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https://www.readbyqxmd.com/read/28743497/molecular-interaction-between-k-ras-and-h-rev107-in-the-ras-signaling-pathway
#1
Chang Woo Han, Mi Suk Jeong, Se Bok Jang
Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines...
July 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28742845/evaluation-of-k-ras-and-p53-expression-in-pancreatic-adenocarcinoma-using-the-cancer-genome-atlas
#2
Liming Lu, Jingchun Zeng
Genetic alterations in K-ras and p53 are thought to be critical in pancreatic cancer development and progression. However, K-ras and p53 expression in pancreatic adenocarcinoma have not been systematically examined in The Cancer Genome Atlas (TCGA) Data Portal. Information regarding K-ras and p53 alterations, mRNA expression data, and protein/protein phosphorylation abundance was retrieved from The Cancer Genome Atlas (TCGA) databases, and analyses were performed by the cBioPortal for Cancer Genomics. The mutual exclusivity analysis showed that events in K-ras and p53 were likely to co-occur in pancreatic adenocarcinoma (Log odds ratio = 1...
2017: PloS One
https://www.readbyqxmd.com/read/28740607/crystal-structure-of-a-human-k-ras-g12d-mutant-in-complex-with-gdp-and-the-cyclic-inhibitory-peptide-krpep-2d
#3
Satoshi Sogabe, Yusuke Kamada, Masanori Miwa, Ayumu Niida, Tomoya Sameshima, Masahiro Kamaura, Kazuko Yonemori, Shigekazu Sasaki, Jun-Ichi Sakamoto, Kotaro Sakamoto
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28732393/microrna-30a-suppresses-tumor-progression-by-blocking-ras-raf-mek-erk-signaling-pathway-in-hepatocellular-carcinoma
#4
Kun Zhou, Xiaoyu Luo, Yu Wang, Dachun Cao, Gang Sun
Emerging reports suggest microRNAs (miRNAs) play a vital role in the progression of malignant tumors. MiR-30a is downregulated in a variety of cancers and acts as a tumor suppressing gene. However, the molecular mechanisms of miRNA-30a in hepatocellular carcinoma (HCC) are still unclear. Hereby, in this study, we detected that miR-30a expression was significantly down-regulated in both HCC tissues compared with adjacent non-cancerous liver tissues, and we also observed that miR-30a expression was lower in HCC cell lines than that of normal controls...
July 17, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28732359/resveratrol-inhibits-age-dependent-spontaneous-tumorigenesis-by-sirt1-mediated-post-translational-modulations-in-the-annual-fish-nothobranchius-guentheri
#5
Tingting Liu, Long Ma, Zhaodi Zheng, Fenglin Li, Shan Liu, Yingbo Xie, Guorong Li
Resveratrol, SIRT1 activator, inhibits carcinogenesis predominantly performed in transgenic animal models, orthotopic cancers of nude mice or different cancer cell lines, but its effects during process of spontaneous tumors using vertebrate models remain untested. Spontaneous liver neoplasm is an age-related disease and is inhibited by resveratrol in the annual fish Nothobranchius guentheri, which indicates that the fish can act as an excellent model to study spontaneous tumorigenesis. Totally, 175 fish were fed with resveratrol and another 175 fish for controls...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28724936/an-engineered-protein-antagonist-of-k-ras-b-raf-interaction
#6
Monique J Kauke, Michael W Traxlmayr, Jillian A Parker, Jonathan D Kiefer, Ryan Knihtila, John McGee, Greg Verdine, Carla Mattos, K Dane Wittrup
Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28700943/a-role-for-mitochondrial-translation-in-promotion-of-viability-in-k-ras-mutant-cells
#7
Timothy D Martin, Danielle R Cook, Mei Yuk Choi, Mamie Z Li, Kevin M Haigis, Stephen J Elledge
Activating mutations in the KRAS oncogene are highly prevalent in tumors, especially those of the colon, lung, and pancreas. To better understand the genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss-of-function screens in two isogenic pairs of cell lines. Since loss of essential genes is uniformly toxic in CRISPR-based screens, we also developed a small hairpin RNA (shRNA) library targeting essential genes. These approaches uncovered a large set of proteins whose loss results in the selective reduction of K-Ras mutant cell growth...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28695301/optimal-use-of-anti-egfr-monoclonal-antibodies-for-patients-with-advanced-colorectal-cancer-a-meta-analysis
#8
REVIEW
E J van Helden, C W Menke-van der Houven van Oordt, M W Heymans, J C F Ket, R van den Oord, H M W Verheul
This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1...
