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Tao Yang, David F Meoli, Javid Moslehi, Dan M Roden
While inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced Q-T prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform as the major effector of the INaL action. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and CHO cells...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
Christopher M Jenkins, Kui Yang, Gaoyuan Liu, Sung Ho Moon, Beverly G Dilthey, Richard W Gross
Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl-ether linkage at the   sn -1 position and are highly enriched in arachidonic acid (AA) at the sn -2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive.  Herein, we report that cytochrome c , in the presence of either cardiolipin (CL), O2 and H2 O2 , or oxidized CL and O2 , catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive α-hydroxy fatty aldehydes...
March 12, 2018: Journal of Biological Chemistry
Hideki Makinoshima, Shigeki Umemura, Ayako Suzuki, Hiroki Nakanishi, Ami Maruyama, Hibiki Udagawa, Sachiyo Mimaki, Shingo Matsumoto, Seiji Niho, Genichiro Ishii, Masahiro Tsuboi, Atsushi Ochiai, Hiroyasu Esumi, Takehiko Sasaki, Koichi Goto, Katsuya Tsuchihara
Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product: PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor...
February 28, 2018: Cancer Research
Ke Liu, Lijing Fang, Haiyan Sun, Zhengyin Pan, Jianchao Zhang, Juntao Chen, Ximing Shao, Wei Wang, Yuanyan Tan, Zhihao Ding, Lijiao Ao, Chunlei Wu, Xiaoqi Liu, Huashun Li, Rui Wang, Wu Su, Hongchang Li
The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter...
February 26, 2018: Molecular Cancer Therapeutics
Hai H Bui, Phillip E Sanders, Diane Bodenmiller, Ming Shang Kuo, Gregory P Donoho, Anthony S Fischl
Phosphatidylinositol (3,4,5) trisphosphate (PIP3 ) is a biologically active membrane phospholipid that is essential for the growth and survival of all eukaryotic cells. We describe a new method that directly measures PIP3 and describe the HPLC separation and measurement of the positional isomers of phosphatidylinositol bisphosphate, PI(3,5)P2 , PI(3,4)P2 and PI(4,5)P2 . Mass spectrometric analyses were performed online using ultra-high performance liquid chromatography (UHPLC)-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative multiple-reaction monitoring (MRM) modes...
February 19, 2018: Analytical Biochemistry
Robert R Kay, Thomas D Williams, Peggy Paschke
In a role distinct from and perhaps more ancient than that in signal transduction, PIP3 and Ras help to spatially organize the actin cytoskeleton into macropinocytic cups. These large endocytic structures are extended by actin polymerization from the cell surface and have at their core an intense patch of active Ras and PIP3, around which actin polymerizes, creating cup-shaped projections. We hypothesize that active Ras and PIP3 self-amplify within macropinocytic cups, in a way that depends on the structural integrity of the cup...
February 14, 2018: Biochemical Journal
Mahesh Chandra Patra, Sangdun Choi
The toll/interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) plays an important role in the toll-like receptor (TLR) 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) on the plasma membrane and PI (3,4,5)-trisphosphate (PIP3) on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP's membrane association are only partially understood...
2018: Frontiers in Immunology
Yen-Hua Chen, Radomir Kratchmarov, Wen-Hsuan W Lin, Nyanza J Rothman, Bonnie Yen, William C Adams, Simone A Nish, Jeffrey C Rathmell, Steven L Reiner
Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation...
January 23, 2018: Cell Reports
Anuja Sathe, Géraldine Chalaud, Immanuel Oppolzer, Kit Yeng Wong, Margarita von Busch, Sebastian C Schmid, Zhichao Tong, Margitta Retz, Juergen E Gschwend, Wolfgang A Schulz, Roman Nawroth
Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences...
2018: PloS One
Inga Baasch Christensen, Esben Nees Mogensen, Helle Hasager Damkier, Jeppe Praetorius
The choroid plexus epithelial cells (CPECs) belong to a small group of polarized cells, where the Na+,K+-ATPase is expressed in the luminal membrane. The basic polarity of the cells is, therefore, still debated. We investigated the subcellular distribution of an array of proteins known to play fundamental roles in either in establishing and maintaining basic cell polarity or the polarized delivery and recycling of plasma membrane proteins. Immunofluorescence histochemical analysis was applied to determine the subcellular localization of apical and basolateral membrane determinants...
January 10, 2018: American Journal of Physiology. Cell Physiology
Sathiya Sekar, Changiz Taghibiglou
Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls...
