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https://www.readbyqxmd.com/read/28212797/ca-2-calmodulin-dependent-protein-kinase-ii-in-vascular-smooth-muscle
#1
F Z Saddouk, R Ginnan, H A Singer
Ca(2+)-dependent signaling pathways are central regulators of differentiated vascular smooth muscle (VSM) contractile function. In addition, Ca(2+) signals regulate VSM gene transcription, proliferation, and migration of dedifferentiated or "synthetic" phenotype VSM cells. Synthetic phenotype VSM growth and hyperplasia are hallmarks of pervasive vascular diseases including hypertension, atherosclerosis, postangioplasty/in-stent restenosis, and vein graft failure. The serine/threonine protein kinase Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator of intracellular Ca(2+) signals...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28209757/cdk4-6-therapeutic-intervention-and-viable-alternative-to-taxanes-in-crpc
#2
James P Stice, Suzanne E Wardell, John D Norris, Alexander P Yllanes, Holly M Alley, Victoria O Haney, Hannah S White, Rachid Safi, Peter S Winter, Kimberly J Cocce, Rigel J Kishton, Scott A Lawrence, Jay C Strum, Donald P McDonnell
: Resistance to second generation AR antagonists and CYP17 inhibitors in patients with castrationresistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to androgen receptor (AR) overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand binding specificity. It has been established that androgens induce cell cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6)...
February 16, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28197539/redirecting-rna-splicing-by-smad3-turns-tgf-%C3%AE-into-a-tumor-promoter
#3
Veenu Tripathi, Ying E Zhang
Transforming growth factor β (TGF-β) is a well-known growth inhibitor of normal epithelial cells, but it is also secreted by solid tumors to promote cancer progression. Our recent discovery of SMAD3-PCBP1 complex with direct RNA-binding properties has shed light on how this conversion is implemented by controlling pre-mRNA splicing patterns.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28193906/cbx3-promotes-colon-cancer-cell-proliferation-by-cdk6-kinase-independent-function-during-cell-cycle
#4
Yao Fan, Haiping Li, Xiaolong Liang, Zheng Xiang
Heterochromatin protein 1γ (CBX3) links histone methylation marks to transcriptional silence, DNA repair and RNA splicing, but a role for CBX3 in cancer remains largely unknown. In this study, we show that CBX3 in colon cancer cells promotes the progression of the cell cycle and proliferation in vitro and in vivo. Cell cycle (G1 phase to S phase) related gene CDK6 and p21 were further identified as targets of CBX3. In addition, we found that enhancing CDK6 suppresses cell proliferation by upregulating inhibitor p21 in the absence of CBX3, and this function is independent of the kinase activity of CDK6...
February 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28185908/purification-and-biophysical-characterization-of-the-aimp2-dx2-protein
#5
Roshan Jha, Hye Young Cho, Ameeq Ul Mushtaq, Kiho Lee, Dae Gyu Kim, Sunghoon Kim, Young Ho Jeon
Besides their primary role in protein synthesis, aminoacyl-tRNA synthetases (AARSs) are involved in several non-canonical processes such as apoptosis, inflammation and angiogenesis through their interactions with various cellular proteins. Nine of these AARSs interact with three aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMPs), forming a multi-synthetase complex (MSC) in eukaryotes. Among the three AIMPs, AIMP2 is involved in controlling cell proliferation and apoptosis. However, a splicing variant of AIMP2 lacking exon 2, referred to as AIMP2-DX2, is oncogenic and compromises the pro-apoptotic activity of AIMP2 by competing with it for p53 and TRAF2...
February 6, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28178200/mechanisms-of-regulation-of-the-chemokine-receptor-network
#6
REVIEW
Martin J Stone, Jenni A Hayward, Cheng Huang, Zil E Huma, Julie Sanchez
The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms by which the interactions of chemokines with chemokine receptors are regulated, including: selective and competitive binding interactions; genetic polymorphisms; mRNA splice variation; variation of expression, degradation and localization; down-regulation by atypical (decoy) receptors; interactions with cell-surface glycosaminoglycans; post-translational modifications; oligomerization; alternative signaling responses; and binding to natural or pharmacological inhibitors...
February 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28170089/depdc5-mutations-in-familial-and-sporadic-focal-epilepsy
#7
Meng-Han Tsai, Chung-Kin Chan, Ying-Chao Chang, Yu-Tzu Yu, Shu-Ting Chuang, Wen-Lang Fan, Sung-Chou Li, Ting-Ying Fu, Wen-Neng Chang, Chia-Wei Liou, Yao-Chung Chuang, Ching-Ching Ng, Daw-Yang Hwang, Kheng-Seang Lim
Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized. We studied a kindred of familial focal epilepsy with variable foci using whole exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing...
