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https://www.readbyqxmd.com/read/28732195/fake-inhibitors-ampk-activation-trumps-inhibition
#1
Christopher G Langendorf, John W Scott, Bruce E Kemp
Protein kinase inhibitors have become increasingly important therapeutic drugs for the treatment of human diseases; however, resistance and off-target effects can limit their use. In this issue of Cell Chemical Biology, Ross et al. (2017) reveal a novel off-target mechanism where the Src kinase inhibitor SU6656 paradoxically primes AMPK for phosphorylation and activation by the upstream kinase LKB1.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28723898/fructose-1-6-bisphosphate-and-aldolase-mediate-glucose-sensing-by-ampk
#2
Chen-Song Zhang, Simon A Hawley, Yue Zong, Mengqi Li, Zhichao Wang, Alexander Gray, Teng Ma, Jiwen Cui, Jin-Wei Feng, Mingjiang Zhu, Yu-Qing Wu, Terytty Yang Li, Zhiyun Ye, Shu-Yong Lin, Huiyong Yin, Hai-Long Piao, D Grahame Hardie, Sheng-Cai Lin
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease...
July 19, 2017: Nature
https://www.readbyqxmd.com/read/28720067/hpv16-e6-e7-upregulates-hif-2%C3%AE-and-vegf-by-inhibiting-lkb1-in-lung-cancer-cells
#3
Jian-Shuang Shao, Jian Sun, Shiyu Wang, Katherine Chung, Jin Tong Du, Jason Wang, Xue-Shan Qiu, En-Hua Wang, Guang-Ping Wu
Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28708087/resveratrol-induced-amp-activated-protein-kinase-activation-is-cell-type-dependent-lessons-from-basic-research-for-clinical-application
#4
Fan Lan, Karen A Weikel, Jose M Cacicedo, Yasuo Ido
Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol's effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK...
July 14, 2017: Nutrients
https://www.readbyqxmd.com/read/28701883/20s-protopanaxadiol-an-aglycosylated-ginsenoside-metabolite-induces-hepatic-stellate-cell-apoptosis-through-liver-kinase-b1-amp-activated-protein-kinase-activation
#5
Sang Mi Park, Eun Hye Jung, Jae Kwang Kim, Kyung Hwan Jegal, Chung A Park, Il Je Cho, Sang Chan Kim
BACKGROUND: Previously, we reported that Korean Red Ginseng inhibited liver fibrosis in mice and reduced the expressions of fibrogenic genes in hepatic stellate cells (HSCs). The present study was undertaken to identify the major ginsenoside responsible for reducing the numbers of HSCs and the underlying mechanism involved. METHODS: Using LX-2 cells (a human immortalized HSC line) and primary activated HSCs, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assays were conducted to examine the cytotoxic effects of ginsenosides...
July 2017: Journal of Ginseng Research
https://www.readbyqxmd.com/read/28700115/lkb1-pro-oncogenic-activity-triggers-cell-survival-in-circulating-tumor-cells
#6
Elisabeth Katharina Trapp, Leonie Majunke, Beate Zill, Harald Sommer, Ulrich Andergassen, Julian Koch, Nadia Harbeck, Sven Mahner, Thomas Wolfram Paul Friedl, Wolfgang Janni, Brigitte Rack, Marianna Alunni-Fabbroni
During intravasation, circulating tumor cells (CTCs) detach from the epithelium of origin and begin the Epithelial-to Mesenchymal-Transition (EMT) process, where they lose epithelial features and pass through the endothelium to enter circulation. Although detachment from the extracellular matrix is a strong source of metabolic stress, which induces anoikis, CTCs can survive. Recently, the tumor suppressor liver kinase B1 (LKB1) has gained attention for its role as a proto-oncogene in restoring the correct ATP/AMP ratio during metabolic stress...
