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https://www.readbyqxmd.com/read/29434871/mechanisms-for-dna-damaging-agent-induced-inactivation-of-erbb2-and-erbb3-via-the-erk-and-p38-signaling-pathways
#1
Chul Min Park, Yuki Kawasaki, Alaa Refaat, Hiroaki Sakurai
Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA-damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase erbB-2 (ErbB2) via extracellular signal-regulated kinase (ERK)-mediated phosphorylation of conserved Thr-669 and Thr-677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29391601/the-oncogenic-tyrosine-kinase-lyn-impairs-the-pro-apoptotic-function-of-bim
#2
Lazaro E Aira, Elodie Villa, Pascal Colosetti, Parvati Gamas, Laurie Signetti, Sandrine Obba, Emma Proics, Fabien Gautier, Béatrice Bailly-Maitre, Arnaud Jacquel, Guillaume Robert, Frédéric Luciano, Philippe P Juin, Jean-Ehrland Ricci, Patrick Auberger, Sandrine Marchetti
Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim...
February 2, 2018: Oncogene
https://www.readbyqxmd.com/read/29391154/o-glcnacylation-affects-%C3%AE-catenin-and-e-cadherin-expression-cell-motility-and-tumorigenicity-of-colorectal-cancer
#3
Shani Ben Harosh-Davidovich, Isam Khalaila
O-GlcNAcylation, the addition of β-N-acetylglucosamine (O-GlcNAc) moiety to Ser/Thr residues, is a sensor of the cell metabolic state. Cancer diseases such as colon, lung and breast cancer, possess deregulated O-GlcNAcylation. Studies during the last decade revealed that O-GlcNAcylation is implicated in cancer tumorigenesis and proliferation. The Wnt/β-catenin signaling pathway and cadherin-mediated adhesion are also implicated in epithelial-mesenchymal transition (EMT), a key cellular process in invasion and cancer metastasis...
January 30, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29383184/stabilization-of-sur8-via-pkc%C3%AE-%C3%AE-degradation-promotes-transformation-and-migration-of-colorectal-cancer-cells
#4
Kug Hwa Lee, Woo-Jeong Jeong, Pu-Hyeon Cha, Sang-Kyu Lee, Do Sik Min, Kang-Yell Choi
Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29375007/recognition-mechanism-of-wilms-tumour-suppressor-protein-and-dna-triplets-insights-from-molecular-dynamics-simulation-and-free-energy-analysis
#5
Ling-Fei Zhang, Qing-Chuan Zheng, Hong-Xing Zhang
The Wilms' tumour suppressor protein (WT1) plays a multifaceted role in human cancer processes. Mutations on its DNA recognition domain could lead to Denys-Drash syndrome (DDS), and alternate splicing results in insertion of the tripeptide Lys-Thr-Ser (KTS) between the third and fourth zinc fingers (ZFs), leading to changes in the DNA-binding function. However, detailed recognition mechanisms of the WT1-DNA complex have not been explored. To clarify the mutational effects upon WT1 towards DNA binding at the atomic level, molecular dynamics (MD) simulations and the molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) method were employed...
January 29, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29351901/xiap-regulation-by-mnk-links-mapk-and-nf%C3%AE%C2%BAb-signaling-to-determine-an-aggressive-breast-cancer-phenotype
#6
Myron K Evans, Michael C Brown, Joseph Geradts, Xuhui Bao, Timothy J Robinson, Mohit Kumar Jolly, Peter Vermeulen, Gregory M Palmer, Matthias Gromeier, Herbert Levine, Michael A Morse, Steven Van Laere, Gayathri R Devi
Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked epidermal growth factor receptor (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors...
January 19, 2018: Cancer Research
https://www.readbyqxmd.com/read/29324354/an-in-depth-prognostic-analysis-of-baseline-blood-lipids-in-predicting-postoperative-colorectal-cancer-mortality-the-fiesta-study
#7
Feng Peng, Dan Hu, Xiandong Lin, Gang Chen, Binying Liang, Ying Chen, Chao Li, Hejun Zhang, Yan Xia, Jinxiu Lin, Xiongwei Zheng, Wenquan Niu
BACKGROUND: Dyslipidaemia is key to colorectal carcinogenesis, and the prediction of baseline triglycerides (TG), total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDLC and LDLC) for postsurgical colorectal cancer mortality has not been researched. OBJECTIVES: We attempted to re-analyse the FIESTA database to assess the prognostic value of three informative lipid derivatives - AI (atherogenic index: (TC - HDLC)/HDLC), THR (TG/HDLC) and LHR (LDLC/HDLC) in predicting colorectal cancer mortality...
