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Lucas O Sousa, Lays M Sobral, Camila S Matsumoto, Fabiano P Saggioro, Rossana V M López, Rodrigo A Panepucci, Carlos Curti, Wilson A Silva, Lewis J Greene, Andréia M Leopoldino
BACKGROUND: MicroRNAs (miRNAs or miRs) are post-transcriptional regulators of eukaryotic cells and knowledge of differences in miR levels may provide new approaches to diagnosis and therapy. METHODS: The present study measured the levels of nine miRs in head and neck squamous cell carcinomas (HNSCC) and determined whether clinical pathological features are associated with differences in miR levels. SET (I2PP2A) and PTEN protein levels were also measured, since their levels can be regulated by miR-199b and miR-21, respectively...
December 2016: BBA Clinical
Shi-Wen Jiang, Siliang Xu, Haibin Chen, Xiaoqiang Liu, Zuoqing Tang, Yugui Cui, Jiayin Liu
SET (SE translocation, SET), a constitutive inhibitor of protein phosphatase 2A (PP2A), is a multifunctional oncoprotein involved in DNA replication, histone modification, nucleosome assembly, gene transcription and cell proliferation. It is widely expressed in human tissues including the gonadal system and brain. Intensive studies have shown that overexpressed SET plays an important role in the development of Alzheimer's disease (AD), and may also contribute to the malignant transformation of breast and ovarian cancers...
January 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
Iliana Serifi, Eleni Tzima, Katerina Soupsana, Zoe Karetsou, Dimitris Beis, Thomais Papamarcaki
The oncoprotein SET/I2PP2A (protein phosphatase 2A inhibitor 2) participates in various cellular mechanisms such as transcription, cell cycle regulation and cell migration. SET is also an inhibitor of the serine/threonine phosphatase PP2A, which is involved in the regulation of cell homeostasis. In zebrafish, there are two paralogous set genes that encode Seta (269 amino acids) and Setb (275 amino acids) proteins which share 94% identity. We show here that seta and setb are similarly expressed in the eye, the otic vesicle, the brain and the lateral line system, as indicated by in situ hybridization labeling...
December 15, 2016: Biochemical Journal
Raffaella Pippa, Ana Dominguez, Raquel Malumbres, Akinori Endo, Elena Arriazu, Nerea Marcotegui, Elizabeth Guruceaga, María D Odero
The SET (I2PP2A) oncoprotein is a potent inhibitor of protein phosphatase 2A (PP2A) that regulates many cell processes and important signaling pathways. Despite the importance of SET overexpression and its prognostic impact in both hematologic and solid tumors, little is known about the mechanisms involved in its transcriptional regulation. In this report, we define the minimal promoter region of the SET gene, and identify a novel multi-protein transcription complex, composed of MYC, SP1, RUNX1 and GATA2, which activates SET expression in AML...
June 6, 2016: Oncotarget
Guangwen Shu, Lang Zhang, Shanqing Jiang, Zhuo Cheng, Guan Wang, Xu Huang, Xinzhou Yang
Our previous study discovered that isoliensinine (isolie) triggers hepatocellular carcinoma (HCC) cell apoptosis via inducing p65 dephosphorylation at Ser536 and inhibition of NF-κB. Here, we showed that isolie promoted p65/PP2A interaction in vitro and in vivo. Repression of PP2A activity or knockdown of the expression of PP2A-C (the catalytic subunit of PP2A) abrogated isolie-provoked p65 dephosphorylation. I2PP2A is an endogenous PP2A inhibitor. Isolie directly impaired PP2A/I2PP2A interaction. Knockdown of I2PP2A boosted p65/PP2A association and p65 dephosphorylation...
June 28, 2016: Oncotarget
Xiaoyong Hu, Consuelo Garcia, Ladan Fazli, Martin Gleave, Michael P Vitek, Marilyn Jansen, Dale Christensen, David J Mulholland
The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence...
