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Ruifang Zheng, George P Studzinski
Differentiation therapy can supplement the therapy of APL, but other subtypes of AML are treated principally with cytotoxic agents, with few lasting remissions. While the induction of monocyte followed by macrophage differentiation by vitamin D derivatives (VDDs) is dramatic in cultured AML cells of all subtypes, attempts to translate this to the clinic have not been effective. Thus, better understanding of the mechanisms underlying VDD-induced differentiation may improve this approach. The key events in this form of differentiation include increased expression of CD11b, and the transcription factor PU...
October 17, 2016: Leukemia & Lymphoma
Qiang Li, Yujie Chen, Xuan Zhang, Shilun Zuo, Hongfei Ge, Yanyan Chen, Xin Liu, John H Zhang, Huaizhen Ruan, Hua Feng
Angiographic vasospasm, especially in the early phases (<72h) of subarachnoid hemorrhage (SAH), is one of the major complications after an aneurysm rupture and is often the cause of delayed neurological deterioration. Scutellarin (SCU), a flavonoid extracted from the traditional Chinese herb Erigeron breviscapus, has been widely accepted as an antioxidant, but the effect of SCU on vasospasm after SAH remains elusive. Endovascular perforation was conducted to induce SAH in Sprague-Dawley rats. Then, the underlying mechanism of the anti-vasospasm effect of SCU was investigated using a modified Garcia scale, India ink angiography, cross-sectional area analysis, immunohistochemistry staining and western blot...
October 11, 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Kangmin Zhuang, Juchang Zhang, Man Xiong, Xianfei Wang, Xiaobei Luo, Lu Han, Yan Meng, Yali Zhang, Wenting Liao, Side Liu
Abnormal expression of cyclin-dependent kinase 5 (CDK5) has been found in several human cancers, whereas the role of CDK5 in the malignant development of colorectal cancer (CRC) has not been well characterized. Here we investigated the role of CDK5 in CRC and found that its expression was much higher in CRC tissues than that in normal tissues with a higher expression level of CDK5 closely correlating to advanced American Joint Committee on Cancer (AJCC) stage, poor differentiation, increased tumor size and poor prognosis of CRC...
October 13, 2016: Cell Death & Disease
Mareike Doerrenberg, Andreas Kloetgen, Kebria Hezaveh, Wilhelm Wössmann, Kirsten Bleckmann, Martin Stanulla, Martin Schrappe, Alice C McHardy, Arndt Borkhardt, Jessica I Hoell
For reasons not yet understood, nearly all infants with acute lymphoblastic leukemia (ALL) are diagnosed with the B-cell type, with T-ALL in infancy representing a very rare exception. Clinical and molecular knowledge about infant T-ALL is still nearly completely lacking and it is also still unclear whether it represents a distinct disease compared to childhood T-ALL. To address this, we performed exome sequencing of three infant cases, which enabled the detection of mutations in NOTCH2, NOTCH3, PTEN, and KRAS...
September 26, 2016: Genes, Chromosomes & Cancer
Nestor Gomez, Tatiana Erazo, Jose M Lizcano
ERK5, the last MAP kinase family member discovered, is activated by the upstream kinase MEK5 in response to growth factors and stress stimulation. MEK5-ERK5 pathway has been associated to different cellular processes, playing a crucial role in cell proliferation in normal and cancer cells by mechanisms that are both dependent and independent of its kinase activity. Thus, nuclear ERK5 activates transcription factors by either direct phosphorylation or acting as co-activator thanks to a unique transcriptional activation TAD domain located at its C-terminal tail...
2016: Frontiers in Cell and Developmental Biology
Li-Na Yu, Li-Hong Sun, Min Wang, Min Yan
Extracellular signal-regulated protein kinase 5 (ERK5), also known as big mitogen-activated protein kinase 1 (MAPK1), is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is expressed in many tissues, including the dorsal root ganglion (DRG) neurons and the spinal cord. In this review, we focus on elaborating ERK5-associated pathway in pathological pain, in which the ERK5/CREB (cyclic adenosine monophosphate (cAMP)-response element-binding protein) pathway plays a crucial role in the transduction of pain signal and contributes to pain hypersensitivity...
2016: Journal of Zhejiang University. Science. B
Fang Zheng, Jiahe Zhang, Siyu Luo, Jing Yi, Ping Wang, Quanqing Zheng, Yurong Wen
Inappropriate expression of microRNA (miR) is strongly associated with carcinogenesis. miR-143 was reported to be one of the most prominent miRs implicated in the genesis and progression of human cancer. However, its correlation with cell proliferation and apoptosis in cervical cancer remains to be fully elucidated. In the present study, it was demonstrated that miR-143 is able to suppress the proliferation of cervical cancer HeLa cells and induce cell apoptosis in a time- and dose-dependent manner. The present study also investigated the potential targets of miR-143, extracellular-signal-regulated kinase 5 (ERK5) and its downstream substrate oncoprotein c-Fos, both of which are involved in cell proliferation and apoptosis...
October 2016: Oncology Letters
Emme C K Lin, Christopher M Amantea, Tyzoon K Nomanbhoy, Helge Weissig, Junichi Ishiyama, Yi Hu, Shyama Sidique, Bei Li, John W Kozarich, Jonathan S Rosenblum
Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Joo-Young Im, Sung-Hoon Yoon, Bo-Kyung Kim, Hyun Seung Ban, Kyoung-Jae Won, Kyung-Sook Chung, Kyeong Eun Jung, Misun Won
The data included in this article are associated with the article entitled "DNA-damage-induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion" (J.Y. Im, S.H. Yoon, B.K. Kim, H.S. Ban, K.J. Won, K.S. Chung, K.E. Jung, M. Won) [1]. Quantitative RT-PCR data revealed that genetic or pharmacological inhibition of extracellular signal-regulated kinase 5 (ERK5) suppresses DDIAS transcription in response to epidermal growth factor (EGF) in Hela cells. p300 did not interact with myocyte enhancer factor 2B (MEF2B), a downstream target of ERK5 and affect transcription of DDIAS...
