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Leucine zipper kinase

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https://www.readbyqxmd.com/read/28641113/enhanced-functional-genomic-screening-identifies-novel-mediators-of-dual-leucine-zipper-kinase-dependent-injury-signaling-in-neurons
#1
Derek S Welsbie, Katherine L Mitchell, Vinod Jaskula-Ranga, Valentin M Sluch, Zhiyong Yang, Jessica Kim, Eugen Buehler, Amit Patel, Scott E Martin, Ping-Wu Zhang, Yan Ge, Yukan Duan, John Fuller, Byung-Jin Kim, Eman Hamed, Xitiz Chamling, Lei Lei, Iain D C Fraser, Ze'ev A Ronai, Cynthia A Berlinicke, Donald J Zack
Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs...
June 21, 2017: Neuron
https://www.readbyqxmd.com/read/28640357/rna-sequencing-of-esophageal-adenocarcinomas-identifies-novel-fusion-transcripts-including-npc1-melk-arising-from-a-complex-chromosomal-rearrangement
#2
Zhixiong Wang, Yulan Cheng, John M Abraham, Rong Yan, Xi Liu, Wei Chen, Sariat Ibrahim, Gary P Schroth, Xiquan Ke, Yulong He, Stephen J Meltzer
BACKGROUND: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC). METHODS: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients...
June 22, 2017: Cancer
https://www.readbyqxmd.com/read/28611248/the-aspergillus-fumigatus-crza-transcription-factor-activates-chitin-synthase-gene-expression-during-the-caspofungin-paradoxical-effect
#3
Laure Nicolas Annick Ries, Marina Campos Rocha, Patrícia Alves de Castro, Rafael Silva-Rocha, Roberto Nascimento Silva, Fernanda Zanolli Freitas, Leandro José de Assis, Maria Célia Bertolini, Iran Malavazi, Gustavo H Goldman
Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the "caspofungin paradoxical effect" (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes...
June 13, 2017: MBio
https://www.readbyqxmd.com/read/28593342/the-role-of-dual-leucine-zipper-kinase-dlk-in-%C3%AE-cell-apoptosis-a-potential-target-for-the-prevention-and-treatment-of-type-2-diabetes-commentary-to-b%C3%A3-rchers-et-al-tnf-%C3%AE-induced-dlk-activation-contributes-to-apoptosis-in-the-%C3%AE-cell-line-hit
#4
EDITORIAL
https://www.readbyqxmd.com/read/28588728/maternal-embryonic-leucine-zipper-kinase-inhibits-epithelial-mesenchymal-transition-by-regulating-transforming-growth-factor-%C3%AE-signaling
#5
Jianjian Cheng, Binyu Qin, Bao Liu, Taibo Huang, Yuguang Li, Lijun Ma
Maternal embryonic leucine zipper kinase (MELK) performs an important role in self-renewal and proliferation of progenitor cells or tumor stem cells, and is expressed in aggressive cancers, contributing to tumorigenesis. However, the function of MELK in metastasis is unknown. In the present study, the lung cancer A549 cell line was utilized in order to study the role of MELK in epithelial-mesenchymal transitions (EMTs), the initial step of tumor metastasis. It was identified that transforming growth factor-β (TGF-β) could downregulate the expression of MELK, and that MELK could inhibit EMT by regulating TGF-β signaling...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28586211/structure-based-design-of-n-3-1h-pyrazolo-3-4-b-pyridin-5-yl-ethynyl-benzenesulfonamides-as-selective-leucine-zipper-and-sterile-%C3%AE-motif-kinase-zak-inhibitors
#6
Yu Chang, Xiaoyun Lu, Marthandam Asokan Shibu, Yi-Bo Dai, Jinfeng Luo, Yan Zhang, Yingjun Li, Peng Zhao, Zhang Zhang, Yong Xu, Zheng-Chao Tu, Qingwen Zhang, Cai-Hong Yun, Chih-Yang Huang, Ke Ding
A series of N-(3-((1H-pyrazolo[3, 4-b]pyridin-5-yl)ethynyl) benzenesulfonamides were rationally designed as highly selective ZAK inhibitors. One of the most promising compound 1h strongly inhibits the kinase activity of ZAK with an IC50 value of 3.3 nM, and dose-dependently suppresses the activation of ZAK downstream signals both in vitro and in vivo. However, the compound is significantly less potent for a majority of the 403 non-mutated kinases evaluated. A high resolution complex crystal structure was further determined to elucidate the detail interaction between an inhibitor and ZAK protein...