November 13, 2015: Scientific Reports
Leena P Bharath, Ting Ruan, Youyou Li, Anindita Ravindran, Xin Wan, Jennifer Kim Nhan, Matthew Lewis Walker, Lance Deeter, Rebekah Goodrich, Elizabeth Johnson, Derek Munday, Robert Mueller, David Kunz, Deborah Jones, Van Reese, Scott A Summers, Pon Velayutham Anandh Babu, William L Holland, Quan-Jiang Zhang, E Dale Abel, J David Symons
Prior studies have implicated accumulation of ceramide in blood vessels as a basis for vascular dysfunction in diet-induced obesity via a mechanism involving type 2 protein phosphatase (PP2A) dephosphorylation of endothelial nitric oxide synthase (eNOS). The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension...
November 2015: Diabetes
Shuhei Enjoji, Ryotaro Yabe, Nobuyuki Fujiwara, Shunya Tsuji, Michael P Vitek, Takuya Mizuno, Takayuki Nakagawa, Tatsuya Usui, Takashi Ohama, Koichi Sato
Canine melanoma is one of the most important diseases in small animal medicine. Protein phosphatase 2A (PP2A), a well conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. SET/I2PP2A is an endogenous inhibitor for PP2A, which directly binds to PP2A and suppresses its phosphatase activity. Elevated SET protein levels have been reported to exacerbate human tumor progression. The role of SET in canine melanoma, however, has not been understood. Here, we investigated the potential therapeutic role for SET inhibitors in canine melanoma...
November 2015: Journal of Veterinary Medical Science
Alkmini Kalousi, Anne-Sophie Hoffbeck, Platonas N Selemenakis, Jordan Pinder, Kienan I Savage, Kum Kum Khanna, Laurent Brino, Graham Dellaire, Vassilis G Gorgoulis, Evi Soutoglou
Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair...
April 7, 2015: Cell Reports
Yanfeng Liu, Pengcheng He, Feng Liu, Xiaoyan Cheng, Mei Zhang
OBJECTIVE: To explore the effect of RNA interference of human I2PP2A gene on the proliferation and apoptosis of retinoic acid-resistant human acute promyelocytic leukemia (APL) cell line NB4-R1. METHODS: Designed and constructed a RNA interference lentiviral vector I2PP2A-shRNA which targeted against I2PP2A gene, then transfected it into NB4-R1 via polybrene mediation. The I2PP2A expression levels before and after transfection were detected by qRT-PCR and Western blot, respectively...
August 2014: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Mohammad Arif, Jianshe Wei, Qi Zhang, Fei Liu, Gustavo Basurto-Islas, Inge Grundke-Iqbal, Khalid Iqbal
Abnormal hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of Tau is regulated by protein phosphatase 2A (PP2A), which in turn is modulated by endogenous inhibitor 2 (I2 (PP2A)). In AD brain, I2 (PP2A) is translocated from neuronal nucleus to cytoplasm, where it inhibits PP2A activity and promotes abnormal phosphorylation of Tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2 (PP2A) containing a conserved basic motif, (179)RKR(181), which is sufficient for directing its nuclear localization...
October 3, 2014: Journal of Biological Chemistry
Limin Chen, Liu-Fei Luo, Junyan Lu, Lianchun Li, Yuan-Fang Liu, Jiang Wang, Hong Liu, Heng Song, Hualiang Jiang, Sai-Juan Chen, Cheng Luo, Keqin Kathy Li
The M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) represents an unmet challenge because of poor clinical outcomes in a sizable portion of patients. In this study,we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treating of multiple sclerosis, shows antitumorigenic activity against the Kasumi-1 cell line, xenograft mouse models and leukemic blasts isolated from AML-M2 patients with t(8;21) translocation. Primary investigation indicated that FTY720 caused cell apoptosis through caspases and protein phosphatase 2A (PP2A) activation...
2014: PloS One
Mahnaz Janghorban, Amy S Farrell, Brittany L Allen-Petersen, Carl Pelz, Colin J Daniel, Jessica Oddo, Ellen M Langer, Dale J Christensen, Rosalie C Sears
The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types...
