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https://www.readbyqxmd.com/read/28445593/nr5a2-discovering-compounds-that-block-tumor-growth-in-pdac
#1
REVIEW
Robert Fletterick
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
April 26, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28430130/timp1-promotes-cell-survival-by-activating-the-pdk1-signaling-pathway-in-melanoma
#2
Mariana Toricelli, Fabiana H M Melo, Aline Hunger, Daniela Zanatta, Bryan E Strauss, Miriam G Jasiulionis
High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics...
April 21, 2017: Cancers
https://www.readbyqxmd.com/read/28402921/mir-155-promotes-cell-proliferation-and-inhibits-apoptosis-by-pten-signaling-pathway-in-the-psoriasis
#3
Longjiang Xu, Hong Len, Xin Shi, Jiang Ji, Jinxiang Fu, Hong Len
MicroRNAs (miRNAs) have been demonstrated to contribute to malignant progression in psoriasis development. The purposes of the study was to evaluated the effects of miRNA-155 on cell proliferation, migration and apoptosis in psoriasis development via PTEN singaling pathway and identify its direct target protein. Quantitative real-time RT-PCR (qRT-PCR) was performed to examine the level of miR-155 in psoriasis cells, miR-155 was downregulated in a psoriasis cell line Hacat by transfected with small interfering RNA (siRNA), respectively...
April 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28371201/ketone-bodies-mimic-the-life-span-extending-properties-of-caloric-restriction
#4
REVIEW
Richard L Veech, Patrick C Bradshaw, Kieran Clarke, William Curtis, Robert Pawlosky, M Todd King
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway...
April 3, 2017: IUBMB Life
https://www.readbyqxmd.com/read/28365441/the-multi-site-docking-protein-gab1-is-constitutively-phosphorylated-independent-from-its-recruitment-to-the-plasma-membrane-in-jak2-v617f-positive-cells-and-mediates-proliferation-of-human-erythroleukaemia-cells
#5
Hannes Bongartz, Wiebke Hessenkemper, Christian Müller, Melissa Fensky, Johannes Fritsch, Katharina Mandel, Iris Behrmann, Claude Haan, Thomas Fischer, Stephan M Feller, Fred Schaper
The constitutively active Janus kinase 2 mutant Jak2-V617F is responsible for cytokine-independent growth of hematopoietic cells and the development of myeloproliferative neoplasms, such as polycythaemia vera and essential thrombocythaemia. Cells expressing Jak2-V617F exhibit constitutive STAT, MAPK, and PI3K signalling, and constitutive association of the multi-site docking protein Gab1 to PIP3 at the plasma membrane. Here, we demonstrate the crucial role of Gab1 for the proliferation of Jak2-V617F-positive human erythroleukaemia (HEL) cells...
March 30, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28360038/insulin-receptor-and-gpcr-crosstalk-stimulates-yap-via-pi3k-and-pkd-in-pancreatic-cancer-cells
#6
Fang Hao, Qinhong Xu, Yinglan Zhao, Jan V Stevens, Steven H Young, James Sinnett-Smith, Enrique Rozengurt
We examined the impact of crosstalk between the insulin receptor (INSR) and G protein-coupled receptor (GPCR) signaling pathways on the regulation of Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in the context of human pancreatic ductal adenocarcinoma (PDAC). Stimulation of PANC-1 or MiaPaCa-2 cells with insulin and neurotensin, a potent mitogenic combination of agonists for these cells, promoted striking YAP nuclear localization and decreased YAP phosphorylation at Ser127 and Ser397...
March 30, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28348208/myo6-is-targeted-by-salmonella-virulence-effectors-to-trigger-pi3-kinase-signaling-and-pathogen-invasion-into-host-cells
#7
Andrew B E Brooks, Daniel Humphreys, Vikash Singh, Anthony C Davidson, Susan D Arden, Folma Buss, Vassilis Koronakis
To establish infections, Salmonella injects virulence effectors that hijack the host actin cytoskeleton and phosphoinositide signaling to drive pathogen invasion. How effectors reprogram the cytoskeleton network remains unclear. By reconstituting the activities of the Salmonella effector SopE, we recapitulated Rho GTPase-driven actin polymerization at model phospholipid membrane bilayers in cell-free extracts and identified the network of Rho-recruited cytoskeleton proteins. Knockdown of network components revealed a key role for myosin VI (MYO6) in Salmonella invasion...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28343126/pi3k-signaling-in-cancer-beyond-akt
#8
REVIEW
Evan C Lien, Christian C Dibble, Alex Toker
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K...