July 12, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28696138/adipoq-adiponectin-induces-cytotoxic-autophagy-in-breast-cancer-cells-through-stk11-lkb1-mediated-activation-of-the-ampk-ulk1-axis
#7
Seung J Chung, Ganji Purnachandra Nagaraju, Arumugam Nagalingam, Nethaji Muniraj, Panjamurthy Kuppusamy, Alyssa Walker, Juhyung Woo, Balázs Győrffy, Ed Gabrielson, Neeraj K Saxena, Dipali Sharma
ADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins...
July 11, 2017: Autophagy
https://www.readbyqxmd.com/read/28694351/phosphorylation-of-ampk-by-upstream-kinases-is-required-for-activity-in-mammalian-cells
#8
Robin Willows, Matthew J Sanders, Bing Xiao, Bhakti R Patel, Stephen R Martin, Jon Read, Jon R Wilson, Julia Hubbard, Steven J Gamblin, David Carling
AMP-activated protein kinase (AMPK) plays a major role in regulating metabolism and has attracted significant attention as a therapeutic target for treating metabolic disorders. AMPK activity is stimulated more than one hundred fold by phosphorylation of threonine 172 (Thr(172)). Binding of AMP to the γ subunit allosterically activates the kinase. Additionally, a number of small molecules e.g. 991, have been identified that bind between the kinase domain and the carbohydrate binding module of the β subunit, stabilising their interaction and leading to activation...
July 10, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28694192/laminar-shear-stress-suppresses-vascular-smooth-muscle-cell-proliferation-through-nitric-oxide-ampk-pathway
#9
Sun Ae Kim, Jin Young Sung, Chang Hoon Woo, Hyoung Chul Choi
In healthy condition, vascular smooth muscle cells (VSMCs) are not directly exposed to shear stresses, because they are shielded by endothelial cell (EC) layer that lines blood vessels. After injury to EC layer caused by rupture of atherosclerotic lesions or invasive techniques such as angioplasty, VSMCs are directly exposed to blood flow which modulate molecular signaling and function. In endothelium, exposure to fluid shear stress has been reported to induce AMP-activated protein kinase (AMPK) phosphorylation and nitric oxide (NO) production...
July 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28674119/cancer-screening-recommendations-and-clinical-management-of-inherited-gastrointestinal-cancer-syndromes-in-childhood
#10
REVIEW
Maria Isabel Achatz, Christopher C Porter, Laurence Brugières, Harriet Druker, Thierry Frebourg, William D Foulkes, Christian P Kratz, Roland P Kuiper, Jordan R Hansford, Hector Salvador Hernandez, Katherine L Nathanson, Wendy K Kohlmann, Leslie Doros, Kenan Onel, Kami Wolfe Schneider, Sarah R Scollon, Uri Tabori, Gail E Tomlinson, D Gareth R Evans, Sharon E Plon
Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types...
July 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28656285/lkb1-promotes-radioresistance-in-esophageal-cancer-cells-exposed-to-radiation-by-suppression-of-apoptosis-and-activation-of-autophagy-via-the-ampk-pathway
#11
Qing He, Jing Li, Feng Dong, Chuanshu Cai, Xi Zou
Liver kinase B (LKB) 1 acts as a tumor suppressor in a broad spectrum of human cancers, and is important in chemoradiotherapy treatment of various tumor types. However, the potential function of LKB1 in esophageal cancer radiotherapy remains to be elucidated. The aim of the present study was to investigate the role of LKB1 in radiosensitivity of esophageal cancer in vivo and in vitro, and to explore its molecular mechanism. Eca‑109 cells transfected with LKB1 overexpression plasmid were xenografted into nude mice and subjected to irradiation and it was observed that the tumor volume was significantly increased in LKB1‑overexpressed tumors compared with that of the control tumors...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28652249/wee1-kinase-inhibitor-azd1775-has-pre-clinical-efficacy-in-lkb1-deficient-non-small-cell-lung-cancer
#12
Amanda L Richer, Jacqueline M Cala, Kelley O'Brien, Vashti M Carson, Landon J Inge, Timothy G Whitsett
G1/S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2/M checkpoint for adaptation to stress and DNA repair, making G2/M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2/M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several pre-clinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28649994/membrane-binding-and-activation-of-lkb1-by-phosphatidic-acid-is-essential-for-development-and-tumour-suppression
#13
Giada Dogliotti, Lars Kullmann, Pratibha Dhumale, Christian Thiele, Olga Panichkina, Gudrun Mendl, Roland Houben, Sebastian Haferkamp, Andreas W Püschel, Michael P Krahn
The serine/threonine kinase LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Many downstream pathways controlled by LKB1 have been described but little is known about the upstream regulatory mechanisms. Here we show that targeting of the kinase to the membrane by a direct binding of LKB1 to phosphatidic acid is essential to fully activate its kinase activity. Consequently, LKB1 mutants that are deficient for membrane binding fail to activate the downstream target AMPK to control mTOR signalling...