June 24, 2014: Proceedings of the National Academy of Sciences of the United States of America
Ryotaro Yabe, Nobuyuki Fujiwara, Takuya Mizuno, Tatsuya Usui, Takashi Ohama, Koichi Sato
SET is an endogenous protein phosphatase 2A (PP2A) inhibitor and is associated with a poor prognosis in human leukemia. Previously, we reported increased SET protein levels in canine lymphoma cell lines and the potential therapeutic application of SET antagonists in canine lymphoma. Here, we found that canine cells express several isoforms of the SET protein. We cloned 4 isoforms of SET, named SETα, β, γ and δ. Genomic BLAST showed that the SET genes are located on chromosomes X, 7, 1 and 8, respectively...
September 2014: Journal of Veterinary Medical Science
Jagadish Loganathan, Jiahua Jiang, Amanda Smith, Andrej Jedinak, Anita Thyagarajan-Sahu, George E Sandusky, Harikrishna Nakshatri, Daniel Sliva
Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice...
June 2014: International Journal of Oncology
Amy S Farrell, Brittany Allen-Petersen, Colin J Daniel, Xiaoyan Wang, Zhiping Wang, Sarah Rodriguez, Soren Impey, Jessica Oddo, Michael P Vitek, Charles Lopez, Dale J Christensen, Brett Sheppard, Rosalie C Sears
UNLABELLED: Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A)...
June 2014: Molecular Cancer Research: MCR
Lays M Sobral, Lucas O Sousa, Ricardo D Coletta, Hamilton Cabral, Lewis J Greene, Eloiza H Tajara, J Silvio Gutkind, Carlos Curti, Andréia M Leopoldino
BACKGROUND: SET/I2PP2A is a multifunctional protein that is up-regulated in head and neck squamous cell carcinoma (HNSCC). The action of SET in HNSCC tumorigenicity is unknown. METHODS: Stable SET knockdown by shRNA (shSET) was established in three HNSCC cell lines: HN12, HN13, and Cal27. Protein expression and phosphorylated protein levels were determined by Western blotting and immunofluorescence, cell migration and invasion were measured by functional analysis, and PP2A activity was determined using a serine/threonine phosphatase assay...
2014: Molecular Cancer
Archana Mukhopadhyay, Kayann Tabanor, Rathnam Chaguturu, Jane V Aldrich
Inhibitor 2 of protein phosphatase 2A (I2PP2A), a biological inhibitor of the cellular serine/threonine protein phosphatase PP2A, is associated with numerous cellular processes that often lead to the formation and progression of cancer. In this study we hypothesized that targeting the inhibition of I2PP2A's multiple functions in prostate cancer cells might prevent cancer progression. We have investigated the effect of the small chain C6-ceramide, known to be a bioactive tumor suppressor lipid, on I2PP2A function, thereby affecting c-Myc signaling and histone acetylation in cells...
October 1, 2013: Cancer Biology & Therapy
Chang Liu, Jürgen Götz
This review is dedicated to Inge Grundke-Iqbal who laid the foundations of the tau field, by isolating tau from the Alzheimer's disease (AD) brain, discovering that tau is hyperphosphorylated, and proving a critical role of protein phosphatase 2A (PP2A) and its endogenous inhibitor I2PP2A in this process. This memorial starts with a few personal notes, and then covers how subcellular fractionation helped in isolating tau. We review in detail the role of PP2A and its endogenous inhibitor in tau phosphorylation...
2013: Journal of Alzheimer's Disease: JAD
Jean-Philippe Chambon, Sandra A Touati, Stéphane Berneau, Damien Cladière, Céline Hebras, Rachel Groeme, Alex McDougall, Katja Wassmann
Haploid gametes are generated through two consecutive meiotic divisions, with the segregation of chromosome pairs in meiosis I and sister chromatids in meiosis II. Separase-mediated stepwise removal of cohesion, first from chromosome arms and later from the centromere region, is a prerequisite for maintaining sister chromatids together until their separation in meiosis II [1]. In all model organisms, centromeric cohesin is protected from separase-dependent removal in meiosis I through the activity of PP2A-B56 phosphatase, which is recruited to centromeres by shugoshin/MEI-S332 (Sgo) [2-5]...
March 18, 2013: Current Biology: CB
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