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John M Hatcher, Guowei Wu, Chuyue Zeng, Jie Zhu, Fan Meng, Sherrina Patel, Wenqiu Wang, Scott B Ficarro, Alan L Leggett, Chelsea E Powell, Jarrod A Marto, Kang Zhang, Jacky Chi Ki Ngo, Xiang-Dong Fu, Tinghu Zhang, Nathanael S Gray
The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations...
February 14, 2018: Cell Chemical Biology
Yumi Sunatani, Radhika Pankaj Kamdar, Mukesh Kumar Sharma, Tadashi Matsui, Ryo Sakasai, Mitsumasa Hashimoto, Yasuhito Ishigaki, Yoshihisa Matsumoto, Kuniyoshi Iwabuchi
X-ray repair cross-complementing group 4 (XRCC4), a repair protein for DNA double-strand breaks, is cleaved by caspases during apoptosis. In this study, we examined the role of XRCC4 in apoptosis. Cell lines, derived from XRCC4-deficient M10 mouse lymphoma cells and stably expressing wild-type XRCC4 or caspase-resistant XRCC4, were established and treated with staurosporine (STS) to induce apoptosis. In STS-induced apoptosis, expression of wild-type, but not caspase-resistant, XRCC4 in XRCC4-deficient cells enhanced oligonucleosomal DNA fragmentation and the appearance of TUNEL-positive cells by promoting nuclear translocation of caspase-activated DNase (CAD), a major nuclease for oligonucleosomal DNA fragmentation...
January 15, 2018: Experimental Cell Research
Fan Wu, Jie Li, Xin Du, Weisan Zhang, Ping Lei, Qiang Zhang
Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in humans, and is characterized by rapid growth, migration, invasion and reoccurrence. Evidence has indicated that the protein and mRNA levels of serine‑arginine protein kinase‑1 (SRPK‑1) are upregulated in NSCLC tissues. However, the functions of SRPK1 and targeted therapy for SRPK1 in the progression and treatment of NSCLC remain to be fully elucidated. In the present study, the mRNA and protein expression levels of SRPK‑1 in NSCLC cells and tissues were analyzed using reverse transcription‑quantitative polymerase chain reaction analysis and SDS‑PAGE, and the role of SRPK1 in the progression of NSCLC was investigated...
August 2017: Molecular Medicine Reports
Raoni Pais Siqueira, Marcus Vinícius de Andrade Barros, Éverton de Almeida Alves Barbosa, Thiago Souza Onofre, Victor Hugo Sousa Gonçalves, Higor Sette Pereira, Abelardo Silva Júnior, Leandro Licursi de Oliveira, Márcia Rogéria Almeida, Juliana Lopes Rangel Fietto, Róbson Ricardo Teixeira, Gustavo Costa Bressan
The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340...
July 7, 2017: European Journal of Medicinal Chemistry
Md Abu Sayed, Yui Umekawa, Kikukatsu Ito
Skunk cabbage (Symplocarpus renifolius) blooms in early spring and its inflorescence, referred to as the spadix, can produce enough heat to melt snow. Here, we investigated glycolytic carbon flow at the PEP branch-point in thermogenic spadices. Our analyses revealed that petals and pistils in thermogenic florets exhibited higher expression of SrPEPC and SrAOX transcripts than those of SrPK, SrPEPCK, and SrPEPtase. Moreover, enzymatic analyses showed high activities of PEPC in the extracts from thermogenic florets...
November 2016: Plant Signaling & Behavior
Raoni Pais Siqueira, Éverton de Almeida Alves Barbosa, Marcelo Depólo Polêto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vinícius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Márcia Rogéria Almeida, Abelardo Silva Júnior, Juliana Lopes Rangel Fietto, Jörg Kobarg, Eduardo Basílio de Oliveira, Robson Ricardo Teixeira, Júlio César Borges, Jose Andrés Yunes, Gustavo Costa Bressan
Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies...
2015: PloS One
Jehoon Kim, Jianzhong Wu
Hepatitis B virus (HBV) controls genome encapsidation and reverse transcription from a single-stranded RNA to a double-stranded DNA through the flexible C-terminal domain (CTD) of the capsid proteins. Although the microscopic structure of the nucleocapsid plays a critical role in the life cycle of HBV, the location of CTD residues at different stages of viral replication remains poorly understood. In this work, we report the radial distributions of individual amino-acid residues of the CTD tails for both empty and RNA-containing HBV capsids by using a coarse-grained model for the key biological components and the classical density functional theory...
