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https://www.readbyqxmd.com/read/28723560/crkl-mediates-p110%C3%AE-dependent-pi3k-signaling-in-pten-deficient-cancer-cells
#1
Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J Eck, Jarrod A Marto, Jean J Zhao, Thomas M Roberts
The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28604963/-phenotypic-and-genotypic-analysis-of-a-fetus-carrying-an-intermediate-22q11-2-deletion-encompassing-the-crkl-gene
#2
Shaobin Lin, Xiaohe Zheng, Heng Gu, Mingzhen Li
OBJECTIVE: To delineate the phenotypic characteristics of 22q11.2 deletion syndrome and the role of CRKL gene in the pathogenesis of cardiac abnormalities. METHODS: G-banded karyotyping, single nucleotide polymorphism (SNP) array and fluorescence in situ hybridization (FISH) were performed on a fetus with tetralogy of Fallot detected by ultrasound. Correlation between the genotype and phenotype was explored after precise mapping of the breakpoints on chromosome 22q11...
June 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28595903/shc004-221a1-a-novel-tyrosine-kinase-potently-inhibits-t315i-mutant-bcr-abl-in-chronic-myeloid-leukemia
#3
Duowei Wang, Yan Zheng, Jiaying Li, Hongxi Wu, Xianjing Li, Ying Tang, Yang Liu, Jiani Li, Rui Sun, Youli Zhou, Jihong Sun, Yong Yang
Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABL(T315I). In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL...
June 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28558797/expression-of-signaling-adaptor-proteins-predicts-poor-prognosis-in-pancreatic-ductal-adenocarcinoma
#4
Lili Wang, Junliang Lu, Huanwen Wu, Li Wang, Xiaolong Liang, Zhiyong Liang, Tonghua Liu
BACKGROUND: Adaptor proteins bridge the gap between cell surface receptors and their downstream signaling elements. The clinicopathological and prognostic values of adaptor proteins remain poorly understood. The purpose of the present study was to explore the expression and prognostic value of three adaptor proteins: GRB2-associated binding protein 2 (GAB2), CRK-like protein (CRKL) and fibroblast growth factor receptor substrate 2 (FRS2) in pancreatic ductal adenocarcinoma (PDAC). METHODS: The expression of GAB2, CRKL, and FRS2 in 77 formalin fixed paraffin embedded (FFPE) samples from 77 PDAC patients, along with three paired fresh PDAC and matched normal tissues from 3 PDAC patients was analyzed by immunohistochemistry and western blot, respectively...
May 30, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28556300/development-of-protein-degradation-inducers-of-oncogenic-bcr-abl-protein-by-conjugation-of-abl-kinase-inhibitors-and-iap-ligands
#5
Norihito Shibata, Naoki Miyamoto, Katsunori Nagai, Kenichiro Shimokawa, Tomoya Sameshima, Nobumichi Ohoka, Takayuki Hattori, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein have been developed recently...
August 2017: Cancer Science
https://www.readbyqxmd.com/read/28526413/tcr-crosslinking-promotes-crk-adaptor-protein-binding-to-tyrosine-phosphorylated-cd3%C3%AE-chain
#6
Guangyu Dong, Rachel Kalifa, Pulak Ranjan Nath, Sigal Gelkop, Noah Isakov
T cell antigen receptor (TCR) binding of a peptide antigen presented by antigen-presenting cells (APCs) in the context of surface MHC molecules initiates signaling events that regulate T cell activation, proliferation and differentiation. A key event in the activation process is the phosphorylation of the conserved tyrosine residues within the CD3 chain immunoreceptor tyrosine-based activation motifs (ITAMs), which operate as docking sites for SH2 domain-containing effector proteins. Phosphorylation of the CD3ζ ITAMs renders the CD3 chain capable of binding the ζ-chain associated protein 70 kDa (ZAP70), a protein tyrosine kinase that is essential for T cell activation...