January 8, 2018: Cancer Epidemiology
https://www.readbyqxmd.com/read/29317228/functions-and-dysfunctions-of-ca2-calmodulin-dependent-protein-kinase-phosphatase-camkp-ppm1f-and-camkp-n-ppm1e
#8
REVIEW
Atsuhiko Ishida, Noriyuki Sueyoshi, Isamu Kameshita
Intracellular signal transduction is built on the basis of the subtle balance between phosphorylation and dephosphorylation. Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F/POPX2) and CaMKP-N (PPM1E/POPX1) are Ser/Thr phosphatases that belong to the PPM (protein phosphatase, Mg2+/Mn2+-dependent) family. The former was discovered in rat brain as a novel protein phosphatase regulating Ca2+/calmodulin-dependent protein kinases (CaMKs), whereas the latter was first identified in human cDNA databases using the rat CaMKP sequence...
January 6, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29283563/spatial-position-regulates-power-of-tryptophan-discovery-of-major-groove-specific-nuclear-localizing-cell-penetrating-tetrapeptide
#9
Debmalya Bhunia, Prasenjit Mondal, Gaurav Das, Abhijit Saha, Pallabi Sengupta, Jagannath Jana, Saswat Mohapatra, Subhrangsu Chatterjee, Surajit Ghosh
Identification of key amino acids is required for development of efficient cell penetrating peptides (CPPs) and has tremendous implications in medicine. Extensive research work enlightened us about the importance of two amino acids, arginine and tryptophan in the cell penetration. Here, we present a top-down approach to show how spatial po-sitions of two tryptophans regulate the cellular entry and nuclear localization. This enables us to develop short nontoxic tetrapeptides with excellent potential of cell penetration and nuclear localization...
December 28, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29243062/pre-clinical-study-of-a-tnfr1-targeted-18f-probe-for-pet-imaging-of-breast-cancer
#10
Hao Fu, Hua Wu, Xianzhong Zhang, Jinxiong Huang, Xiaojiang He, Lichun Chen, Wei Guo, Xiuyu Guo, Bing Hao, Yesen Li
Tumor necrosis factor receptor 1 (TNFR1) is overexpressed in several varieties of carcinoma, including breast cancer. WH701 (Ala-Thr-Ala-Gln-Ser-Ala-Tyr-Gly), which was identified by phage display, can specifically bind to TNFR1. In this study, we labeled WH701 with 18F and investigated its tumor diagnostic value. WH701 was synthesized by standard Fmoc-solid phase synthetic protocols and conjugated by NOTA-NHS. NOTA-WH701 was radiolabeled with 18F using NOTA-AlF chelation reaction. The tumor target properties were evaluated in vitro and in vivo using MCF-7 xenografts and inflammation models...
December 14, 2017: Amino Acids
https://www.readbyqxmd.com/read/29210629/development-of-a-substrate-identification-method-for-human-scp1-phosphatase-using-phosphorylation-mimic-phage-display
#11
Kodai Otsubo, Takashi Yoneda, Atsushi Kaneko, Seiya Yagi, Kazuhiro Furukawa, Yoshiro Chuman
Protein phosphorylation is strictly regulated by protein kinases and protein phosphatases, and disordered regulation of protein phosphorylation often causes serious diseases, such as cancer. Protein phosphatases are divided into two major groups: tyrosine (Tyr) phosphatases and serine/threonine (Ser/Thr) phosphatases. Substrate trapping mutants are frequently used to characterize Tyr phosphatases and identify their substrates; however, a rapid and simple method to identify substrates for Ser/Thr phosphatases has yet to be developed...
December 5, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/29206917/tunicamycin-induced-er-stress-in-breast-cancer-cells-neither-expresses-grp78-on-the-surface-nor-secretes-it-into-the-media
#12
Jesús E Serrano-Negrón, Zhenbo Zhang, Andrea P Rivera-Ruiz, Aditi Banerjee, Eva C Romero-Nutz, Neysharie Sánchez-Torres, Krishna Baksi, Dipak K Banerjee
GRP78 (an Mr 78 kDa calcium dependent glucose binding protein) located in ER lumen. It functions as ER chaperone and translocates proteins for glycosylation at the asparagine residue present in the sequon Asn-X-Ser/Thr. Paraffin sections from N-glycosylation inhibitor tunicamycin treated ER-/PR-/HER2+ (double negative) breast tumor in athymic nude mice exhibited reduced N-glycan but increased GRP78 expression. We have evaluated the effect of tunicamycin on cellular localization of GRP78 in metastatic human breast cancer cells MDA-MB-231 (ER-/PR-/HER2-)...
