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Evan F Garner, Adele P Williams, Laura L Stafman, Jamie M Aye, Elizabeth Mroczek-Musulman, Blake P Moore, Jerry E Stewart, Gregory K Friedman, Elizabeth A Beierle
Group 3 tumors account for 28% of medulloblastomas and have the worst prognosis. FTY720, an immunosuppressant currently approved for treatment of multiple sclerosis, has shown antitumor effects in several human cancer cell lines. We hypothesized that treatment with FTY720 (fingolimod) would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). Three Group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was detected by immunohistochemistry and immunoblotting...
May 2, 2018: Scientific Reports
Gustavo Basurto-Islas, Jin-Hua Gu, Yunn Chyn Tung, Fei Liu, Khalid Iqbal
Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD...
April 14, 2018: Journal of Alzheimer's Disease: JAD
Shuhei Enjoji, Ryotaro Yabe, Shunya Tsuji, Kazuhiro Yoshimura, Hideyoshi Kawasaki, Masashi Sakurai, Yusuke Sakai, Hiroko Takenouchi, Shigefumi Yoshino, Shoichi Hazama, Hiroaki Nagano, Hiroko Oshima, Masanobu Oshima, Michael P Vitek, Tetsuya Matsuura, Yoshitaka Hippo, Tatsuya Usui, Takashi Ohama, Koichi Sato
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Chemotherapies against gastric cancer often fail, with cancer recurrence due potentially to the persistence of cancer stem cells. This unique subpopulation of cells in tumors possesses the ability to self-renew and dedifferentiate. These cancer stem cells are critical for initiation, maintenance, metastasis, and relapse of cancers; however, the molecular mechanisms supporting cancer stemness remain largely unknown...
March 2018: Molecular Cancer Research: MCR
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...
August 15, 2017: Oncotarget
Satoru Kake, Shunya Tsuji, Shuhei Enjoji, Sayaka Hanasaki, Hiroshi Hayase, Ryotaro Yabe, Yuiko Tanaka, Takayuki Nakagawa, Hao-Ping Liu, Shih-Chieh Chang, Tatsuya Usui, Takashi Ohama, Koichi Sato
Canine mammary tumor is the most common neoplasm in female dogs, and it has generated considerable attention as a translational model for human breast cancer. Ser/Thr protein phosphatase 2A (PP2A) plays a critical role as a tumor suppressor, and SET/I2PP2A, the endogenous inhibitory protein of PP2A, binds directly to PP2A and suppresses its phosphatase activity. Here, we investigated the role of SET in the tumorigenic growth in canine mammary tumor as well as in the sensitivity of tumors to existing therapeutics...
June 27, 2017: Scientific Reports
Lays M Sobral, Ricardo D Coletta, Luciane C Alberici, Carlos Curti, Andréia M Leopoldino
The multifunctional SET/I2PP2A protein is known to be overexpressed in head and neck squamous cell carcinoma. However, SET has been reported to have apparently conflicting roles in promoting cancer cell survival under oxidative stress conditions and preventing invasion and metastasis, complicating efforts to understand the contribution of SET to carcinogenesis. In the present study, we overexpressed SETin a spontaneously immortalized oral keratinocyte cell line (NOK-SI SET) and demonstrated that SET upregulation alone was sufficient to transform cells...
September 2017: FEBS Journal
Shi-Wen Jiang, Siliang Xu, Haibin Chen, Jiayin Liu, Ping Duan
SET (SE translocation, SET) is an evolutionarily conserved gene broadly expressed in various human tissues, especially in the gonadal and neural system. As a multitasking protein, SET is involved in essential cell processes such as histone modification, chromatin remodeling, DNA repair, gene transcription, and androgen synthesis. Recent studies showed that SET is overexpressed in breast cancers, ovary cancers and a variety of other malignancies. The strong correlation between SET expression levels and survival of ovarian cancer patients, and SET-mediated activation of androgen synthesis, strongly indicated that this factor may play a significant role in gynecologic cancers...
2017: Current Drug Targets
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
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