September 16, 2014: Biophysical Journal
Michael C Brown, Jeffrey D Bryant, Elena Y Dobrikova, Mayya Shveygert, Shelton S Bradrick, Vidyalakshmi Chandramohan, Darell D Bigner, Matthias Gromeier
UNLABELLED: Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogen- or stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38α MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m(7)G) "cap"-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs)...
November 2014: Journal of Virology
Michael C Brown, Mikhail I Dobrikov, Matthias Gromeier
UNLABELLED: Translation machinery is a major recipient of the principal mitogenic signaling networks involving Raf-ERK1/2 and phosphoinositol 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR). Picornavirus internal ribosomal entry site (IRES)-mediated translation and cytopathogenic effects are susceptible to the status of such signaling cascades in host cells. We determined that tumor-specific cytotoxicity of the poliovirus/rhinovirus chimera PVSRIPO is facilitated by Raf-ERK1/2 signals to the mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) and its effects on the partitioning/activity of the Ser/Arg (SR)-rich protein kinase (SRPK) (M...
November 2014: Journal of Virology
Changshin Yoon, Daejin Kim, Seonghan Kim, Ga Bin Park, Dae Young Hur, Jae Wook Yang, Sae Gwang Park, Yeong Seok Kim
PURPOSE: To investigate the effect of the overexpression of miRNA-9 to the ratio of pro- and anti-angiogenic isoforms of vascular endothelial growth factor (VEGF) in human retinal pigment cells (ARPE-19). METHODS: Oxidative stress was induced to ARPE-19 cells by 4-hydroxynonenal (4-HNE), tert-butyl hydroperoxide (t-BH), and hypoxia chamber with 1% O₂. Expression patterns of miRNAs were validated by qPCR. Relative mRNA levels of VEGF and PEDF were measured by semi-quantitative PCR...
September 2014: Graefe's Archive for Clinical and Experimental Ophthalmology
Brandon E Aubol, Joseph A Adams
The SRPK family of protein kinases regulates mRNA splicing by phosphorylating an essential group of factors known as SR proteins, so named for a C-terminal domain enriched in arginine-serine dipeptide repeats (RS domains). SRPKs phosphorylate RS domains at numerous sites altering SR protein subcellular localization and splicing function. The RS domains in these splicing factors differ considerably in overall length and dipeptide layout. Despite their importance, little is known about how these diverse RS domains interact with SRPKs and regulate SR protein phosphorylation...
July 22, 2014: Biochemistry
Melissa V Gammons, Oleg Fedorov, David Ivison, Chunyun Du, Tamsyn Clark, Claire Hopkins, Masatoshi Hagiwara, Andrew D Dick, Russell Cox, Steven J Harper, Jules C Hancox, Stefan Knapp, David O Bates
PURPOSE: Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. We tested the hypothesis that topical (eye drop) SRPK1-selective inhibitors could be generated that reduce pro-angiogenic isoforms, and prevent choroidal neovascularization in vivo...
September 5, 2013: Investigative Ophthalmology & Visual Science
Chi Bun Chan, Keqiang Ye
Serine-arginine protein kinases (SRPKs) are a group of serine kinases that recognize and phosphorylate protein substrates with serine-arginine dipeptide repeats. They are mainly involved in regulating pre-mRNA splicing via phosphorylating splicing factors, such as ASF/SF2 and SC35. Nevertheless, the functions of SRPKs in the nervous system are sketchy, although the kinases have significant expression in neurons. Our recent studies demonstrate that one of the SRPK members, SRPK2, participates in the neuronal survival, cell cycle progression, and memory determination in Alzheimer's disease...
2013: Reviews in the Neurosciences
Melissa V R Gammons, Andrew D Dick, Steven J Harper, David O Bates
PURPOSE: We tested the hypothesis that recombinant human VEGF-A165b and the serine arginine protein kinase (SRPK) inhibitor, SRPIN340, which controls splicing of the VEGF-A pre-mRNA, prevent neovascularization in a rodent model of retinopathy of prematurity (ROP). METHODS: In the 50/10 oxygen-induced retinopathy (50/10 OIR) model that exposes newborn rats to repeated cycles of 24 hours of 50% oxygen alternating with 24 hours of 10% oxygen, pups received intraocular injections of SRPIN340, vehicle, VEGF165b, anti-VEGF antibody, or saline...
