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Ras protein

LaDonya Jackson, Wael Eldahshan, Susan C Fagan, Adviye Ergul
For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated...
March 15, 2018: International Journal of Molecular Sciences
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
Laura Rosenberg, Charles H Yoon, Gaurav Sharma, Monica M Bertagnolli, Nancy L Cho
Desmoid tumors (DTs) are unusual neoplasms of mesenchymal origin that exhibit locally invasive behavior. Surgical resection is the initial treatment of choice for DTs. For patients with recurrent or unresectable disease, however, medical options are limited. Sorafenib is a multikinase inhibitor with known anti-tumor activity in various cancers via suppression of the PI3K/Akt/mTOR pathway. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and molecular mechanism of action...
March 10, 2018: Carcinogenesis
Guohong Wen, Huadong Wang, Zhaohui Zhong
BACKGROUND: Oral tumor is a heterogeneous group of tumors, in which it has several different histopathological and molecular features. Recently, genetic and epigenetic alterations are often detected in the development of oral cancer. Gene promoter hypermethylation leads to the silencing of cancer related genes without changes of genes sequence. To clarify the effect of RAS association domain family protein 1a (RASSF1A), retinoic acid receptor beta (RARβ), and E-cadherin (CDH1) promoter hypermethylation on the risk of oral cancer, we performed this meta-analysis...
March 2018: Medicine (Baltimore)
Kumar Parijat Tripathi, Marina Piccirillo, Mario Rosario Guarracino
BACKGROUND: The endomembrane system, known as secretory pathway, is responsible for the synthesis and transport of protein molecules in cells. Therefore, genes involved in the secretory pathway are essential for the cellular development and function. Recent scientific investigations show that ER and Golgi apparatus may provide a convenient drug target for cancer therapy. On the other hand, it is known that abundantly expressed genes in different cellular organelles share interconnected pathways and co-regulate each other activities...
March 8, 2018: BMC Bioinformatics
Bojie Cong, Shizue Ohsawa, Tatsushi Igaki
Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic 'neoplastic tumor-suppressor' genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells...
March 14, 2018: Oncogene
Jerry C Madukwe, Elisabeth E Garland-Kuntz, Angeline M Lyon, Alan V Smrcka
Phospholipase C (PLC) enzymes hydrolyze membrane phosphatidylinositol 4,5 bisphosphate (PIP2) and regulate Ca2+ and protein kinase signaling in virtually all mammalian cell types. Chronic activation of the PLCɛ isoform downstream of G protein-coupled receptors (GPCRs) contributes to the development of cardiac hypertrophy. We have previously shown that PLCε-catalyzed hydrolysis of Golgi-associated phosphatidylinositol 4-phosphate (PI4P) in cardiac myocytes depends on G protein βγ subunits released upon stimulation with endothelin-1...
March 13, 2018: Journal of Biological Chemistry
Fumihiko Hakuno, Shin-Ichiro Takahashi
Insulin-like growth factors (IGFs) bind specifically to the IGF-I receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src-homology collagen (Shc). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain containing signaling molecules...
March 13, 2018: Journal of Molecular Endocrinology
Sheng Liu, Josephine Iaria, Richard J Simpson, Hong-Jian Zhu
BACKGROUND: Transformation by oncogene Ras overcomes TGF-β mediated growth inhibition in epithelial cells. However, it cooperates with each other to mediate epithelial to mesenchymal transition (EMT). The mechanism of how these two pathways interact with each other is controversial. METHODS: Molecular techniques were used to engineer expression plasmids for Ras, SPRY, TGF-β receptors, type I and II and ubiquitin. Immunoprecipitation and western blots were employed to determine protein-protein interactions, preotein levels, protein phosphorylation while immunofluorecesent staining for molecular co-localization...
March 13, 2018: Cell Communication and Signaling: CCS
Diana David, Arun Surendran, Jissa V Thulaseedharan, Asha S Nair
BACKGROUND: Smurf2 E3 ubiquitin ligase physically associates with and regulate the stability of distinct cellular protein substrates. The multi-functional scaffold protein Connector enhancer of kinase suppressor of ras 2 (CNKSR2) plays a key role in regulating cell proliferation, and differentiation through multiple receptor tyrosine kinase pathways. The aim of this study was to investigate whether the interaction between Smurf2 and CNKSR2 has any significant role in the post transcriptional regulation of CNKSR2 expression in breast cancer...
March 13, 2018: BMC Cancer
Kiyoshi Takagi, Yasuhiro Miki, Yoshiaki Onodera, Takanori Ishida, Mika Watanabe, Hironobu Sasano, Takashi Suzuki
Rho GTPase activating protein 15 (ARHGAP15) is a recently identified GTPase activating protein which enhances intrinsic hydrolysis of GTP-bound Ras-related C3 botulinus toxin substrate (Rac1), resulting in inactivation of Rac1. Although a lot of studies have pointed out the pivotal roles of the Rac1 pathway in the progression of breast carcinomas, the clinical significance of ARHGAP15 has remained largely unknown in human breast carcinomas. Therefore, we immunolocalized ARHGAP15 in one hundred breast carcinoma tissues...
