Displaying publications 1 - 20 of 260 in total

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  1. Almajali B, Al-Jamal HAN, Wan Taib WR, Ismail I, Johan MF, Doolaanea AA, et al.
    Asian Pac J Cancer Prev, 2021 Mar 01;22(3):879-885.
    PMID: 33773553 DOI: 10.31557/APJCP.2021.22.3.879
    OBJECTIVE: The natural compound, thymoquinone (TQ) has demonstrated potential anticancer properties in inhibiting cell proliferation and promoting apoptosis in myeloid leukemia cells, breast cancer cells, and others. However, the effect mechanism of TQ on AML cells still not fully understood. In this study, the authors examined the effects of TQ on the expression of JAK/STAT-negative regulator genes SOCS-1, SOCS-3, and SHP-1, and their consequences on cell proliferation and apoptosis in HL60 leukemia cells.

    METHODS: MTT and trypan blue exclusion tests were conducted to determine the 50% inhibitory concentration (IC50) and cell proliferation. FITC Annexin and Guava® reagent were used to study the cell apoptosis and examine the cell cycle phases, respectively. The expression of JAK/STAT-negative regulator genes, SOCS-1, SOCS-3, and SHP-1, was investigated using reverse transcriptase- quantitative PCR (RT-qPCR).

    RESULTS: TQ demonstrated a potential inhibition of HL60 cell proliferation and a significant increase in apoptotic cells in dose and time-dependent manner. TQ significantly induced cycle arrest at G0-G1 phase (P < 0.001) and enhanced the re-expression of JAK/STAT-negative regulator genes.

    CONCLUSION: TQ potentially inhibited HL60 cell proliferation and significantly increased apoptosis with re-expression of JAK/STAT-negative regulator genes suggesting that TQ could be a new therapeutic candidate for leukemia therapy.
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    Matched MeSH terms: STAT Transcription Factors
  2. Greenwood MP, Greenwood M, Mecawi AS, Antunes-Rodrigues J, Paton JF, Murphy D
    Mol Brain, 2016 Jan 07;9:1.
    PMID: 26739966 DOI: 10.1186/s13041-015-0182-2
    BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.

    RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.

    CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

    Matched MeSH terms: Transcription Factors/metabolism
  3. Lim LY, Vidnovic N, Ellisen LW, Leong CO
    Br. J. Cancer, 2009 Nov 3;101(9):1606-12.
    PMID: 19773755 DOI: 10.1038/sj.bjc.6605335
    p53 is the most commonly mutated tumour-suppressor gene in human cancers. Unlike other tumour-suppressor genes, most p53 cancer mutations are missense mutations within the core domain, leading to the expression of a full-length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose tumour suppression activity but also gain new oncogenic activities to promote tumourigenesis.
    Matched MeSH terms: Transcription Factors
  4. Teoh SL, Das S
    Curr Drug Targets, 2017 Nov 30;18(16):1880-1892.
    PMID: 27628948 DOI: 10.2174/1389450117666160907153338
    BACKGROUND: The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression. The Hippo pathway (also known as the Salvador-Warts-Hippo pathway) is the latest emerging concept in cancers. The Hippo pathway plays an important role in controlling the size of the tissue and organ by virtue of its action on cell proliferation and apoptosis.

    OBJECTIVE: In the present review, we highlight the mammalian Hippo pathway, role of its core members, its upstream regulators, downstream effectors and the resistance cases in lung cancers.

    RESULTS: Specific interaction of Mer with cell surface hyaluronan receptor CD44 is vital in cell contact inhibition, thereby activating Hippo pathway. Both transcription co-activators YAP and TAZ (also known as WWTR1, being homologs of Drosophila Yki) are important regulators of proliferation and apoptosis, and serve as major downstream effectors of the Hippo pathway. Mutation of NF2, the upstream regulator of Hippo pathway is linked to the cancers.

    CONCLUSION: Targeting YAP and TAZ may be important for future drug delivery and treatment.