December 26, 2017: Neuroscience Letters
Fiona B Naughton, Antreas C Kalli, Mark S P Sansom
Pleckstrin homology (PH) domains mediate protein-membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH-PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH-PIP interactions are largely unknown. Molecular dynamics (MD) simulations using a coarse-grained model enables estimation of free energy landscapes for the interactions of 12 different PH domains with membranes containing PIP2 or PIP3, allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes...
December 19, 2017: Journal of Molecular Biology
Martin Ezeani, Sunday Elom
The incidence of QT prolongation and torsades de pointes is on the rise due to the use of cardiovascular and non-cardiovascular drugs. Robust efforts have been made and are still ongoing to understand the underlying mechanisms that can enhance or prevent the development of drug-induced proarrhythmia. A caveat in the use of antiarrhythmic drugs is the ability to obtain safe action potential prolongation therapeutic effects, through IKr blockade. This remains as yet completely unachievable, as blockers of the potassium channel have not provided complete safe measures...
2017: Open Heart
Yu-Hsiu Wang, Anushya Hariharan, Giulia Bastianello, Yusuke Toyama, G V Shivashankar, Marco Foiani, Michael P Sheetz
Phosphoinositide lipids (PPIs) are enriched in the nucleus and are accumulated at DNA damage sites. Here, we investigate roles of nuclear PPIs in DNA damage response by sequestering specific PPIs with the expression of nuclear-targeted PH domains, which inhibits recruitment of Ataxia telangiectasia and Rad3-related protein (ATR) and reduces activation of Chk1. PPI-binding domains rapidly (< 1 s) accumulate at damage sites with local enrichment of PPIs. Accumulation of PIP3 in complex with the nuclear receptor protein, SF1, at damage sites requires phosphorylation by inositol polyphosphate multikinase (IPMK) and promotes nuclear actin assembly that is required for ATR recruitment...
December 14, 2017: Nature Communications
Alicja Pacholewska, Matthias F Kraft, Vincent Gerber, Vidhya Jagannathan
MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis...
December 12, 2017: Genes
Thomas C Buckles, Brian P Ziemba, Glenn R Masson, Roger L Williams, Joseph J Falke
Cellular pathways controlling chemotaxis, growth, survival, and oncogenesis are activated by receptor tyrosine kinases and small G-proteins of the Ras superfamily that stimulate specific isoforms of phosphatidylinositol-3-kinase (PI3K). These PI3K lipid kinases phosphorylate the constitutive lipid phosphatidylinositol-4,5-bisphosphate (PIP2 ) to produce the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3 ). Progress has been made in understanding direct, moderate PI3K activation by receptors...
December 5, 2017: Biophysical Journal
Jixian Liu, Xinhuang Yao, Da Wu, Yiwang Ye, Qiang Wu, Suyue Liu, Hao Wu
Previous studies have suggested that the B‑cell lymphoma 2 (Bcl‑2) inhibitor, TW37, may induce apoptosis of the non‑small cell lung cancer cell line, H1975/epidermal growth factor receptor‑tyrosine kinase inhibitor (EGFR‑TKI), which exhibits secondary resistance to EGFR‑TKI. However, the effects of TW37 on H1975/EGFR‑TKI cells remain unclear. The aim of the present study was to investigate the effects of TW37 on the growth of H1975/EGFR‑TKI cells and explore the underlying mechanisms. An in vitro study was performed, whereby H1975/EGFR‑TKI cells were treated with serially increasing concentrations of TW37...
February 2018: Molecular Medicine Reports
Jing Wang, Liling Xu, Samina Shaheen, Sichen Liu, Wenjie Zheng, Xiaolin Sun, Zhanguo Li, Wanli Liu
The growth of B cell receptor (BCR) microclusters upon antigen stimulation drives B cell activation. Here, we show that PI3K-mediated PIP3 production is required for the growth of BCR microclusters. This growth is likely inhibited by PTEN and dependent on its plasma membrane binding and lipid phosphatase activities. Mechanistically, we find that PIP3 -dependent recruitment and activation of a guanine nucleotide exchange factor, Dock2, is required for the sustained growth of BCR microclusters through remodeling of the F-actin cytoskeleton...
November 28, 2017: Cell Reports
Yoshibumi Ueda, Moritoshi Sato
Structures arising from actin-based cell membrane movements, including ruffles, lamellipodia, and filopodia, play important roles in a broad spectrum of cellular functions, such as cell motility, axon guidance in neurons, wound healing, and micropinocytosis. Previous studies investigating these cell membrane dynamics often relied on pharmacological inhibition, RNA interference, and constitutive active/dominant negative protein expression systems. However, such studies did not allow the modulation of protein activity at specific regions of cells, tissues, and organs in animals with high spatial and temporal precision...
November 16, 2017: Biochemical and Biophysical Research Communications
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