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Arpita Baisantry, Sagar Bhayana, Christoph Wrede, Jan Hegermann, Hermann Haller, Anette Melk, Roland Schmitt
Autophagy and senescence are two distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the two processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC...
October 7, 2016: Cell Cycle
Hongping Xia, Shik Nie Kong, Jianxiang Chen, Ming Shi, Karthik Sekar, Veerabrahma Pratap Seshachalam, Muthukumar Rajasekaran, Brian Kim Poh Goh, London Lucien Ooi, Kam M Hui
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival...
September 28, 2016: Cancer Letters
Barbora Melkes, Lucie Hejnova, Jiri Novotny
There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2...
September 6, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Pooja Ghatalia, Eddy S Yang, Brittany N Lasseigne, Ryne C Ramaker, Sara J Cooper, Dongquan Chen, Sunil Sudarshan, Shi Wei, Arjun S Guru, Amy Zhao, Tiffiny Cooper, Deborah L Della Manna, Gurudatta Naik, Richard M Myers, Guru Sonpavde
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets...
2016: PloS One
A T Stefka, J-H Park, Y Matsuo, S Chung, Y Nakamura, A J Jakubowiak, S Rosebeck
No abstract text is available yet for this article.
2016: Blood Cancer Journal
Yubao Wang, Michael Begley, Qing Li, Hai-Tsang Huang, Ana Lako, Michael J Eck, Nathanael S Gray, Timothy J Mitchison, Lewis C Cantley, Jean J Zhao
The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle...
August 30, 2016: Proceedings of the National Academy of Sciences of the United States of America
B Schmidt, K Bergmann, J Kaufeld, A Melk
OBJECTIVE: Left ventriuclar mass (LVM) is a strong predictor of cardiovascular events. In patients with chronic kidney disease and in patients on dialysis left ventricular hypertrophy is highly prevalent. Overcoming uremia by renal transplantation might improve LVM. However, after transplantation treatment with steroids and calcineurin inhibitors increases blood pressure and therefore might counteract the positive effect of restoring renal function.We performed a metaanalysis of the available evidence from observational studies in patientts after renal tranplantation...
September 2016: Journal of Hypertension
Arivazhagan Arimappamagan, Kruthika, Rose Dawn, Kondaiah Paturu, Vani Santosh
INTRODUCTION: Molecular heterogeneity in glioblastoma (GBM) is a novel area of research recently. Because tumor infiltrating front in GBM is often left behind following tumor decompression, knowledge of its genetic makeup can improve the rationale of potential molecular targets. METHODS: MRI localized biopsies of the tumor core and peritumoral brain zone (PBZ) were obtained from 25 GBM patients. The PBZ samples containing 15% to 30% tumor cells and core samples with predominantly tumor cells along with 8 nonneoplastic brain tissues were selected for a whole Genome Gene Expression Microarray...
August 2016: Neurosurgery
Anke Doyon, Bettina Schmiedchen, Anja Sander, Aysun Bayazit, Ali Duzova, Nur Canpolat, Daniela Thurn, Karolis Azukaitis, Ali Anarat, Justine Bacchetta, Sevgi Mir, Rukshana Shroff, Ebru Yilmaz, Cengiz Candan, Markus Kemper, Michel Fischbach, Gerard Cortina, Günter Klaus, Matthias Wuttke, Anna Köttgen, Anette Melk, Uwe Querfeld, Franz Schaefer
BACKGROUND AND OBJECTIVES: Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5...
July 7, 2016: Clinical Journal of the American Society of Nephrology: CJASN
N I Moiseeva, O Yu Susova, A A Mitrofanov, D Yu Panteleev, G V Pavlova, N A Pustogarov, A A Stavrovskaya, E Yu Rybalkina
Glioblastomas (GBL) are the most common and aggressive brain tumors. They are distinguished by high resistance to radiation and chemotherapy. To find novel approaches for GBL classification, we obtained 16 primary GBL cell cultures and tested them with real-time PCR for mRNA expression of several genes (YB-1, MGMT, MELK, MVP, MDR1, BCRP) involved in controlling cell proliferation and drug resistance. The primary GBL cultures differed in terms of proliferation rate, wherein a group of GBL cell cultures with low proliferation rate demonstrated higher resistance to temozolomide...
June 2016: Biochemistry. Biokhimii︠a︡
A A Stavrovskaya, S S Shushanov, E Yu Rybalkina
Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed...
February 2016: Biochemistry. Biokhimii︠a︡
Corey Speers, Shuang G Zhao, Vishal Kothari, Alyssa Santola, Meilan Liu, Kari Wilder-Romans, Joseph R Evans, Nidhi Batra, Harry Bartelink, Daniel F Hayes, Theodore S Lawrence, Powel H Brown, Lori J Pierce, Felix Y Feng
PURPOSE: While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC), thus it is clear that additional targets for radiosensitization and treatment are critically needed. EXPERIMENTAL DESIGN: Expression microarrays, qRT-PCR, and western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition...