July 10, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28692598/membrane-lipids-and-cell-signaling
#9
Hannah Sunshine, Maria Luisa Iruela-Arispe
PURPOSE OF REVIEW: Reception and transmission of signals across the plasma membrane has been a function generally attributed to transmembrane proteins. In the last 3 years, however, a growing number of reports have further acknowledged important contributions played by membrane lipids in the process of signal transduction. RECENT FINDINGS: In particular, the constituency of membrane lipids can regulate how proteins with SH2 domains and molecules like K-Ras expose their catalytic domains to the cytosol and interact with effectors and second messengers...
July 7, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28692342/targeting-the-%C3%AE-4-%C3%AE-5-interface-of-ras-results-in-multiple-levels-of-inhibition
#10
Russell Spencer-Smith, Lie Li, Sheela Prasad, Akiko Koide, Shohei Koide, John P O'Bryan
Generation of RAS-targeted therapeutics has long been considered a "holy grail" in cancer research. However, a lack of binding pockets on the surface of RAS and its picomolar affinity for guanine nucleotides have made isolation of inhibitors particularly challenging. We recently described a monobody, termed NS1, that blocks RAS signaling and oncogenic transformation. NS1 binds to the α4-β6-α5 interface of H-RAS and K-RAS thus preventing RAS dimerization and nanoclustering, which in turn prevents RAS-stimulated dimerization and activation of RAF...
July 10, 2017: Small GTPases
https://www.readbyqxmd.com/read/28692295/identification-and-characterization-of-von-hippel-lindau-recruiting-proteolysis-targeting-chimeras-protacs-of-tank-binding-kinase-1
#11
Andrew P Crew, Kanak Raina, Hanqing Dong, Yimin Qian, Jing Wang, Dominico Vigil, Yevgeniy V Serebrenik, Brian D Hamman, Alicia Morgan, Caterina Ferraro, Kam Siu, Taavi K Neklesa, James D Winkler, Kevin G Coleman, Craig M Crews
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities...
July 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28680740/haploinsufficient-tumor-suppressor-genes
#12
Kazushi Inoue, Elizabeth A Fry
Haploinsufficiency of tumor suppressor genes (TSGs) indicates that the reduced levels of proteins in cells that lack one allele of the genomic locus results in the inability of the cell to execute normal cellular functions contributing to tumor development. Representative cases of haploinsufficient TSGs are p27(Kip1), p53, DMP1, NF1, and PTEN. Tumor development is significantly accelerated in both mice with homozygous and heterozygous gene deletion, with expression of the wild type allele in the latter. Newly characterized TSGs such as AML1, EGR1, TGFβR1/2, and SMAD4 have also shown haploid insufficiency for tumor suppression...
2017: Advances in Medicine and Biology
https://www.readbyqxmd.com/read/28679352/identification-of-two-distinct-molecular-subtypes-by-digital-rna-counting-of-non-invasive-follicular-tumour-with-papillary-like-nuclear-features-niftp
#13
Riccardo Giannini, Clara Ugolini, Anello Marcello Poma, Maria Urpì, Cristina Niccoli, Rossella Elisei, Massimo Chiarugi, Paolo Vitti, Paolo Miccoli, Fulvio Basolo
Backgound. The follicular variant (FV) is one of the most common variants of papillary thyroid carcinoma (PTC). Clinically, the FVPTC is considered a low-risk variant of PTC, and the encapsulated forms of FVPTC represent a group of thyroid tumours with an overall good prognosis. Consequently, these neoplasms were very recently reclassified as "non-invasive follicular tumour with papillary-like nuclear features (NIFTP)". From a molecular standpoint, NIFTP appears similar to the follicular pattern thyroid neoplasm; however, limited data are currently available regarding their gene expression profile...
July 5, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28674184/steady-state-levels-of-phosphorylated-mitogen-activated-protein-kinase-kinase-1-2-determined-by-mortalin-hspa9-and-protein-phosphatase-1-alpha-in-kras-and-braf-tumor-cells
#14
Pui-Kei Wu, Seung-Keun Hong, Jong-In Park
Although deregulation of MEK/ERK activity is a key feature in cancer, high magnitude MEK/ERK activity can paradoxically induce growth inhibition. Therefore, additional mechanisms may exist to modulate MEK/ERK activity in favor of tumor cell proliferation. We previously reported that mortalin/HSPA9 can facilitate proliferation of certain KRAS- and BRAF-tumor cells by modulating MEK/ERK activity. In this study, we demonstrate that mortalin can regulate MEK/ERK activity via protein phosphatase 1α (PP1α). We found that PP1α inhibition increases steady-state levels of phosphorylated MEK1/2 in various tumor cells expressing B-Raf(V600E) or K-Ras(G12D/V) Intriguingly, co-immunoprecipitation and in vitro binding assays revealed that mortalin facilitates PP1α-mediated MEK1/2 dephosphorylation by promoting PP1α-MEK1/2 interaction in an ATP-sensitive manner...