    Matched MeSH terms: Transcription Factors
  5. Martin D, Degese MS, Vitale-Cross L, Iglesias-Bartolome R, Valera JLC, Wang Z, et al.
    Nat Commun, 2018 07 09;9(1):2372.
    PMID: 29985391 DOI: 10.1038/s41467-018-04590-1
    Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
    Matched MeSH terms: Transcription Factors
  6. Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G, Wu T, et al.
    Nat Commun, 2021 08 17;12(1):4997.
    PMID: 34404774 DOI: 10.1038/s41467-021-24921-z
    Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.
    Matched MeSH terms: Basic Helix-Loop-Helix Transcription Factors
  7. Raghavendran HR, Mohan S, Genasan K, Murali MR, Naveen SV, Talebian S, et al.
    Colloids Surf B Biointerfaces, 2016 Mar 1;139:68-78.
    PMID: 26700235 DOI: 10.1016/j.colsurfb.2015.11.053
    Scaffolds with structural features similar to the extracellular matrix stimulate rapid osteogenic differentiation in favorable microenvironment and with growth factor supplementation. In this study, the osteogenic potential of electrospun poly-l-lactide/hydroxyapatite/collagen (PLLA/Col/HA, PLLA/HA and PLLA/Col) scaffolds were tested in vitro with the supplementation of platelet derived growth factor-BB (PDGF-BB). Cell attachment and topography, mineralization, extracellular matrix protein localization, and gene expression of the human mesenchymal stromal cells were compared between the fibrous scaffolds PLLA/Col/HA, PLLA/Col, and PLLA/HA. The levels of osteocalcin, calcium, and mineralization were significantly greater in the PLLA/Col/HA and PLLA/HA compared with PLLA/Col. High expression of fibronectin, intracellular adhesion molecule, cadherin, and collagen 1 (Col1) suggests that PLLA/Col/HA and PLLA/HA scaffolds had superior osteoinductivity than PLLA/Col. Additionally, osteopontin, osteocalcin, osterix, Runt-related transcription factor 2 (Runx2), and bone morphogenic protein (BMP2) expression were higher in PLLA/Col/HA and PLLA/HA compared with PLLA/Col. In comparison with PLLA/Col, the PLLA/Col/HA and PLLA/HA scaffolds presented a significant upregulation of the genes Runx2, Col 1, Integrin, osteonectin (ON), bone gamma-carboxyglutamic acid-containing protein (BGALP), osteopontin (OPN), and BMP2. The upregulation of these genes was further increased with PDGF-BB supplementation. These results show that PDGF-BB acts synergistically with PLLA/Col/HA and PLLA/HA to enhance the osteogenic differentiation potential. Therefore, this combination can be used for the rapid expansion of bone marrow stromal cells into bone-forming cells for tissue engineering.
    Matched MeSH terms: Transcription Factors/genetics; Transcription Factors/metabolism
  8. Wong KK, Gascoyne DM, Brown PJ, Soilleux EJ, Snell C, Chen H, et al.
    Leukemia, 2014 Feb;28(2):362-72.
    PMID: 23884370 DOI: 10.1038/leu.2013.224
    We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.
    Matched MeSH terms: Forkhead Transcription Factors/genetics*; Forkhead Transcription Factors/metabolism
  9. Hor SY, Lee SC, Wong CI, Lim YW, Lim RC, Wang LZ, et al.
    Pharmacogenomics J, 2008 Apr;8(2):139-46.
    PMID: 17876342
    Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
    Matched MeSH terms: Transcription Factors/genetics*; Transcription Factors/metabolism
  10. Wong KK, Gascoyne DM, Soilleux EJ, Lyne L, Spearman H, Roncador G, et al.
    Oncotarget, 2016 Aug 16;7(33):52940-52956.
    PMID: 27224915 DOI: 10.18632/oncotarget.9507
    FOXP2 shares partially overlapping normal tissue expression and functionality with FOXP1; an established diffuse large B-cell lymphoma (DLBCL) oncogene and marker of poor prognosis. FOXP2 is expressed in the plasma cell malignancy multiple myeloma but has not been studied in DLBCL, where a poor prognosis activated B-cell (ABC)-like subtype display partially blocked plasma cell differentiation. FOXP2 protein expression was detected in ABC-DLBCL cell lines, and in primary DLBCL samples tumoral FOXP2 protein expression was detected in both germinal center B-cell-like (GCB) and non-GCB DLBCL. In biopsies from DLBCL patients treated with immunochemotherapy (R-CHOP), ≥ 20% nuclear tumoral FOXP2-positivity (n = 24/158) correlated with significantly inferior overall survival (OS: P = 0.0017) and progression-free survival (PFS: P = 0.0096). This remained significant in multivariate analysis against either the international prognostic index score or the non-GCB DLBCL phenotype (P < 0.05 for both OS and PFS). Expression of BLIMP1, a