May 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
B Barry Touré, John Giraldes, Troy Smith, Elizabeth R Sprague, Yaping Wang, Simon Mathieu, Zhuoliang Chen, Yuji Mishina, Yun Feng, Yan Yan-Neale, Subarna Shakya, Dongshu Chen, Matthew Meyer, David Puleo, J Tres Brazell, Christopher Straub, David Sage, Kirk Wright, Yanqiu Yuan, Xin Chen, Jose Duca, Sean Kim, Li Tian, Eric Martin, Kristen Hurov, Wenlin Shao
MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency...
May 26, 2016: Journal of Medicinal Chemistry
Wenbin Ji, Christopher Arnst, Aaron R Tipton, Michael E Bekier, William R Taylor, Tim J Yen, Song-Tao Liu
OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells...
2016: PloS One
Theresa A Koleck, Yvette P Conley
Research is beginning to suggest that the presence and/or severity of symptoms reported by breast cancer survivors may be associated with disease-related factors of cancer. In this article, we present a novel approach to the identification and prioritization of biologically plausible candidate genes to investigate relationships between genomic variation and symptom variability in breast cancer survivors. Cognitive dysfunction is utilized as a representative breast cancer survivor symptom to elucidate the conceptualization of and justification for our cellular, disease-based approach to address symptom variability in cancer survivors...
2016: Breast Cancer: Targets and Therapy
Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo, Roseli da Silva, Marcela Gimenez, Gisele Nunes Reis, Jean-Pierre Tassan, Jose Cesar Rosa, Miyuki Uno
BACKGROUND: Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine kinase involved in cell cycle, differentiation, proliferation, and apoptosis. These multiple features are consistent with it being a potential anticancer target. Nevertheless, the MELK pathway in tumorigenesis is not yet completely understood. This study aims to identify proteins associated with MELK pathway in astrocytomas. To this end, proteomic data of the human glioma cell line U87MG transfected with siRNA for MELK were compared with non-target transfected control cells and compared with oligonucleotide microarray data...
2016: Proteome Science
Sara Karlsson, Susanne Henningsson, Daniel Hovey, Anna Zettergren, Lina Jonsson, Diana S Cortes, Jonas Melke, Petri Laukka, Håkan Fischer, Lars Westberg
The ability to recognize the identity of faces and voices is essential for social relationships. Although the heritability of social memory is high, knowledge about the contributing genes is sparse. Since sex differences and rodent studies support an influence of estrogens and androgens on social memory, polymorphisms in the estrogen and androgen receptor genes (ESR1, ESR2, AR) are candidates for this trait. Recognition of faces and vocal sounds, separately and combined, was investigated in 490 subjects, genotyped for 10 single nucleotide polymorphisms (SNPs) in ESR1, four in ESR2 and one in the AR Four of the associations survived correction for multiple testing: women carrying rare alleles of the three ESR2 SNPs, rs928554, rs1271572 and rs1256030, in linkage disequilibrium with each other, displayed superior face recognition compared with non-carriers...
June 2016: Social Cognitive and Affective Neuroscience
Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park
T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells...
April 5, 2016: Oncotarget
Anna Zettergren, Sara Karlsson, Daniel Hovey, Lina Jonsson, Jonas Melke, Henrik Anckarsäter, Paul Lichtenstein, Sebastian Lundström, Lars Westberg
Autism spectrum disorders (ASDs) are more prevalent in boys than in girls, indicating that high levels of testosterone during early development may be a risk factor. Evidence for this hypothesis comes from studies showing associations between fetal testosterone levels, as well as indirect measures of prenatal androgenization, and ASDs and autistic-like traits (ALTs). In a recent study we reported associations between ALTs and single nucleotide polymorphisms (SNPs) in the genes encoding estrogen receptor 1 (ESR1), steroid-5-alpha-reductase, type 2 (SRD5A2) and sex hormone-binding globulin (SHBG) in a subset (n=1771) from the Child and Adolescent Twin Study in Sweden (CATSS)...
June 2016: Psychoneuroendocrinology
Suyoun Chung, Kyoko Kijima, Aiko Kudo, Yoshiko Fujisawa, Yosuke Harada, Akiko Taira, Naofumi Takamatsu, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura
MELK is upregulated in various types of human cancer and is known to be associated with cancer progression, maintenance of stemness, and poor prognosis. OTS167, a MELK kinase inhibitor, shows potent growth-suppressive effect on human tumors in a xenograft model, but the detailed mode of action has not been fully elucidated. In this study, we demonstrate the molecular mechanism of action of MELK inhibitor OTS167 in a preclinical model. OTS167-treated cells caused morphological transformation, induced the differentiation markers, and reduced stem-cell marker expression...
April 5, 2016: Oncotarget
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