May 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28500033/proteomic-responses-to-elevated-ocean-temperature-in-ovaries-of-the-ascidian-ciona-intestinalis
#7
Chelsea E Lopez, Hannah C Sheehan, David A Vierra, Paul A Azzinaro, Thomas H Meedel, Niall G Howlett, Steven Q Irvine
Ciona intestinalis, a common sea squirt, exhibits lower reproductive success at the upper extreme of the water temperatures it experiences in coastal New England. In order to understand the changes in protein expression associated with elevated temperatures, and possible response to global temperature change, we reared C. intestinalis from embryos to adults at 18°C (a temperature at which they reproduce normally at our collection site in Rhode Island) and 22°C (the upper end of the local temperature range)...
July 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28496102/partial-microduplication-in-the-histone-acetyltransferase-complex-member-kansl1-is-associated-with-congenital-heart-defects-in-22q11-2-microdeletion-syndrome-patients
#8
Luis E León, Felipe Benavides, Karena Espinoza, Cecilia Vial, Patricia Alvarez, Mirta Palomares, Guillermo Lay-Son, Macarena Miranda, Gabriela M Repetto
22q11.2 microdeletion syndrome (22q11.2DS) is the most common microdeletion disorder in humans, with an incidence of 1/4000 live births. It is caused by a heterozygous deletion of 1.5-3 Mb on chromosome region 22q11.2. Patients with the deletion present features that include neuropsychiatric problems, craniofacial abnormalities and cardiovascular malformations. However, the phenotype is highly variable and the factors related to the clinical heterogeneity are not fully understood. About 65% of patients with 22q11...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28439006/murine-model-indicates-22q11-2-signaling-adaptor-crkl-is-a-dosage-sensitive-regulator-of-genitourinary-development
#9
Meade Haller, Qianxing Mo, Akira Imamoto, Dolores J Lamb
The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKLCRKL encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans...
May 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28321124/combined-inhibition-of-%C3%AE-catenin-and-bcr-abl-synergistically-targets-tyrosine-kinase-inhibitor-resistant-blast-crisis-chronic-myeloid-leukemia-blasts-and-progenitors-in-vitro-and-in-vivo
#10
H Zhou, P Y Mak, H Mu, D H Mak, Z Zeng, J Cortes, Q Liu, M Andreeff, B Z Carter
Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in granulocyte-macrophage progenitors, and highest among a novel CD34(+)CD38(+)CD123(hi)Tim-3(hi) subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells...
April 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28300289/dehydrocostus-lactone-suppresses-proliferation-of-human-chronic-myeloid-leukemia-cells-through-bcr-abl-jak-stat-signaling-pathways
#11
Hong Cai, Xiaosong Qin, Chunhui Yang
This study evaluates the anticancer effects of dehydrocostus lactone, a plant-derived sesquiterpene lactone, on human chronic myeloid leukemia cells. Dehydrocostus lactone significantly inhibits cell proliferation by inducing cells to undergo cell cycle arrest, apoptosis, and differentiation. Dehydrocostus lactone suppresses the expression of cyclin B1, cyclin A, cyclin E, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 1 (CDK1) and increases p21 expression, resulting in S-G2/M phase arrest in K562 cells...