marker of plasmacytic differentiation that is commonly inactivated in ABC-DLBCL, did not correlate with patient outcome or FOXP2 expression in this series. Increased frequency of FOXP2 expression significantly correlated with FOXP1-positivity (P = 0.0187), and FOXP1 co-immunoprecipitated FOXP2 from ABC-DLBCL cells indicating that these proteins can co-localize in a multi-protein complex. FOXP2-positive DLBCL had reduced expression of HIP1R (P = 0.0348), which is directly repressed by FOXP1, and exhibited distinct patterns of gene expression. Specifically in ABC-DLBCL these were associated with lower expression of immune response and T-cell receptor signaling pathways. Further studies are warranted to investigate the potential functional cooperativity between FOXP1 and FOXP2 in repressing immune responses during the pathogenesis of high-risk DLBCL.
    Matched MeSH terms: Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism*
  11. Tham YY, Choo QC, Muhammad TST, Chew CH
    Mol Biol Rep, 2020 Dec;47(12):9595-9607.
    PMID: 33259010 DOI: 10.1007/s11033-020-06019-9
    Mitochondrial dysfunction plays a crucial role in the central pathogenesis of insulin resistance and type 2 diabetes mellitus. Macrophages play important roles in the pathogenesis of insulin resistance. Lauric acid is a 12-carbon medium chain fatty acid (MCFA) found abundantly in coconut oil or palm kernel oil and it comes with multiple beneficial effects. This research objective was to uncover the effects of the lauric acid on glucose uptake, mitochondrial function and mitochondrial biogenesis in insulin-resistant macrophages. THP-1 monocytes were differentiated into macrophages and induce insulin resistance, before they were treated with increasing doses of lauric acid (5 μM, 10 μM, 20 μM, and 50 μM). Glucose uptake assay, cellular ROS and ATP production assays, mitochondrial content and membrane potential assay were carried out to analyse the effects of lauric acid on insulin resistance and mitochondrial biogenesis in the macrophages. Quantitative RT-PCR (qRT-PCR) and western blot analysis were also performed to determine the expression of the key regulators. Insulin-resistant macrophages showed lower glucose uptake, GLUT-1 and GLUT-3 expression, and increased hallmarks of mitochondrial dysfunction. Interestingly, lauric acid treatment upregulated glucose uptake, GLUT-1 and GLUT-3 expressions. The treatment also restored the mitochondrial biogenesis in the insulin-resistant macrophages by improving ATP production, oxygen consumption, mitochondrial content and potential, while it promoted the expression of mitochondrial biogenesis regulator genes such as TFAM, PGC-1α and PPAR-γ. We show here that lauric acid has the potential to improve insulin sensitivity and mitochondrial dysregulation in insulin-resistant macrophages.
    Matched MeSH terms: Transcription Factors/genetics; Transcription Factors/metabolism
  12. Coste C, Gérard N, Dinh CP, Bruguière A, Rouger C, Leong ST, et al.
    Biomolecules, 2020 09 02;10(9).
    PMID: 32887413 DOI: 10.3390/biom10091266
    Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.
    Matched MeSH terms: p300-CBP Transcription Factors/antagonists & inhibitors; p300-CBP Transcription Factors/chemistry
  13. Leong, Melody Pui Yee, Usman Bala, Lim, Chai Ling, Rozita Rosli, Cheah, Pike-See, Ling, King-Hwa
    Neuroscience Research Notes, 2018;1(1):21-41.
    MyJurnal
    Ts1Cje is a mouse model of Down syndrome (DS) with partial triplication of chromosome 16, which encompasses a high number of human chromosome 21 (HSA21) orthologous genes. The mouse model exhibits muscle weakness resembling hypotonia in DS individuals. The effect of extra gene dosages on muscle weakness or hypotonia in Ts1Cje and DS individuals remains unknown. To identify molecular dysregulation of the skeletal muscle, we compared the transcriptomic signatures of soleus and extensor digitorum longus (EDL) muscles between the adult Ts1Cje and disomic littermates. A total of 166 and 262 differentially expressed protein-coding genes (DEGs) were identified in the soleus and EDL muscles, respectively. The partial trisomy of MMU16 in Ts1Cje mice has a greater effect on gene expression in EDL. Top-down clustering analysis of all DEGs for represented functional ontologies revealed 5 functional clusters in soleus associated with signal transduction, development of reproductive system, nucleic acid biosynthesis, protein modification and metabolism as well as regulation