February 7, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28167755/conformational-disruption-of-pi3k%C3%AE-regulation-by-immunodeficiency-mutations-in-pik3cd-and-pik3r1
#8
Gillian L Dornan, Braden D Siempelkamp, Meredith L Jenkins, Oscar Vadas, Carrie L Lucas, John E Burke
Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110δ catalytic (PIK3CD) subunit or the ubiquitously expressed p85α regulatory (PIK3R1) subunit of class IA phosphoinositide 3-kinases (PI3Ks). There are two classes of APDS: APDS1 that arises from p110δ mutations that are analogous to oncogenic mutations found in the broadly expressed p110α subunit and APDS2 that occurs from a splice mutation resulting in p85α with a central deletion (Δ434-475)...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28167572/an-oncogenic-alk-fusion-and-an-rras-mutation-in-kras-mutation-negative-pancreatic-ductal-adenocarcinoma
#9
Yoko Shimada, Takashi Kohno, Hideki Ueno, Yoshinori Ino, Hideyuki Hayashi, Takashi Nakaoku, Yasunari Sakamoto, Shunsuke Kondo, Chigusa Morizane, Kazuaki Shimada, Takuji Okusaka, Nobuyoshi Hiraoka
PURPOSE: Oncogenic mutations in the KRAS gene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without the KRAS mutation. METHODS: Whole-exome and transcriptome sequencing was performed on four cases of KRAS mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases. RESULTS: One case harbored an oncogenic DCTN1-ALK fusion...
February 6, 2017: Oncologist
https://www.readbyqxmd.com/read/28161458/effect-of-mptp-on-mrna-expression-of-pgc-1%C3%AE-in-mouse-brain
#10
Rita Torok, Andras Salamon, Evelin Sumegi, Denes Zadori, Gabor Veres, Mate Fort Molnar, Laszlo Vecsei, Peter Klivenyi
The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Besides the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). Achieving neuroprotection via CNS-targeted pharmacological stimulation is limited due to poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option...
February 1, 2017: Brain Research
https://www.readbyqxmd.com/read/28159830/therapeutic-strategies-for-restoring-tau-homeostasis
#11
Zapporah T Young, Sue Ann Mok, Jason E Gestwicki
Normal tau homeostasis is achieved when the synthesis, processing, and degradation of the protein is balanced. Together, the pathways that regulate tau homeostasis ensure that the protein is at the proper levels and that its posttranslational modifications and subcellular localization are appropriately controlled. These pathways include the enzymes responsible for posttranslational modifications, those systems that regulate mRNA splicing, and the molecular chaperones that control tau turnover and its binding to microtubules...
February 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28155653/novel-group-based-qsar-and-combinatorial-design-of-ck-1%C3%AE-inhibitors-as-neuroprotective-agents
#12
Kopal Joshi, Sukriti Goyal, Sonam Grover, Salma Jamal, Aditi Singh, Pawan Dhar, Abhinav Grover
BACKGROUND: Tar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS). Among the reported isoforms and splice variants of CK-1 protein superfamily, CK-1δ is known to phosphorylate different serine and threonine sites on TDP-43 protein in vitro and thus qualifies as a potential target for ALS treatment. RESULTS: The developed GQSAR (group based quantitative structure activity relationship) model displayed satisfactory statistical parameters for the dataset of experimentally reported N-Benzothiazolyl-2-Phenyl Acetamide derivatives...
December 22, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/28154181/usp39-deubiquitinase-is-essential-for-kras-driven-cancer
#13
Julia M Fraile, Eusebio Manchado, Amaia Lujambio, Victor Quesada, Diana Campos-Iglesias, Thomas Webb, Scott W Lowe, Carlos Lopez-Otin, Jose M P Freije
KRAS is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify USP39, which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of DHX38, encoding an USP39-interacting splicing factor, also reduces the viability of these cells...