June 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28578021/transcriptome-profiling-of-the-floral-buds-and-discovery-of-genes-related-to-sex-differentiation-in-the-dioecious-cucurbit-coccinia-grandis-l-voigt
#7
Jatindra Nath Mohanty, Sanghamitra Nayak, Sumita Jha, Raj Kumar Joshi
Dioecious species offer an inclusive structure to study the molecular basis of sexual dimorphism in angiosperms. Despite having a small genome and heteromorphic sex chromosomes, Coccinia grandis is a highly neglected dioecious species with little information available on its physical state, genetic orientation and key sex-defining elements. In the present study, we performed RNA-Seq and DGE analysis of male (MB) and female (FB) buds in C. grandis to gain insights into the molecular basis of sex determination in this plant...
May 31, 2017: Gene
https://www.readbyqxmd.com/read/28550372/tnf%C3%AE-induced-dlk-activation-contributes-to-apoptosis-in-the-beta-cell-line-hit
#8
Svenja Börchers, Rohollah Babaei, Catarina Klimpel, Jorge Duque Escobar, Sabine Schröder, Roland Blume, Muhammad Nasir Hayat Malik, Elke Oetjen
Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT. In the present study, it was investigated whether TNFα or IL-1β stimulates DLK enzymatic activity. Immunoblot analysis, transient transfection with luciferase reporter gene assays, and immunofluorescence were used...
May 27, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28539269/ursodeoxycholic-acid-attenuates-experimental-autoimmune-arthritis-by-targeting-th17-and-inducing-pampk-and-transcriptional-corepressor-smile
#9
Eun-Jung Lee, Jeong-Eun Kwon, Min-Jung Park, Kyung-Ah Jung, Da-Som Kim, Eun-Kyung Kim, Seung Hoon Lee, Jong Young Choi, Sung-Hwan Park, Mi-La Cho
BACKGROUND: Ursodeoxycholic acid (UDCA) has been known that UDCA has prominent effects on liver, however, there is little known about its influence on autoimmune disease. Here, the benefit of UDCA on arthritis rheumatoid (RA) in vivo was tested. METHODS: RA mouse were induced using collagen II (CIA, collagen induced arthritis) where the disease severity or UDCA-related signaling pathway such as AMP-activated protein kinase (AMPK) or small heterodimer partner interacting leucine zipper protein (SMILE) was evaluated by westerblot and immunohistochemical staining...
May 21, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28536141/melk-and-ezh2-cooperate-to-regulate-medulloblastoma-cancer-stem-like-cell-proliferation-and-differentiation
#10
Hailong Liu, Qianwen Sun, Youliang Sun, Junping Zhang, Hongyu Yuan, Shuhuan Pang, Xueling Qi, Haoran Wang, Mingshan Zhang, Hongwei Zhang, Chunjiang Yu, Chunyu Gu
Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma...
May 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28528776/structural-basis-of-tpr-mediated-oligomerization-and-activation-of-oncogenic-fusion-kinases
#11
Kuntal Pal, Abhishek Bandyopadhyay, X Edward Zhou, Qingping Xu, David P Marciano, Joseph S Brunzelle, Smitha Yerrum, Patrick R Griffin, George Vande Woude, Karsten Melcher, H Eric Xu
The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2-142), the MET fusion partner of oncogenic TPR-MET. TPR(2-142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature...
June 6, 2017: Structure
https://www.readbyqxmd.com/read/28440222/dual-leucine-zipper-kinase-dependent-perk-activation-contributes-to-neuronal-degeneration-following-insult
#12
Martin Larhammar, Sarah Huntwork-Rodriguez, Zhiyu Jiang, Hilda Solanoy, Arundhati Sengupta Ghosh, Bei Wang, Joshua S Kaminker, Kevin Huang, Jeffrey Eastham-Anderson, Michael Siu, Zora Modrusan, Madeline M Farley, Marc Tessier-Lavigne, Joseph W Lewcock, Trent A Watkins
The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4)...
April 25, 2017: ELife
https://www.readbyqxmd.com/read/28438385/small-molecules-inhibit-stat3-activation-autophagy-and-cancer-cell-anchorage-independent-growth
#13
Donghui Zhou, Maya Z Springer, David Xu, Degang Liu, Andy Hudmon, Kay F Macleod, Samy O Meroueh
Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s...