of gene expression. On the other hand, only 3 functional clusters were observed for EDL namely neuron and cell development, protein modification and metabolic processes as well as ion transport. A total of 11 selected DEGs were validated using qPCR (disomic DEGs: Mansc1; trisomic DEGs: Itsn1, Rcan1, Synj1, Donson, Dyrk1a, Ifnar1, Ifnar2, Runx1, Sod1 and Tmem50b). The validated DEGs were implicated in neuromuscular junction signalling (Itsn1, Syn1), oxidative stress (Sod1, Runx1) and chronic inflammation processes (Runx1, Rcan1, Ifnar1, Ifnar2). Other validated DEGs have not been well-documented as involved in the skeletal muscle development or function, thus serve as interesting novel candidates for future investigations. To our knowledge, the study was the first attempt to determine the transcriptomic profiles of both soleus and EDL muscles in Ts1Cje mice. It provides new insights on the possible disrupted molecular pathways associated with hypotonia in DS individuals.
    Matched MeSH terms: Transcription Factors
  14. Siar CH, Ng KH
    J Oral Pathol Med, 2014 Jan;43(1):45-52.
    PMID: 23560539 DOI: 10.1111/jop.12065
    Epithelial-to-mesenchymal transition (EMT) via the mechanism of transcription repression is a crucial process for the induction of invasiveness in many human tumors. Ameloblastoma is a benign odontogenic epithelial neoplasm with a locally infiltrative behavior. Twist, an EMT promoter, has been implicated in its invasiveness. The roles of the other transcription factors remain unclarified.
    Matched MeSH terms: Transcription Factors/analysis*
  15. Zawawi MS, Dharmapatni AA, Cantley MD, McHugh KP, Haynes DR, Crotti TN
    Biochem Biophys Res Commun, 2012 Oct 19;427(2):404-9.
    PMID: 23000414 DOI: 10.1016/j.bbrc.2012.09.077
    Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p<0.05) reduced the expression of NFATc1, CathK, OSCAR, FcRγ, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p<0.05) decreased CathK, OSCAR, FcRγ, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.
    Matched MeSH terms: NFATC Transcription Factors/antagonists & inhibitors*
  16. Abdul Rahman H, Manzor NF, Tan GC, Tan AE, Chua KH
    Med J Malaysia, 2008 Jul;63 Suppl A:57-8.
    PMID: 19024982
    Angiogenic induction was made to promote angiogenesis by differentiating stem cells towards endothelial cells. However, the stemness property of induced cells has not been revealed yet. Hence, we aim to evaluate the differential mRNA expression of stemness genes in human chorion-derived stem cells (CDSC) after being cultured in EDM50 comprised bFGF and VEGF. Results indicated that CDSC cultured in EMD50 expressed significantly higher mRNA level of Sox-2, FZD9, BST-1 and Nestin. In addition Oct-4, FGF-4 and ABCG-2 were also upregulated. Our finding suggested that CDSC after angiogenic induction enhanced its stem cell properties. This could be contributed for the mechanism of stem cell therapy in ischemic problem.
    Matched MeSH terms: SOXB1 Transcription Factors/genetics*
  17. Lim A, Tan D, Price P, Kamarulzaman A, Tan HY, James I, et al.
    AIDS, 2007 Jul 31;21(12):1525-34.
    PMID: 17630546
    To examine the relationships between blood CD4 natural regulatory T (Treg) cells, plasma HIV RNA level, CD4 T-cell count and immune activation in untreated HIV-infected patients and immunodeficient patients beginning antiretroviral therapy (ART), using a novel phenotype to define Treg cells (CD25CD127CD4). Data were compared with established Treg cell markers (FoxP3, CTLA-4 and GITR).
    Matched MeSH terms: Forkhead Transcription Factors/blood
  18. Nairismägi ML, Tan J, Lim JQ, Nagarajan S, Ng CC, Rajasegaran V, et al.
    Leukemia, 2016 06;30(6):1311-9.
    PMID: 26854024 DOI: 10.1038/leu.2016.13
    Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
    Matched MeSH terms: STAT Transcription Factors/metabolism*
  19. Pfister NT, Fomin V, Regunath K, Zhou JY, Zhou W, Silwal-Pandit L, et al.
    Genes Dev., 2015 Jun 15;29(12):1298-315.
    PMID: 26080815 DOI: 10.1101/gad.263202.115
    Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.
    Matched MeSH terms: Transcription Factors/metabolism
  20. Darabi H, McCue K, Beesley J, Michailidou K, Nord S, Kar S, et al.
    Am J Hum Genet, 2015 Jul 02;97(1):22-34.
    PMID: 26073781 DOI: 10.1016/j.ajhg.2015.05.002
    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
    Matched MeSH terms: Transcription Factors/genetics*
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