March 23, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28295876/a-vicious-partnership-between-akt-and-phlda3-to-facilitate-neuroendocrine-tumors
#9
Masahiro Takikawa, Rieko Ohki
Neuroendocrine tumors (NETs) are rare cancers that generally have a poor prognosis. Accurate diagnosis and proper treatment of these tumors requires a better understanding of the molecular mechanisms underlying the development of NETs. It has been shown that the mTOR inhibitor everolimus can improve the progression-free survival of pancreatic NET (PanNET) patients, suggesting that inhibition of the PI3K-Akt-mTOR pathway may suppress the progression of PanNETs. PHLDA3 is a novel tumor suppressor protein that inhibits Akt activation by competition for binding to PIP3 ...
March 12, 2017: Cancer Science
https://www.readbyqxmd.com/read/28292823/correction-annular-pip3-accumulation-controls-actin-architecture-and-modulates-cytotoxicity-at-the-immunological-synapse
#10
Audrey Le Floc'h, Yoshihiko Tanaka, Niels S Bantilan, Guillaume Voisinne, Grégoire Altan-Bonnet, Yoshinori Fukui, Morgan Huse
No abstract text is available yet for this article.
April 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28287114/regulation-of-inflammation-and-tumorigenesis-by-the-tipe-family-of-phospholipid-transfer-proteins
#11
REVIEW
Jason R Goldsmith, Youhai H Chen
The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation...
March 13, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28263967/characterization-of-pten-mutations-in-brain-cancer-reveals-that-pten-mono-ubiquitination-promotes-protein-stability-and-nuclear-localization
#12
Jr-M Yang, P Schiapparelli, H-N Nguyen, A Igarashi, Q Zhang, S Abbadi, L M Amzel, H Sesaki, A Quiñones-Hinojosa, M Iijima
PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28250113/cxcl12-induced-macropinocytosis-modulates-two-distinct-pathways-to-activate-mtorc1-in-macrophages
#13
Regina Pacitto, Isabella Gaeta, Joel A Swanson, Sei Yoshida
Although growth factors and chemokines elicit different overall effects on cells-growth and chemotaxis, respectively-and activate distinct classes of cell-surface receptors, nonetheless, they trigger similar cellular activities and signaling pathways. The growth factor M-CSF and the chemokine CXCL12 both stimulate the endocytic process of macropinocytosis, and both activate the mechanistic target of rapamycin complex 1 (mTORC1), a protein complex that regulates cell metabolism. Recent studies of signaling by M-CSF in macrophages identified a role for macropinocytosis in the activation of mTORC1, in which delivery of extracellular amino acids into lysosomes via macropinocytosis was required for activation of mTORC1...
March 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28248320/non-coding-rna-the-cancer-link-rna-between-pip3-and-akt
#14
Eytan Zlotorynski
No abstract text is available yet for this article.
April 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28247964/pi-3-4-p2-plays-critical-roles-in-the-regulation-of-focal-adhesion-dynamics-of-mda-mb-231-breast-cancer-cells
#15
Miki Fukumoto, Takeshi Ijuin, Tadaomi Takenawa
Phosphoinositides play pivotal roles in the regulation of cancer cell phenotypes. Among them, phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2 ) localizes to the invadopodia, and positively regulates tumor cell invasion. In this study, we examined the effect of PI(3,4)P2 on focal adhesion dynamics in MDA-MB-231 basal breast cancer cells. Knockdown of SHIP2, a phosphatidylinositol 3,4,5-trisphosphatase (PIP3 ) 5-phosphatase that generates PI(3,4)P2 , in MDA-MB-231 breast cancer cells, induced the development of focal adhesions and cell spreading, leading to the suppression of invasion...
