function and mitochondrial energy homoeostasis in the diabetic heart

In diabetic cardiomyopathy, mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation, leading to metabolic disturbances. Fibroblast growth factor 19 (FGF19) acts as a metabolic regulator and may have a cardioprotective role on diabetic cardiomyopathy. In this study, we investigated the effects of FGF19 on energy metabolism. FGF19 treatment of diabetic hearts exhibited higher glucose uptake and lower lipid profiles, suggesting changes in energy metabolism. The protective effects of FGF19 prevented ventricular dysfunction in diabetic hearts and improved mitochondrial function by the upregulation of PGC-1α expression. On the other side, knockdown of PGC-1α by siRNA attenuated the effects of FGF19 on the enhancement of mitochondrial function and energy efficiency. Taken together, these results show that FGF19 exhibited improved mitochondrial efficiency, which might be associated with higher cardiac contractility in diabetic hearts. It is also of note that modulation of PGC-1α, which is responsible for the activation by FGF19, may be a therapeutic target for diabetic cardiomyopathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA FLVCR1-AS1 contributes to the proliferation and invasion of lung cancer by sponging miR-573 to upregulate the expression of E2F transcription factor 3

Lung cancer is one of the most common causes of cancer-related death all over the world. In recent years, long non-coding RNAs (lncRNAs) have been reported to play critical roles in the development and progression of human malignancies. In the present study, we aimed to study the role and mechanism of FLVCR1-AS1 in human non-small cell lung cancer (NSCLC). Results revealed that FLVCR1-AS1 was markedly upregulated in NSCLC tissues and cell lines. Knockdown of FLVCR1-AS1 significantly inhibited the proliferation, migration, invasion and promoted apoptosis of NSCLC cells, and suppressed tumor growth of NSCLC in vivo. Moreover, we explored regulatory mechanism, and found that FLVCR1-AS1 functioned as a competing endogenous RNA (ceRNA) by directly binding to miRNA-573, and E2F transcription factor 3 (E2F3) was identified as a down-stream target of miR-573. FLVCR1-AS1 positively regulated E2F3 expression through inhibiting miR-573 in NSCLC cells. Our findings suggested that FLVCR1-AS1/miR-573/E2F3 axis was an important signaling pathway in mediating tumorigenesis and progression of NSCLC, and further indicated that FLVCR1-AS1 could be a novel diagnostic biomarker and therapeutic target for NSCLC.

60 APPLIED LIFE SCIENCES↗