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https://www.readbyqxmd.com/read/28534965/cucurbitacin%C3%A2-b-induces-autophagy-and-apoptosis-by-suppressing-cip2a-pp2a-mtorc1-signaling-axis-in-human-cisplatin-resistant-gastric-cancer-cells
#1
Xuewen Liu, Chao Duan, Juanli Ji, Te Zhang, Xiaoning Yuan, Yunfei Zhang, Wenjing Ma, Jingyuan Yang, Linsen Yang, Zhiguo Jiang, Huiliang Yu, Ying Liu
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple kinds of tumors including gastric cancer (GC). Mammalian target of rapamycin complex 1 (mTORC1) over-activation is detected in GC and many other cancers. Previous study found that CIP2A/mTORC1 controls cell growth and autophagy through direct association. CIP2A plays an 'oncogenic nexus' in several cancer types to participate in the tumorigenic transformation and chemoresistance. In the present study, we investigated whether Cucurbitacin B (CuB), a natural compound found in Cucurbitaceae, can be used in cisplatin (DDP)-resistant human GC cell line SGC7901/DDP...
May 18, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28526544/interleukin-18-gene-deletion-protects-against-sepsis-induced-cardiac-dysfunction-by-inhibiting-pp2a-activity
#2
Yoshitaka Okuhara, Shunichi Yokoe, Toshihiro Iwasaku, Akiyo Eguchi, Koichi Nishimura, Wen Li, Makiko Oboshi, Yoshiro Naito, Toshiaki Mano, Michio Asahi, Haruki Okamura, Tohru Masuyama, Shinichi Hirotani
BACKGROUND: Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. METHODS AND RESULTS: Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS...
May 4, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28516459/pp2a-deactivation-is-a-common-event-in-oral-cancer-and-reactivation-by-fty720-shows-promising-therapeutic-potential
#3
Bharath Kumar Velmurugan, Chien-Hung Lee, Shang-Lun Chiang, Chun-Hung Hua, Mei-Chung Chen, Shu-Hui Lin, Kun-Tu Yeh, Ying-Chin Ko
Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets...
May 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28514186/apc-c-cdc20-mediates-deprotection-of-centromeric-cohesin-at-meiosis-ii-in-yeast
#4
Katarzyna Jonak, Ievgeniia Zagoriy, Tugce Oz, Peter Graf, Julie Rojas, Valentina Mengoli, Wolfgang Zachariae
Cells undergoing meiosis produce haploid gametes through one round of DNA replication followed by two rounds of chromosome segregation. This requires that cohesin complexes, which establish sister chromatid cohesion during S phase, are removed in a stepwise manner. At meiosis I, the separase protease triggers the segregation of homologous chromosomes by cleaving cohesin's Rec8 subunit on chromosome arms. Cohesin persists at centromeres because the PP2A phosphatase, recruited by the shugoshin protein, dephosphorylates Rec8 and thereby protects it from cleavage...
May 17, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28512245/merkel-cell-polyomavirus-small-t-antigen-initiates-merkel-cell-carcinoma-like-tumor-development-in-mice
#5
Monique E Verhaegen, Doris Mangelberger, Paul W Harms, Markus Eberl, Dawn M Wilbert, Julia Meireles, Christopher K Bichakjian, Thomas L Saunders, Sunny Y Wong, Andrzej A Dlugosz
Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a non-proliferative population of neuroendocrine cells which arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of pre-term transgenic mice, we show that epidermis-targeted co-expression of sT and the cell fate determinant atonal bHLH transcription factor 1 (Atoh1) leads to development of widespread cellular aggregates with histology and marker expression mimicking that of human intraepidermal MCC...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28507044/pp2a-b56-controls-assembly-of-the-apc-c-cdc20-complex
#6
(no author information available yet)
No abstract text is available yet for this article.
May 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28505155/oxidative-stress-and-expression-of-insulin-signaling-proteins-in-the-brain-of-diabetic-rats-role-of-nigella-sativa-oil-and-antidiabetic-drugs
#7
Mahmoud Balbaa, Shaymaa A Abdulmalek, Sofia Khalil
BACKGROUND AND OBJECTIVES: Insulin resistance of the brain is a specific form of type2-diabetes mellitus (T2DM) and the active insulin-signaling pathway plays a neuroprotective role against damaging conditions and Alzheimer's progression. The present study identifies the mediated emerging effects of the Nigella sativa oil (NSO) on the memory enhancing process, its anti-oxidative, acetylcholinestrase (AChE) inhibition, anti-brain insulin resistance and anti-amyloidogenic activities. In addition, the possible role of some anti-diabetic drugs in the neuro-protection processes and their effect in combination with NSO and/or the insulin receptor inhibitor IOMe-AG538 were investigated...