March 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28255248/microrna-320-inhibits-invasion-and-induces-apoptosis-by-targeting-crkl-and-inhibiting-erk-and-akt-signaling-in-gastric-cancer-cells
#12
Yue Zhao, Qianze Dong, Enhua Wang
MicroRNA-320 (miR-320) downregulation has been reported in several human cancers. Until now, its expression pattern and biological roles in human cancer remain unknown. This study aims to clarify its clinical expression pattern and biological function in gastric cancers. We found miR-320 level was downregulated in gastric cancer tissues. miR-320 mimic was transfected in SGC-7901 cells with low endogenous expression. miR-320 inhibitor was used in BGC-823 cells with high endogenous expression. We found that miR-320 inhibited SGC-7901 proliferation and invasion, with decreased expression of cyclin D1 and MMP9 at both mRNA and protein levels...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28245379/-effect-of-homoharringtonine-combined-with-imatinib-on-the-k562-g01-cells-and-its-mechanism
#13
Jing-Jing Wu, Yi-Han Ding, Zhi-Kui Deng, Yu-Ye Shi, Xue-Ying Lu, Yu-Feng Li
OBJECTIVE: To explore the effect of homoharringtonine(HHT) combined with imatinib(IM) on proliferation and apoptosis of K562/G01 cells and its potential mechanism. METHODS: K562/G01 cells were cultured with HHT and/or IM. CCK-8 assay was used to detect cell proliferation. Cell apoptosis and phosphorylated tyrosine levels were analyzed by flow cytometry. The expression levels of p210, PI3K, p-Akt and Akt protein were determined by Western blot. RESULTS: Compared with HHT or IM alone, drug combination significantly inhibited cell proliferation and induced apoptosis of K562/G01 cells (both P< 0...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28239297/up-regulation-of-crkl-by-microrna-335-methylation-is-associated-with-poor-prognosis-in-gastric-cancer
#14
Jia-Kui Zhang, Yong-Shuang Li, Chun-Dong Zhang, Dong-Qiu Dai
BACKGROUND: MicroRNAs have been suggested to play a vital role in regulating carcinogenesis, tumor progression and invasion. MiR-335 is involved in suppressing metastasis and invasion in various human cancers. However, the mechanisms responsible for the aberrant expression of miR-335 in gastric cancer (GC) remain unknown. METHODS: Expression of miR-335 in four GC cell lines and 231 GC tissues was determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR)...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28123521/crkl-overexpression-promotes-cell-proliferation-and-inhibits-apoptosis-in-endometrial-carcinoma
#15
Le Cai, He Wang, Qing Yang
The v-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) protein is important in cancer progression. However, its expression pattern and biological roles in human endometrial carcinoma remain unexplored. The potential mechanism of CRKL-induced cancer progression is still unclear. The present study aimed to explore the expression pattern and biological roles of CRKL in human endometrial carcinoma. Using immunohistochemistry, it was observed that the CRKL protein was overexpressed in 50.5% (44/87) of endometrial carcinoma tissues...
January 2017: Oncology Letters
https://www.readbyqxmd.com/read/28121514/genetic-drivers-of-kidney-defects-in-the-digeorge-syndrome
#16
Esther Lopez-Rivera, Yangfan P Liu, Miguel Verbitsky, Blair R Anderson, Valentina P Capone, Edgar A Otto, Zhonghai Yan, Adele Mitrotti, Jeremiah Martino, Nicholas J Steers, David A Fasel, Katarina Vukojevic, Rong Deng, Silvia E Racedo, Qingxue Liu, Max Werth, Rik Westland, Asaf Vivante, Gabriel S Makar, Monica Bodria, Matthew G Sampson, Christopher E Gillies, Virginia Vega-Warner, Mariarosa Maiorana, Donald S Petrey, Barry Honig, Vladimir J Lozanovski, Rémi Salomon, Laurence Heidet, Wassila Carpentier, Dominique Gaillard, Alba Carrea, Loreto Gesualdo, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E van Wijk, Adela Arapovic, Mirna Saraga-Babic, Marijan Saraga, Nenad Kunac, Ali Samii, Donna M McDonald-McGinn, Terrence B Crowley, Elaine H Zackai, Dorota Drozdz, Monika Miklaszewska, Marcin Tkaczyk, Przemyslaw Sikora, Maria Szczepanska, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, John M Darlow, Prem Puri, David Barton, Emilio Casolari, Susan L Furth, Bradley A Warady, Zoran Gucev, Hakon Hakonarson, Hana Flogelova, Velibor Tasic, Anna Latos-Bielenska, Anna Materna-Kiryluk, Landino Allegri, Craig S Wong, Iain A Drummond, Vivette D'Agati, Akira Imamoto, Jonathan M Barasch, Friedhelm Hildebrandt, Krzysztof Kiryluk, Richard P Lifton, Bernice E Morrow, Cecile Jeanpierre, Virginia E Papaioannou, Gian Marco Ghiggeri, Ali G Gharavi, Nicholas Katsanis, Simone Sanna-Cherchi
BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies...