August 27, 2013: Investigative Ophthalmology & Visual Science
Brandon E Aubol, Ryan M Plocinik, Jonathan C Hagopian, Chen-Ting Ma, Maria L McGlone, Reeti Bandyopadhyay, Xiang-Dong Fu, Joseph A Adams
SR proteins are essential splicing factors whose biological function is regulated through phosphorylation of their C-terminal RS domains. Prior studies have shown that cytoplasmic-nuclear translocalization of the SR protein SRSF1 is regulated by multisite phosphorylation of a long Arg-Ser repeat in the N-terminus of the RS domain while subnuclear localization is controlled by phosphorylation of a shorter Arg-Ser repeat along with several Ser-Pro dipeptides in the C-terminus of the RS domain. To better understand how these two kinases partition Arg-Ser versus Ser-Pro specificities, we monitored the phosphorylation of SRSF1 by CLK1 and SRPK1...
August 23, 2013: Journal of Molecular Biology
Zhenyu Dong, Kousuke Noda, Atsuhiro Kanda, Junichi Fukuhara, Ryo Ando, Miyuki Murata, Wataru Saito, Masatoshi Hagiwara, Susumu Ishida
PURPOSE: To investigate the applicability of serine/arginine-rich protein kinase (SRPK)-specific inhibitor, SRPIN340, for attenuation of choroidal neovascularization (CNV) formation using a mouse model. METHODS: Laser photocoagulation was performed to induce CNV in C57BL/6J mice, followed by intravitreal injection of SRPIN340 or vehicle. Seven days after the treatment, the CNV size was evaluated using a flatmount technique. Protein levels of vascular endothelial growth factor (VEGF) and inflammation-associated molecules, such as monocyte chemoattractant protein (MCP)-1 and intercellular adhesion molecule (ICAM)-1, in the retinal pigment epithelium-choroid complex were measured with enzyme-linked immunosorbent assay...
2013: Molecular Vision
Colin P De Souza, Shahr B Hashmi, Aysha H Osmani, Peter Andrews, Carol S Ringelberg, Jay C Dunlap, Stephen A Osmani
The filamentous fungi are an ecologically important group of organisms which also have important industrial applications but devastating effects as pathogens and agents of food spoilage. Protein kinases have been implicated in the regulation of virtually all biological processes but how they regulate filamentous fungal specific processes is not understood. The filamentous fungus Aspergillus nidulans has long been utilized as a powerful molecular genetic system and recent technical advances have made systematic approaches to study large gene sets possible...
2013: PloS One
Benjamin J Loh, C Fiona Cullen, Nina Vogt, Hiroyuki Ohkura
In Drosophila oocytes, after the completion of recombination, meiotic chromosomes form a compact cluster called the karyosome within the nucleus, and later assemble spindle microtubules without centrosomes. Although these oocyte-specific phenomena are also observed in humans, their molecular basis is not well understood. Here, we report essential roles for the conserved kinase SRPK in both karyosome formation and spindle microtubule assembly in oocytes. We have identified a female-sterile srpk mutant through a cytological screen for karyosome defects...
October 1, 2012: Journal of Cell Science
Zhihong Zhou, Jinsong Qiu, Wen Liu, Yu Zhou, Ryan M Plocinik, Hairi Li, Qidong Hu, Gourisanker Ghosh, Joseph A Adams, Michael G Rosenfeld, Xiang-Dong Fu
Pre-mRNA splicing is regulated by developmental and environmental cues, but little is known about how specific signals are transduced in mammalian cells to regulate this critical gene expression step. Here, we report massive reprogramming of alternative splicing in response to EGF signaling. By blocking individual branches in EGF signaling, we found that Akt activation plays a major role, while other branches, such as the JAK/STAT and ERK pathways, make minor contributions to EGF-induced splicing. Activated Akt next branches to SR protein-specific kinases, rather than mTOR, by inducing SRPK autophosphorylation that switches the splicing kinases from Hsp70- to Hsp90-containing complexes...
August 10, 2012: Molecular Cell
Zhaohua Tang, Maria Luca, Laura Taggart-Murphy, Jessica Portillio, Cathey Chang, Ayse Guven, Ren-Jang Lin, Johanne Murray, Antony Carr
Schizosaccharomyces pombe Dsk1 is an SR protein-specific kinase (SRPK), whose homologs have been identified in every eukaryotic organism examined. Although discovered as a mitotic regulator with protein kinase activity toward SR splicing factors, it remains largely unknown about what and how Dsk1 contributes to cell cycle and pre-mRNA splicing. In this study, we investigated the Dsk1 function by determining interacting factors and cellular localization of the kinase. Consistent with its reported functions, we found that pre-mRNA processing and cell cycle factors are prominent among the proteins co-purified with Dsk1...
October 1, 2012: Experimental Cell Research
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