December 2016: Data in Brief
Maria Elena Bravo-Adame, Rosario Vera-Estrella, Bronwyn J Barkla, Cecilia Martínez-Campos, Angel Flores-Alcantar, Jose Pablo Ocelotl-Oviedo, Gustavo Pedraza-Alva, Yvonne Rosenstein
CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR)...
September 8, 2016: Immunology
Jianguo Wu, Hongyan Cui, Zhifeng Zhu, Li Wang
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer. Has-miR-200b-3p is generally recognized as one of the fundamental regulators of EMT. In this study, we found that the expression of miR-200b-3p was downregulated in glioma tissues and human glioma cells U87 and U251. Meanwhile, Up-regulating miR-200b-3p enhanced E-cadherin, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-200b-3p on tumor growth...
September 23, 2016: Biochemical and Biophysical Research Communications
Fengbao Luo, Jian Shi, Qianqian Shi, Xianlin Xu, Ying Xia, Xiaozhou He
Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis...
2016: Cellular Physiology and Biochemistry
Seong Ji Park, Yu Sun Choi, Seungkoo Lee, Young Jae Lee, Suntaek Hong, Sanghwa Han, Byung-Chul Kim
Transforming growth factor-β1 (TGF-β1) promotes tumor metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in cancer cells. In this study, we investigated the effects of BIX02189 and XMD8-92, pharmacologic inhibitors of the MEK5 [mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK)5] signaling pathway, on the EMT and migration of cancer cells induced by TGF-β1. In human A549 lung cancer cells, TGF-β1-induced EMT, cell motility, and expression of matrix metalloproteinase-2 were completely inhibited by BIX02189, but not by XMD8-92 or small interference RNAs specific to MEK5 and ERK5...
October 28, 2016: Cancer Letters
Kinga Wrobel, Yiru Chen Zhao, Eylem Kulkoyluoglu, Karen Lee Ann Chen, Kadriye Hieronymi, Jamie Holloway, Sarah Li, Tania Ray, Partha Sarathi Ray, Yosef Landesman, Alexander Edward Lipka, Rebecca Lee Smith, Zeynep Madak-Erdogan
Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies...
October 2016: Molecular Endocrinology
Charles A C Williams, Rosalia Fernandez-Alonso, Jinhua Wang, Rachel Toth, Nathanael S Gray, Greg M Findlay
Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward primed pluripotency...
August 16, 2016: Cell Reports
Adrien Rousseau, Anne Bertolotti
The proteasome is essential for the selective degradation of most cellular proteins, but how cells maintain adequate amounts of proteasome is unclear. Here we show that there is an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1, the inhibition of which induced all known yeast 19S regulatory particle assembly-chaperones (RACs), as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen-activated protein kinase, Mpk1, acts to increase the supply of RACs and proteasome subunits under challenging conditions in order to maintain proteasomal degradation and cell viability...
August 11, 2016: Nature
Ling Lu, Jia Chen, Hua Tang, Ling Bai, Chun Lu, Kehuan Wang, Manli Li, Yinmei Yan, Ling Tang, Rui Wu, Yang Ye, Longtao Jin, Zhaofeng Liang
Tobacco smoke is an important risk factor of gastric cancer. Epithelial-mesenchymal transition is a crucial pathophysiological process in cancer development. ERK5 regulation of epithelial-mesenchymal transition may be sensitive to cell types and/or the cellular microenvironment and its role in the epithelial-mesenchymal transition process remain elusive. Epigallocatechin-3-gallate (EGCG) is a promising chemopreventive agent for several types of cancers. In the present study we investigated the regulatory role of ERK5 in tobacco smoke-induced epithelial-mesenchymal transition in the stomach of mice and the preventive effect of EGCG...
2016: Nutrients
Fei Teng, Meng Guo, Fang Liu, Ce Wang, Jiayong Dong, Lei Zhang, You Zou, Rui Chen, Keyan Sun, Hong Fu, Zhiren Fu, Wenyuan Guo, Guoshan Ding
A central aim in cancer research is to identify genes with altered expression patterns in tumor specimens and their potential role in tumorigenesis. Most types of tumors, including hepatocellular carcinoma (HCC), are heterogeneous in terms of genotype and phenotype. Thus, traditional analytical methods like the t-test fail to identify all oncogenes from expression profiles. In this study, we performed a meta-Cancer Outlier Profile Analysis (meta-COPA) across six microarray datasets for HCC from the GEO database...
July 18, 2016: Oncotarget
Joo-Young Im, Sung-Hoon Yoon, Bo-Kyung Kim, Hyun Seung Ban, Kyoung-Jae Won, Kyung-Sook Chung, Kyeong Eun Jung, Misun Won
DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells...
July 10, 2016: Biochimica et Biophysica Acta
Stephanie M Myers, Ruth H Bawn, Louise C Bisset, Timothy J Blackburn, Betty Cottyn, Lauren Molyneux, Ai-Ching Wong, Celine Cano, William Clegg, Ross W Harrington, Hing Leung, Laurent Rigoreau, Sandrine Vidot, Bernard T Golding, Roger J Griffin, Tim Hammonds, David R Newell, Ian R Hardcastle
The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57 617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development...
August 8, 2016: ACS Combinatorial Science
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