June 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#14
Zhaobo Li, Lihong Zhou, Chrisostomos Prodromou, Velibor Savic, Laurence H Pearl
Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28632727/post-translational-regulation-contributes-to-the-loss-of-lkb1-expression-through-sirt1-deacetylase-in-osteosarcomas
#15
Nadège Presneau, Laure Alice Duhamel, Hongtao Ye, Roberto Tirabosco, Adrienne M Flanagan, Malihe Eskandarpour
BACKGROUND: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1(+/-)) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS. METHODS: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches...
June 20, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28630390/kavalactone-yangonin-induces-autophagy-and-sensitizes-bladder-cancer-cells-to-flavokawain-a-and-docetaxel-via-inhibition-of-the-mtor-pathway
#16
Liu Zhongbo, Ha U-Syn, Yu Ke, Wu Chunli, Yokoyama Noriko, Zi Xiaolin
Consumption of kava (Piper methysticum Forst) has been linked to reduced cancer risk in the South Pacific Islands. Kavalactones are major bioactive components in kava root extracts, which have recently demonstrated anti-cancer activities. However, molecular mechanisms of kavalactones' anti-cancer action remain largely unknown. We have identified two kavalactones, yangonin and 5' 6'-dehydrokawain, as potent inducers of autophagic cell death in bladder cancer cells. The effect of yangonin inducing autophagy is associated with increased expression of beclin and ATG5...
June 20, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28628912/liver-kinase-b1-amp-activated-protein-kinase-pathway-activation-attenuated-the-progression-of-endotoxemia-in-the-diabetic-mice
#17
Yan Yang, Ruolan Dong, Danli Hu, Zhihui Chen, Menglu Fu, Dao Wen Wang, Xizhen Xu, Ling Tu
BACKGROUND/AIMS: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. METHODS: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#18
Fiona A Ross, Simon A Hawley, F Romana Auciello, Graeme J Gowans, Abdelmadjid Atrih, Douglas J Lamont, D Grahame Hardie
SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1...
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28621313/lkb1-maintains-treg-cell-lineage-identity
#19
Di Wu, Yuechen Luo, Wei Guo, Qing Niu, Ting Xue, Fei Yang, Xiaolei Sun, Song Chen, Yuanyuan Liu, Jingru Liu, Zhina Sun, Chunxiao Zhao, Huifang Huang, Fang Liao, Zhongchao Han, Dongming Zhou, Yongguang Yang, Guogang Xu, Tao Cheng, Xiaoming Feng
Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp3 expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown. Here, we show that Lkb1 maintains Treg cell lineage identity by stabilizing Foxp3 expression and enforcing suppressor function. Upon T-cell receptor (TCR) stimulation Lkb1 protein expression is upregulated in Treg cells but not in conventional T cells. Mice with Treg cell-specific deletion of Lkb1 develop a fatal early-onset autoimmune disease, with no Foxp3 expression in most Treg cells...
June 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28620021/correction-for-wolff-et-al-cell-type-dependent-regulation-of-mtorc1-by-redd1-and-the-tumor-suppressors-tsc1-tsc2-and-lkb1-in-response-to-hypoxia
#20
Nicholas C Wolff, Silvia Vega-Rubin-de-Celis, Xian-Jin Xie, Diego H Castrillon, Wareef Kabbani, James Brugarolas
No abstract text is available yet for this article.
July 1, 2017: Molecular and Cellular Biology
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