February 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28152480/securinine-enhances-smn2-exon-7-inclusion-in-spinal-muscular-atrophy-cells
#14
Yu-Chia Chen, Jan-Gowth Chang, Ting-Yuan Liu, Yuh-Jyh Jong, Wei-Lin Cheng, Chung-Yee Yuo
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28135068/development-of-potent-selective-srpk1-inhibitors-as-potential-topical-therapeutics-for-neovascular-eye-disease
#15
Jennifer Batson, Hamish D Toop, Clara Redondo, Roya Babaei-Jadidi, Apirat Chaikuad, Stephen F Wearmouth, Brian Gibbons, Claire Allen, Cynthia Tallant, Jingxue Zhang, Chunyun Du, Jules Hancox, Tom Hawtrey, Joana Da Rocha, Renate Griffith, Stefan Knapp, David O Bates, Jonathan C Morris
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/anti-angiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity...
January 30, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28122580/identification-of-small-molecule-modulators-of-hiv-1-tat-and-rev-protein-accumulation
#16
Ahalya Balachandran, Raymond Wong, Peter Stoilov, Sandy Pan, Benjamin Blencowe, Peter Cheung, P Richard Harrigan, Alan Cochrane
BACKGROUND: HIV-1 replication is critically dependent upon controlled processing of its RNA and the activities provided by its encoded regulatory factors Tat and Rev. A screen of small molecule modulators of RNA processing identified several which inhibited virus gene expression, affecting both relative abundance of specific HIV-1 RNAs and the levels of Tat and Rev proteins. RESULTS: The screen for small molecules modulators of HIV-1 gene expression at the post-transcriptional level identified three (a pyrimidin-7-amine, biphenylcarboxamide, and benzohydrazide, designated 791, 833, and 892, respectively) that not only reduce expression of HIV-1 Gag and Env and alter the accumulation of viral RNAs, but also dramatically decrease Tat and Rev levels...
January 26, 2017: Retrovirology
https://www.readbyqxmd.com/read/28113034/biomimetic-enamel-regeneration-mediated-by-leucine-rich-amelogenin-peptide
#17
S Y Kwak, A Litman, H C Margolis, Y Yamakoshi, J P Simmer
We report here a novel biomimetic approach to the regeneration of human enamel. The approach combines the use of inorganic pyrophosphate (PPi) to control the onset and rate of enamel regeneration and the use of leucine-rich amelogenin peptide (LRAP), a nonphosphorylated 56-amino acid alternative splice product of amelogenin, to regulate the shape and orientation of growing enamel crystals. This study builds on our previous findings that show LRAP can effectively guide the formation of ordered arrays of needle-like hydroxyapatite (HA) crystals in vitro and on the known role mineralization inhibitors, like PPi, play in the regulation of mineralized tissue formation...
January 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28106752/the-promoting-effect-of-the-extracellular-matrix-peptide-tniiia2-derived-from-tenascin-c-in-colon-cancer-cell-infiltration
#18
Hideo Suzuki, Manabu Sasada, Sadahiro Kamiya, Yuka Ito, Hikaru Watanabe, Yuko Okada, Kazuma Ishibashi, Takuya Iyoda, Akinori Yanaka, Fumio Fukai
The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, it was found that the peptide derived from the alternative splicing domain A2 in TNC, termed TNIIIA2, has been shown to influence a variety of cellular processes, such as survival, proliferation, migration, and differentiation. In this study, we investigated the effect of TNC/TNIIIA2 on the invasion and metastasis of colon cancer cells, Colon26-M3...
January 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28105192/akt-dependent-activation-of-erk-by-cyclin-d1b-contributes-to-cell-invasiveness-and-tumorigenicity
#19
Chul Jang Kim, Yukihiro Tambe, Ken-Ichi Mukaisho, Hiroyuki Sugihara, Akihiro Kawauchi, Hirokazu Inoue
A total of two major isoforms, cyclin D1a and cyclin D1b, are generated from the human cyclin D1 gene by alternative splicing. Cyclin D1b is scarcely expressed in normal tissues; however, it is expressed at a high frequency in certain types of cancerous tissue. The present authors previously constructed cyclin D1b transgenic (Tg) mice and identified rectal tumors, including adenocarcinoma and sessile serrated adenoma, in 62.5% of female Tg mice. In addition, the present authors indicated that cyclin D1b expression enhances phosphorylation of extracellular signal-regulated kinase (Erk) in these rectal tumors, and in mouse embryonic fibroblast (MEF) cells and human 293T cells...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28103691/sudemycin-k-a-synthetic-antitumor-splicing-inhibitor-variant-with-improved-activity-and-versatile-chemistry
#20
Kamil Makowski, Luisa Vigevani, Fernando Albericio, Juan Valcárcel, Mercedes Álvarez
Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore...
20, 2017: ACS Chemical Biology
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