December 1, 2017: Glycobiology
https://www.readbyqxmd.com/read/29202403/design-synthesis-and-structure-activity-relationship-of-a-focused-library-of-%C3%AE-phenylalanine-derivatives-as-novel-eef2k-inhibitors-with-apoptosis-inducing-mechanisms-in-breast-cancer
#13
Yongzhi Guo, Yuqian Zhao, Guan Wang, Yi Chen, Yingnan Jiang, Liang Ouyang, Bo Liu
Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a β-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29191835/phosphorylation-of-human-enhancer-filamentation-1-hef1-stimulates-interaction-with-polo-like-kinase-1-leading-to-hef1-localization-to-focal-adhesions
#14
Kyung Ho Lee, Jeong-Ah Hwang, Sun-Ok Kim, Jung Hee Kim, Sang Chul Shin, Eunice EunKyeong Kim, Kyung S Lee, Kunsoo Rhee, Byeong Hwa Jeon, Jeong Kyu Bang, Hyunjoo Cha-Molstad, Nak-Kyun Soung, Jae-Hyuk Jang, Sung-Kyun Ko, Hee Gu Lee, Jong Seog Ahn, Yong Tae Kwon, Bo Yeon Kim
Elevated expression of human enhancer filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is an essential stimulus for the metastatic process of various solid tumors. This process requires HEF1 localization to focal adhesions (FAs). Although the association of HEF1 with FAs is considered to play a role in cancer cell migration, the mechanism targeting HEF1 to FAs remains unclear. Moreover, upregulation of polo-like kinase 1 (Plk1) positively correlates with human cancer metastasis, yet how Plk1 deregulation promotes metastasis remains elusive...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29183267/in-silico-evaluation-of-the-resistance-of-the-t790m-variant-of-epidermal-growth-factor-receptor-kinase-to-cancer-drug-erlotinib
#15
Inderpal Singh, Shashank Singh, Vijeshwar Verma, Vladimir N Uversky, Ratna Chandra
Epidermal growth factor receptor (EGFR) kinase is implicated in cancer development due to either overexpression or activation variants in its functional intracellular kinase domain. Threonine to Methionine (Thr 790 Met) is one such variant observed commonly in patients showing resistance to kinase inhibitor drug Erlotinib. Two mechanisms for resistance have been proposed (1) steric hindrance and (2) enhanced binding to ATP. In this study, we employed molecular dynamics simulations and studied both the mechanisms...
November 28, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29170453/association-of-protein-kinase-ck2-inhibition-with-cellular-radiosensitivity-of-non-small-cell-lung-cancer
#16
Qianwen Li, Ke Li, Tianyang Yang, Sheng Zhang, Yu Zhou, Zhenyu Li, Jinrong Xiong, Fangzheng Zhou, Xiaoshu Zhou, Li Liu, Rui Meng, Gang Wu
Protein kinase CK2 is a highly conserved protein Ser/Thr protein kinase and plays important roles in cell proliferation, protein translation and cell survival. This study investigated the possibility of using CK2 inhibition as a new approach for increasing the efficacy of radiotherapy in non-small cell lung cancer (NSCLC) and its underlying mechanisms. Kinase inhibition of CK2 was attempted either by using the specific CK2 inhibitor, Quinalizarin or by applying siRNA interference technology to silence the expression of the catalytic subunit of CK2 in A549 and H460 cells...
November 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141657/local-estrogen-axis-in-the-human-bone-microenvironment-regulates-estrogen%C3%A2-receptor-positive%C3%A2-breast-cancer-cells
#17
Derek F Amanatullah, John S Tamaresis, Pauline Chu, Michael H Bachmann, Nhat M Hoang, Deborah Collyar, Aaron T Mayer, Robert B West, William J Maloney, Christopher H Contag, Bonnie L King
BACKGROUND: Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear...
November 15, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29125030/exploring-the-effect-of-d61g-mutation-on-shp2-cause-gain-of-function-activity-by-a-molecular-dynamics-study
#18
Hong-Lian Li, Ying Ma, Chang-Jie Zheng, Wen-Yan Jin, Wen-Shan Liu, Run-Ling Wang
Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic (MD) simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively...
November 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29097203/galangin-enhances-tgf-%C3%AE-1-mediated-growth-inhibition-by-suppressing-phosphorylation-of-threonine-179-residue-in-smad3-linker-region
#19
Mi-Kyung Kwak, Kyung-Min Yang, Jinah Park, Siyoung Lee, Yuna Park, Eunji Hong, Eun Jin Sun, Haein An, Sujin Park, Kyoungwha Pang, Jihee Lee, Jin Muk Kang, Pyunggang Kim, Akira Ooshima, Seong-Jin Kim
Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells...
October 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29066540/tgf-%C3%AE-receptor-i-ii-trafficking-and-signaling-at-primary-cilia-are-inhibited-by-ceramide-to-attenuate-cell-migration-and-tumor-metastasis
#20
Salih Gencer, Natalia Oleinik, Jisun Kim, Shanmugam Panneer Selvam, Ryan De Palma, Mohammed Dany, Rose Nganga, Raquela J Thomas, Can E Senkal, Philip H Howe, Besim Ogretmen
Signaling by the transforming growth factor-β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)-generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia...
October 24, 2017: Science Signaling
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