July 3, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28665983/different-levels-of-let-7d-expression-modulate-response-of-fadu-cells-to-irradiation-and-chemotherapeutics
#15
Katarzyna Monika Lamperska, Tomasz Kolenda, Anna Teresiak, Anna Kowalik, Marta Kruszyna-Mochalska, Weronika Jackowiak, Renata Bliźniak, Weronika Przybyła, Marta Kapałczyńska, Piotr Kozlowski
The implication of the let-7 family in cancer development is multifaceted. The family acts as tumor suppressor miRNA although overexpression of let-7 has also been described in many types of cancer, including head and neck squamous cell carcinoma (HNSCC). The aim of this study includes whether different expression levels of let-7d has an influence on chemo- and radiosensitivity. FaDu cell line models with a gradually increased level of let-7d (models from A to E) were generated with the lentiviral system. Expression levels of pluripotency, chemo-radioresistance/apoptosis, and targets of mRNAs were analyzed by real-time reverse transcription-PCR (qRT-PCR)...
2017: PloS One
https://www.readbyqxmd.com/read/28661467/early-and-late-induction-of-kras-and-hras-proto-oncogenes-by-reactive-oxygen-species-in-primary-astrocytes
#16
Samantha Messina, Erika Di Zazzo, Bruno Moncharmont
Astrocytes, one of the predominant types of glial cells, function as both supportive and metabolic cells for the brain. Among mammalian tissues, the highest levels of p21(Ras) protein are detected in the brain. Here, we investigated the expression of KRAS and HRAS proto-oncogenes in primary astrocytes following acute oxidative stimulation. Reactive oxygen species (ROS) changed the expression of proto-oncogenes at both transcriptional and translational levels. De novo protein synthesis analysis measured approximate values of proteins half-life, ranging from 1-4 h, of the different H- and K- isoforms by western blot analysis...
June 29, 2017: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/28656580/potential-lung-carcinogenicity-induced-by-chronic-exposure-to-pm2-5-in-the-rat
#17
Xiaoli Hu, Qingzhao Li, Shifeng Shao, Qiang Zeng, Shoufang Jiang, Qi Wu, Chunyang Jiang
Exposure to fine particulate matter (PM2.5) may increase lung cancer risk, but the underlying mechanisms are poorly understood. This study explored the potential carcinogenicity in rat lung induced by chronic exposure to PM2.5. Adult male rats (200-220 g) were treated with PM2.5 (10 mg/kg body weight) by tracheal perfusion once per week for 1 year; the rats were killed, and expression of tumor markers (carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), squamous cell carcinoma antigen (SCCA)), cancer-related genes, and pathological changes were detected...
June 28, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28652417/k-ras-mutations-as-the-earliest-driving-force-in-a-subset-of-colorectal-carcinomas
#18
REVIEW
Nikolaos Margetis, Myrsini Kouloukoussa, Kyriaki Pavlou, Spyridon Vrakas, Theodoros Mariolis-Sapsakos
K-ras oncogene is a key factor in colorectal cancer. Based on published and our data we propose that K-ras could be the oncogene responsible for the inactivation of the tumor-suppressor gene APC, currently considered as the initial step in colorectal tumorigenesis. K-ras fulfills the criteria of the oncogene-induced DNA damage model, as it can provoke well-established causes for inactivating tumor-suppressors, i.e. DNA double-strand breaks (causing allele deletion) and ROS production (responsible for point mutation)...
July 2017: In Vivo
https://www.readbyqxmd.com/read/28647697/analysis-of-k-ras-interactions-by-biotin-ligase-tagging
#19
Christopher Ritchie, Andrew Mack, Logan Harper, Ayna Alfadhli, Philip J S Stork, Xiaolin Nan, Eric Barklis
BACKGROUND: Mutations of the human K-Ras 4B (K-Ras) G protein are associated with a significant proportion of all human cancers. Despite this fact, a comprehensive analysis of K-Ras interactions is lacking. Our investigations focus on characterization of the K-Ras interaction network. MATERIALS AND METHODS: We employed a biotin ligase-tagging approach, in which tagged K-Ras proteins biotinylate neighbor proteins in a proximity-dependent fashion, and proteins are identified via mass spectrometry (MS) sequencing...
July 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28644440/lncrna-sarcc-suppresses-renal-cell-carcinoma-rcc-progression-via-altering-the-androgen-receptor-ar-mirna-143-3p-signals
#20
Wei Zhai, Yin Sun, Changcheng Guo, Guanghui Hu, Mingchao Wang, Jiayi Zheng, WanYing Lin, Qingbo Huang, Gonghui Li, Junhua Zheng, Chawnshang Chang
While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK...
June 23, 2017: Cell Death and Differentiation
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