2017: PloS One
https://www.readbyqxmd.com/read/28504652/a-smap-in-the-face-for-cancer
#8
Shirish Shenolikar
Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504649/activation-of-tumor-suppressor-protein-pp2a-inhibits-kras-driven-tumor-growth
#9
Jaya Sangodkar, Abbey Perl, Rita Tohme, Janna Kiselar, David B Kastrinsky, Nilesh Zaware, Sudeh Izadmehr, Sahar Mazhar, Danica D Wiredja, Caitlin M O'Connor, Divya Hoon, Neil S Dhawan, Daniela Schlatzer, Shen Yao, Daniel Leonard, Alain C Borczuk, Giridharan Gokulrangan, Lifu Wang, Elena Svenson, Caroline C Farrington, Eric Yuan, Rita A Avelar, Agnes Stachnik, Blake Smith, Vickram Gidwani, Heather M Giannini, Daniel McQuaid, Kimberly McClinch, Zhizhi Wang, Alice C Levine, Rosalie C Sears, Edward Y Chen, Qiaonan Duan, Manish Datt, Shozeb Haider, Avi Ma'ayan, Analisa DiFeo, Neelesh Sharma, Matthew D Galsky, David L Brautigan, Yiannis A Ioannou, Wenqing Xu, Mark R Chance, Michael Ohlmeyer, Goutham Narla
Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28500640/dysregulation-of-the-mek-erk-mnk1-signaling-cascade-by-middle-t-antigen-of-the-trichoydsplasia-spinulosa-polyomavirus
#10
Julie H Wu, Deepika Narayanan, Rebecca A Simonette, Peter L Rady, Stephen K Tyring
BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumor (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies...
May 13, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28500231/discovery-of-a-novel-small-molecule-inhibitor-that-targets-pp2a-%C3%AE-catenin-signaling-and-restricts-tumor-growth-and-metastasis
#11
Shrankhla Maheshwari, Avula S Rao, Akhilesh Singh, L Ravithej Singh, Gopala R Palnati, Rakesh K Arya, Srikanth H Cheruvu, Sudhir Shahi, Tanuj Sharma, Sanjeev Meena, Anup K Singh, Ruchir Kant, Mohammed Riyazuddin, Himangsu K Bora, Mohammad I Siddiqi, Jiaur R Gayen, Koneni V Sashidhara, Dipak Datta
Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug like properties. Here, we report synthesis and discovery of a novel small molecule inhibitor of PP2A-β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug like properties of the molecule. Inhibiting PP2A and β-Catenin interaction by selectively engaging PR55α binding site, our most potent small molecule inhibitor diminished the expression of active β-Catenin and its target proteins c-Myc and cyclin D1...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28496991/torc1-coordinates-the-conversion-of-sic1-from-a-target-to-an-inhibitor-of-cyclin-cdk-cks1
#12
Marta Moreno-Torres, Malika Jaquenoud, Marie-Pierre Péli-Gulli, Raffaele Nicastro, Claudio De Virgilio
Eukaryotic cell cycle progression through G1-S is driven by hormonal and growth-related signals that are transmitted by the target of rapamycin complex 1 (TORC1) pathway. In yeast, inactivation of TORC1 restricts G1-S transition due to the rapid clearance of G1 cyclins (Cln) and the stabilization of the B-type cyclin (Clb) cyclin-dependent kinase (CDK) inhibitor Sic1. The latter mechanism remains mysterious but requires the phosphorylation of Sic1-Thr(173) by Mpk1 and inactivation of the Sic1-pThr(173)-targeting phosphatase (PP2A(Cdc55)) through greatwall kinase-activated endosulfines...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28487562/protein-phosphatase-2a-pp2a-regulates-eg5-to-control-mitotic-progression
#13
Yang Liu, Zhong Zhang, Hui Liang, Xuyang Zhao, Ling Liang, Guangxi Wang, Jingyi Yang, Yan Jin, Michael A McNutt, Yuxin Yin
EG5 (KIF11) is a member of the kinesin-like protein family involved in centrosome separation and bipolar spindle formation. When a cell enters mitosis, CDK1 phosphorylates EG5 at Thr926 and promotes EG5 localization on the mitotic spindle which drives bipolar spindle formation. EG5 provides power for spindle movement and thus controls the dynamics of spindle assembly. However, little is known about EG5 regulation or how EG5 detaches from the spindle upon mitotic exit. In this study we identify EG5 as a novel substrate of PP2A phosphatase, and we show that the PP2A/B55α complex plays an important role in mitotic exit by a mechanism involving EG5...