March 10, 2018: International Journal of Molecular Sciences
Priscilla Segges, Stephany Corrêa, Bárbara Du Rocher, Gabriela Vera-Lozada, Flavia Krsticevic, Debora Arce, Cinthya Sternberg, Eliana Abdelhay, Rocio Hassan
Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7...
March 13, 2018: International Journal of Molecular Sciences
Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A Yap, Maureen Hattersley, Mark J O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein)...
March 12, 2018: Cancer Cell
Qiwei Chen, Liang Zhu, Huafeng Zong, Xishuang Song, Lina Wang, Xuejian Wang, Deyong Yang, Jianbo Wang
We previously found that in normal epithelia of the prostate, localization of AQP3 is limited to the cell membranes; however, the expression of AQP3 protein in cancer epithelia is distributed to the plasma. Yet, the detailed mechanism remains unclear. In the present study, PC‑3 cell derivatives with stable knockdown of RAS like proto‑oncogene A (RalA) and overexpression of E‑cadherin were established. We found that overexpression of E‑cadherin and knockdown of RaLA resulted in an increase in AQP3 in prostate cancer cell plasma membranes...
March 9, 2018: Oncology Reports
Zhen-Lu Li, Priyanka Prakash, Matthias Buck
Association of Raf kinase with activated Ras triggers downstream signaling cascades toward regulating transcription in the cells' nucleus. Dysregulation of Ras-Raf signaling stimulates cancers. We investigate the C-Raf RBD and CRD regions when bound to oncogenic K-Ras4B at the membrane. All-atom molecular dynamics simulations suggest that the membrane plays an integral role in regulating the configurational ensemble of the complex. Remarkably, the complex samples a few states dynamically, reflecting a competition between C-Raf CRD- and K-Ras4B- membrane interactions...
February 28, 2018: ACS Central Science
Hui Chen, Zhiying Xu, Bin Yang, Xiaoli Zhou, Hongfang Kong
OBJECTIVE: RASGRF1 is a guanine nucleotide exchange factor, which promotes the release of GDP from inactive Ras and stabilizes the apoprotein. In this study, the methylation status of RASGRF1 promoter and its correlation with clinicopathological parameters were evaluated in colorectal cancer (CRC). METHODS: Methylation-specific PCR and bisulfate-sequencing PCR were carried out to investigate the promoter methylation status of the RASGRF1 gene in tumor tissues and adjacent non-tumor tissues of 68 CRC patients...
January 2018: Annals of Clinical and Laboratory Science
Allen Cohn, Michael A Morse, Bert O'Neil, Samuel Whiting, Claire Coeshott, John Ferraro, Donald Bellgrau, David Apelian, Timothy C Rodell
We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with advanced colorectal or pancreas cancer, was designed to evaluate safety, immunogenicity, response, and overall survival of ascending doses of the GI-4000 series of products, which express 3 different forms of mutated Ras proteins. The study enrolled 33 heavily pretreated subjects (14 with pancreas and 19 with colorectal cancer), whose tumors were genotyped before enrollment to identify the specific ras mutation and thereby to identify which GI-4000 product to administer...
April 2018: Journal of Immunotherapy
Zhimin Du, Ki Hyung Kim, Juil Kim, Yuseok Moon
Adlay is a cereal crop that has long been used as traditional herbal medicine and as a highly nourishing food. However, deoxynivalenol (DON), the most prevalent trichothecene mycotoxin worldwide, frequently spoils grains, including adlay, via fungal infection. On the basis of an assumption that the actions of DON in the gut could be modified by adlay consumption, we simulated the impacts of co-exposure in enterocytes and investigated the effectiveness of treatment with adlay for reducing the risk of DON-induced inflammation and epithelia barrier injury...
2018: Frontiers in Immunology
Marcel Wiesweg, Henning Reis, Tobias Köster, Moritz Goetz, Karl Worm, Thomas Herold, Andreas Paul, Alexander Dechêne, Brigitte Schumacher, Peter Markus, Isabel Virchow, Karina Kostbade, Nathalie Wolf, Gregor Zaun, Martin Metzenmacher, Kurt W Schmid, Martin Schuler, Stefan Kasper
BACKGROUND: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. PATIENTS AND METHODS: A prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF)...
February 17, 2018: Clinical Colorectal Cancer
Xiaojie Deng, Zhen Liu, Xiong Liu, Qiaofen Fu, Tongyuan Deng, Juan Lu, Yiyi Liu, Zixi Liang, Qingping Jiang, Chao Cheng, Weiyi Fang
This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop...
February 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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