February 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28029654/abcg2-confers-promotion-in-gastric-cancer-through-modulating-downstream-crkl-in-vitro-combining-with-biostatistics-mining
#17
Junqing Wang, Zhou Yunyun, Lu Wang, Xuehua Chen, Zhenggang Zhu
ABCG2, member of ATP-binding cassette (ABC) transporter family, is known as crucial regulator related to multi-drug resistance in human tumors and has recently been putatively studied as human carcinoma cell biomarker. While, effects of ABCG2 on human gastric cancer (GC) has not been illustrated thoroughly. In this study, by applying biostatistics mining methods, we observed that ABCG2 is frequently aberrantly expressed in GC patients through exploring dataset of GSE19826 in NCBI GEO database. Contemporary, extreme up-regulation of ABCG2 was discovered in both GC specimens and cell lines of our center, from which we observed high level of ABCG2 associated with GC clinicopathologic features and poor outcomes...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/27928132/improved-fret-biosensor-for-the-measurement-of-bcr-abl-activity-in-chronic-myeloid-leukemia-cells
#18
Mika Horiguchi, Mari Fujioka, Takeshi Kondo, Yoichiro Fujioka, Xinxin Li, Kosui Horiuchi, Aya O Satoh, Prabha Nepal, Shinya Nishide, Asuka Nanbo, Takanori Teshima, Yusuke Ohba
Although the co-development of companion diagnostics with molecular targeted drugs is desirable, truly efficient diagnostics are limited to diseases in which chromosomal translocations or overt mutations are clearly correlated with drug efficacy. Moreover, even for such diseases, few methods are available to predict whether drug administration is effective for each individual patient whose disease is expected to respond to the drug(s). We have previously developed a biosensor based on the principle of Förster resonance energy transfer to measure the activity of the tyrosine kinase BCR-ABL and its response to drug treatment in patient-derived chronic myeloid leukemia cells...
February 2, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/27926512/depression-of-oncogenecity-by-dephosphorylating-and-degrading-bcr-abl
#19
Miao Gao, Zheng-Lan Huang, Kun Tao, Qing Xiao, Xin Wang, Wei-Xi Cao, Min Xu, Jing Hu, Wen-Li Feng
Aberrant phosphorylation and overexpression of BCR-ABL fusion protein are responsible for the main pathogenesis in chronic myeloid leukemia (CML). Phosphorylated BCR-ABL Y177 recruits GRB2 adaptor and triggers leukemic RAS-MAPK and PI3K-AKT signals. In this study, we engineered a SPOA system to dephosphorylate and degrade BCR-ABL by targeting BCR-ABL Y177. We tested its effect on BCR-ABL phosphorylation and expression, as well as cell proliferation and apoptosis in CML cells. We found that SPOA remarkably dephosphorylated BCR-ABL Y177, prevented GRB2 recruitment, and uncoupled RAS-MAPK and PI3K-AKT signals...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/27899998/expression-level-of-crkl-and-axl-combined-with-exon-19-deletion-in-egfr-and-alk-status-confer-differential-prognosis-of-lung-adenocarcinoma-subtypes
#20
Yi-Ran Cai, Yu-Jie Dong, Hong-Bo Wu, Da-Ping Yu, Li-Juan Zhou, Dan Su, Li Zhang, Xue-Jing Chen
Non-small cell lung cancer (NSCLC) is a lethal cancer-related disease in population. Adenocarcinoma (AC) is subclassified into several subtypes based on the new classification by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society in 2011. Correlation between original expression of Crk-like (CRKL) and anaplastic lymphoma receptor tyrosine kinase in diverse histological components of AC and epidermal growth factor receptor (EGFR) or ALK status was evaluated by immunohistochemistry and sequencing in present study...
November 2016: Oncology Letters
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