March 23, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28396258/dlk-silencing-attenuated-neuron-apoptosis-through-jip3-ma2k7-jnk-pathway-in-early-brain-injury-after-sah-in-rats
#14
Cheng Yin, Guang-Fu Huang, Xiao-Chuan Sun, Zongduo Guo, John H Zhang
OBJECTIVE: Dual leucine zipper kinase (DLK/MA3K12) has been reported involved in apoptosis and neuronal degeneration during neural development and traumatic brain injury. This study was designed to investigate the role of DLK with its adaptor protein JNK interacting protein-3 (JIP3), and its downstream MA2K7/JNK signaling pathway in early brain injury (EBI) after subarachnoid hemorrhage (SAH) in a rat model. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory...
April 8, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28362657/epigenetics-of-cd4-t-cells-in-autoimmune-diseases
#15
Zijun Wang, Christopher Chang, Qianjin Lu
PURPOSE OF REVIEW: Autoimmune disorders are a group of overactive symptoms because of abnormal immune responses. Progress of novel mechanisms for autoimmune diseases has been restrained by incomplete understanding of immune disturbance. Recent advances in autoimmune diseases have been well documented by epigenetic alterations (DNA methylation, histone modification, and microRNAs), which alter the transcription activity of genes that are involved in autoimmune responses. RECENT FINDINGS: Multiple environmental factors (trichloroethylene, breast milk, and vitamin C) initiate aberrant epigenetic modifications in CD4 T cells, leading to a list of transcriptional deregulations in several genes (Ifng, Cd70, Tnf, Dnmt3a, and Foxp3) that determine T-cell identity...
July 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/28351607/discovery-of-a-potent-inhibitor-of-melk-that-inhibits-expression-of-the-anti-apoptotic-protein-mcl-1-and-tnbc-cell-growth
#16
Ramakrishna Edupuganti, Juliana M Taliaferro, Qiantao Wang, Xuemei Xie, Eun Jeong Cho, Fnu Vidhu, Pengyu Ren, Eric V Anslyn, Chandra Bartholomeusz, Kevin N Dalby
Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK...
May 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28337968/crispr-cas9-mutagenesis-invalidates-a-putative-cancer-dependency-targeted-in-on-going-clinical-trials
#17
Ann Lin, Christopher J Giuliano, Nicole M Sayles, Jason M Sheltzer
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types...
March 24, 2017: ELife
https://www.readbyqxmd.com/read/28275243/the-microrna-expression-signature-of-small-cell-lung-cancer-tumor-suppressors-of-mir-27a-5p-and-mir-34b-3p-and-their-targeted-oncogenes
#18
Keiko Mizuno, Hiroko Mataki, Takayuki Arai, Atsushi Okato, Kazuto Kamikawaji, Tomohiro Kumamoto, Tsubasa Hiraki, Kazuhito Hatanaka, Hiromasa Inoue, Naohiko Seki
Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous...
March 9, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28230786/sex-specificity-of-mineralocorticoid-target-gene-expression-during-renal-development-and-long-term-consequences
#19
Laurence Dumeige, Caroline Storey, Lyvianne Decourtye, Melanie Nehlich, Christophe Lhadj, Say Viengchareun, Laurent Kappeler, Marc Lombès, Laetitia Martinerie
Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance...
February 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28222251/prognostic-methylation-markers-for-overall-survival-in-cytogenetically-normal-patients-with-acute-myeloid-leukemia-treated-on-swog-trials
#20
Xiaoyu Qu, Megan Othus, Jerry Davison, Yu Wu, Liying Yan, Soheil Meshinchi, Fabiana Ostronoff, Elihu H Estey, Jerry P Radich, Harry P Erba, Frederick R Appelbaum, Min Fang
BACKGROUND: Aberrant DNA methylation is known to occur in patients with acute myeloid leukemia (AML), whereas methylation signatures and prognostic markers have been proposed. The objective of the current study was to evaluate all CpG sites of the genome and identify prognostic methylation markers for overall survival in patients with AML with normal karyotype (AML-NK). METHODS: AML-NK samples from 7 SWOG trials were analyzed using a novel genome-wide approach called "CHARMcox" (comprehensive high-throughput array-based relative methylation analysis combined with the Cox proportional hazards model) controlling for known clinical covariates...
February 21, 2017: Cancer
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