March 1, 2017: Cancer Science
https://www.readbyqxmd.com/read/28247205/the-mechanism-of-jurkat-cells-apoptosis-induced-by-aggregatibacter-actinomycetemcomitans-cytolethal-distending-toxin
#16
Hui-Ping Chen, Lu Li, Xu Chen, Mi-Fang Yang, Yu Ye, Xiao-Qian Wang, Yan Xu
Cytolethal distending toxin (CDT) which is produced by Aggregatibacter actinomycetemcomitans causes apoptosis in lymphocytes. But the specific mechanism is not clear. The aim of our research was to investigate the effect and mechanism during this process. The wild-type CdtA, CdtB, CdtC (CdtA(W), CdtB(W), CdtC(W)) and mutant CdtB (CdtB(M)) were expressed and purified respectively and the purity of each subunit was examined by BandScan software. And the type I deoxyribonuclease and PI-3,4,5-triphosphate (PI-3,4,5-P3, PIP3) phosphatase activity were detected by DNA agarose gel electrophoresis and enzyme-linked immunosorbent assay respectively...
June 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28218907/the-link-a-lncrna-interacts-with-ptdins-3-4-5-p3-to%C3%A2-hyperactivate-akt%C3%A2-and-confer-resistance-to-akt%C3%A2-inhibitors
#17
Aifu Lin, Qingsong Hu, Chunlai Li, Zhen Xing, Guolin Ma, Cheng Wang, Jun Li, Yin Ye, Jun Yao, Ke Liang, Shouyu Wang, Peter K Park, Jeffrey R Marks, Yan Zhou, Jianwei Zhou, Mien-Chie Hung, Han Liang, Zhibin Hu, Hongbing Shen, David H Hawke, Leng Han, Yubin Zhou, Chunru Lin, Liuqing Yang
Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 or PIP3) mediates signalling pathways as a second messenger in response to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the 'RNA world', physiological RNA-phospholipid interactions and their involvement in essential cellular processes have remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, long intergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP3 at the single-nucleotide level, facilitating AKT-PIP3 interaction and consequent enzymatic activation...
March 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28196852/inpp4b-and-pten-loss-leads-to-pi-3-4-p2-accumulation-and-inhibition-of-pi3k-in-tnbc
#18
Darien E Reed, Kevan M Shokat
Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR) and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients and still lacks an effective targeted therapy(1,2). Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer(3). Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3,4-bisphosphate (PI-3,4-P2) creating phosphatidylinositol-3-phosphate(4)...
February 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28174296/ca-2-dependent-focal-exocytosis-of-golgi-derived-vesicles-helps-phagocytic-uptake-in-macrophages
#19
Nimi Vashi, Syed Bilal Ahmad Andrabi, Swapnil Ghanwat, Mrutyunjay Suar, Dhiraj Kumar
The role of Golgi apparatus during phagocytic uptake by macrophages has been ruled out in the past. Notably, all such reports were limited to Fcγ receptor-mediated phagocytosis. Here, we unravel a highly devolved mechanism for recruitment of Golgi-derived secretory vesicles during phagosome biogenesis, which was important for uptake of most cargos, except the IgG-coated ones. We report recruitment of mannosidase-II-positive Golgi-derived vesicles during uptake of diverse targets, including latex beads, Escherichia coli, Salmonella typhimurium, and Mycobacterium tuberculosis in human and mouse macrophages...
March 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28157504/pi-3-4-5-p3-engagement-restricts-akt-activity-to-cellular-membranes
#20
Michael Ebner, Iva Lučić, Thomas A Leonard, Ivan Yudushkin
Protein kinase B/Akt regulates cellular metabolism, survival, and proliferation in response to hormones and growth factors. Hyperactivation of Akt is frequently observed in cancer, while Akt inactivation is associated with severe diabetes. Here, we investigated the molecular and cellular mechanisms that maintain Akt activity proportional to the activating stimulus. We show that binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3) or PI(3,4)P2 to the PH domain allosterically activates Akt by promoting high-affinity substrate binding...
February 2, 2017: Molecular Cell
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