May 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28483815/drosophila-dalmatian-combines-sororin-and-shugoshin-roles-in-establishment-and-protection-of-cohesion
#14
Takashi Yamada, Eri Tahara, Mai Kanke, Keiko Kuwata, Tomoko Nishiyama
Sister chromatid cohesion is crucial to ensure chromosome bi-orientation and equal chromosome segregation. Cohesin removal via mitotic kinases and Wapl has to be prevented in pericentromeric regions in order to protect cohesion until metaphase, but the mechanisms of mitotic cohesion protection remain elusive in Drosophila Here, we show that dalmatian (Dmt), an ortholog of the vertebrate cohesin-associated protein sororin, is required for protection of mitotic cohesion in flies. Dmt is essential for cohesion establishment during interphase and is enriched on pericentromeric heterochromatin...
May 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28465465/nlrp3-inflammasome-assembly-is-regulated-by-phosphorylation-of-the-pyrin-domain
#15
Andrea Stutz, Carl-Christian Kolbe, Rainer Stahl, Gabor L Horvath, Bernardo S Franklin, Olivia van Ray, Rebecca Brinkschulte, Matthias Geyer, Felix Meissner, Eicke Latz
NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD)...
May 2, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28445932/high-cftr-expression-in-philadelphia-chromosome-positive-acute-leukemia-protects-and-maintains-continuous-activation-of-bcr-abl-and-related-signaling-pathways-in-combination-with-pp2a
#16
Xi Yang, Tianyou Yan, Yuping Gong, Xuehua Liu, Huaqin Sun, Wenming Xu, Chunsen Wang, Duolan Naren, Yuhuan Zheng
Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl- and HCO3-. Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome-positive(Ph+) acute leukemia, including Ph+ B cell acute lymphoblastic leukemia(Ph+ B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC)...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28442576/determination-of-dendritic-spine-morphology-by-the-striatin-scaffold-protein-strn4-through-interaction-with-the-phosphatase-pp2a
#17
Lianfeng Lin, Louisa Hoi-Ying Lo, Quanwei Lyu, Kwok-On Lai
Dendritic spines are heterogeneous and exist with various morphologies. Altered spine morphology might underlie the cognitive deficits in neurodevelopmental disorders such as autism, but how different subtypes of dendritic spines are selectively maintained along development is still poorly understood. Spine maturation requires spontaneous activity of N-methyl-D-aspartate (NMDA) receptor and local dendritic protein synthesis. STRN4 (also called Zinedin) belongs to the striatin family of scaffold proteins, and some of the potential striatin-interacting proteins are encoded by autism risk genes...
April 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28441529/mps1-regulates-kinetochore-microtubule-attachment-stability-via-the-ska-complex-to-ensure-error-free-chromosome-segregation
#18
John Maciejowski, Hauke Drechsler, Kathrin Grundner-Culemann, Edward R Ballister, Jose-Antonio Rodriguez-Rodriguez, Veronica Rodriguez-Bravo, Mathew J K Jones, Emily Foley, Michael A Lampson, Henrik Daub, Andrew D McAinsh, Prasad V Jallepalli
The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1's error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore...
April 24, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28439046/protein-phosphatase-2a-regulatory-subunit-b55%C3%AE-functions-in-mouse-oocyte-maturation-and-early-embryonic-development
#19
Shuang Liang, Jing Guo, Jeong-Woo Choi, Kyung-Tae Shin, Hai-Yang Wang, Yu-Jin Jo, Nam-Hyung Kim, Xiang-Shun Cui
Protein phosphatase 2A regulatory subunit B55α (PP2A-B55α) has been studied in mitosis. However, its functions in mammalian meiosis and early embryonic development remain unknown. Here, we report that PP2A-B55α is critical for mouse oocyte meiosis and preimplantation embryo development. Knockdown of PP2A-B55α in oocytes led to abnormal asymmetric division, disordered spindle dynamics, defects in chromosome congression, an increase in aneuploidy, and induction of the DNA damage response. Moreover, knockdown of PP2A-B55α in fertilized mouse zygotes impaired development to the blastocyst stage...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28438603/pp2a-catalytic-subunit-silence-by-microrna-429-activates-ampk-and-protects-osteoblastic-cells-from-dexamethasone
#20
Shiguang Guo, Caiyun Chen, Feng Ji, Li Mao, Yue Xie
Activation of AMP-activated protein kinase (AMPK) could efficiently protect osteoblasts from dexamethasone (Dex). Here, we aim to induce AMPK activation through miRNA-mediated downregulating its phosphatase, protein phosphatase 2A (PP2A). We discovered that microRNA-429 ("miR-429") targets the catalytic subunit of PP2A (PP2A-c). Significantly, expression of miR-429 downregulated PP2A-c and activated AMPK (p-AMPKα1 Thr172) in human osteoblastic cells (OB-6 and hFOB1.19 lines). Remarkably, miR-429 expression alleviated Dex-induced osteoblastic cell death and apoptosis...
April 21, 2017: Biochemical and Biophysical Research Communications
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