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https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#1
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
#2
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
#3
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
#4
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...
June 19, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#5
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...
June 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28621313/lkb1-maintains-treg-cell-lineage-identity
#6
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
#7
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
https://www.readbyqxmd.com/read/28598439/erratum-lkb1-inactivation-drives-lung-cancer-lineage-switching-governed-by-polycomb-repressive-complex-2
#8
Haikuo Zhang, Christine Fillmore Brainson, Shohei Koyama, Amanda J Redig, Ting Chen, Shuai Li, Manav Gupta, Carolina Garcia-de-Alba, Margherita Paschini, Grit S Herter-Sprie, Gang Lu, Xin Zhang, Bryan P Marsh, Stephanie J Tuminello, Chunxiao Xu, Zhao Chen, Xiaoen Wang, Esra A Akbay, Mei Zheng, Sangeetha Palakurthi, Lynette M Sholl, Anil K Rustgi, David J Kwiatkowski, J Alan Diehl, Adam J Bass, Norman E Sharpless, Glenn Dranoff, Peter S Hammerman, Hongbin Ji, Nabeel Bardeesy, Dieter Saur, Hideo Watanabe, Carla F Kim, Kwok-Kin Wong
This corrects the article DOI: 10.1038/ncomms14922.
June 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28592638/sestrin2-prevents-age-related-intolerance-to-ischemia-and-reperfusion-injury-by-modulating-substrate-metabolism
#9
Nanhu Quan, Wanqing Sun, Lin Wang, Xu Chen, Xinchun Zhou, Courtney Cates, Quan Liu, Yang Zheng, Ji Li
A novel stress-inducible protein, Sestrin2 (Sesn2), declines in the heart with aging. AMPK has emerged as a pertinent stress-activated kinase that has been shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sesn2 and AMPK in the ischemic heart. To determine whether ischemic AMPK activation-modulated by the Sesn2-AMPK complex in the heart-is impaired in aging that sensitizes the heart to ischemic insults, young C57BL/6 mice (age 3-4 mo), middle-age mice (age 10-12 mo), and aged mice (age 24-26 mo) were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia...
June 7, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28591951/-expressions-and-significance-of-pten-and-lkb1-in-non-small-cell-lung-cancer
#10
Yang Li, Ying Li, Hui Yang, Ping Wang
OBJECTIVES: To analyze the correlation between the expression of PTEN and LKB1 in non-small cell lung cancer (NSCLC). METHODS: Paraffin blocks of 74 cases of NSCLC patients were collected, and the expression of LKB1 and PTEN were detected by immunohistochemistry. The clinical related index and the correlation with the expression of PTEN and LKB1 were analyzed to explore the expression clinical significance of them. RESULTS: The PTEN and LKB1 expression positive rate were 47...
July 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28588189/metabolic-injury-induced-nlrp3-inflammasome-activation-dampens-phospholipid-degradation
#11
Elena Rampanelli, Evelyn Orsó, Peter Ochodnicky, Gerhard Liebisch, Pieter J Bakker, Nike Claessen, Loes M Butter, Marius A van den Bergh Weerman, Sandrine Florquin, Gerd Schmitz, Jaklien C Leemans
The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pathways of metabolic renal injury through LDL-induced lipotoxicity and metainflammation. Our in vitro and in vivo analysis revealed a direct lipotoxic effect of metabolic overloading on tubular renal cells through a multifaceted mechanism that includes intralysosomal lipid amassing, lysosomal dysfunction, oxidative stress, and tubular dysfunction...
June 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28581518/activation-of-tumor-suppressor-lkb1-by-honokiol-abrogates-cancer-stem-like-phenotype-in-breast-cancer-via-inhibition-of-oncogenic-stat3
#12
S Sengupta, A Nagalingam, N Muniraj, M Y Bonner, P Mistriotis, A Afthinos, P Kuppusamy, D Lanoue, S Cho, P Korangath, M Shriver, A Begum, V F Merino, C-Y Huang, J L Arbiser, W Matsui, B Győrffy, K Konstantopoulos, S Sukumar, P A Marignani, N K Saxena, D Sharma
Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1(-/-) mice...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28576925/cps1-promotes-tumor-growth-in-kras-lkb1-mutant-nsclc
#13
(no author information available yet)
LKB1 loss upregulates CPS1 to increase tumor growth by maintaining pyrimidine levels.
June 2, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28561066/wipi3-and-wipi4-%C3%AE-propellers-are-scaffolds-for-lkb1-ampk-tsc-signalling-circuits-in-the-control-of-autophagy
#14
Daniela Bakula, Amelie J Müller, Theresia Zuleger, Zsuzsanna Takacs, Mirita Franz-Wachtel, Ann-Katrin Thost, Daniel Brigger, Mario P Tschan, Tancred Frickey, Horst Robenek, Boris Macek, Tassula Proikas-Cezanne
Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28560405/mark2-inhibits-the-growth-of-hela-cells-through-ampk-and-reverses-epithelial-mesenchymal-transition
#15
Ge Xu, Yinggang Ge, Xiaohong Tao, Qing Gao, Xiaoyan Liang
Microtubule affinity-regulating kinases (MARKs; MARK1, MARK2, MARK3 and MARK4) act directly downstream of LKB1, the multitasking tumor-suppressor kinase, and thereby mediate its biological effects. Current understanding of the function of MARKs is greatly restricted to regulation of cell polarity. However, whether or how MARKs contribute to cellular growth control remains largely unknown. In the present study, we utilized an inducible lentiviral expression system that allows rapid MARK expression in LKB1-deficient HeLa cells, and characterized additional functions of MARKs: overexpression of MARK2 in HeLa cells resulted in a decrease in cell growth, inhibition of colony formation and arrest in G1 cell cycle phase, with AMPK as the putative downstream effector upregulating the expression of p21 and p16...
May 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28553939/linking-e-cadherin-mechanotransduction-to-cell-metabolism-through-force-mediated-activation-of%C3%A2-ampk
#16
Jennifer L Bays, Hannah K Campbell, Christy Heidema, Michael Sebbagh, Kris A DeMali
The response of cells to mechanical force is a major determinant of cell behaviour and is an energetically costly event. How cells derive energy to resist mechanical force is unknown. Here, we show that application of force to E-cadherin stimulates liver kinase B1 (LKB1) to activate AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. LKB1 recruits AMPK to the E-cadherin mechanotransduction complex, thereby stimulating actomyosin contractility, glucose uptake and ATP production. The increase in ATP provides energy to reinforce the adhesion complex and actin cytoskeleton so that the cell can resist physiological forces...
June 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28551846/ampk-and-sirt1-activation-contribute-to-inhibition-of-neuroinflammation-by-thymoquinone-in-bv2-microglia
#17
Ravikanth Velagapudi, Abdelmeneim El-Bakoush, Izabela Lepiarz, Folashade Ogunrinade, Olumayokun A Olajide
Thymoquinone is a known inhibitor of neuroinflammation. However, the mechanism(s) involved in its action remain largely unknown. In this study, we investigated the roles of cellular reactive oxygen species (ROS), 5' AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) in the anti-neuroinflammatory activity of thymoquinone. We investigated effects of the compound on ROS generation in LPS-activated microglia using the fluorescent 2',7'-dichlorofluorescin diacetate (DCFDA)-cellular ROS detection. Immunoblotting was used to detect protein levels of p40(phox), gp91(phox), AMPK, LKB1 and SIRT1...
May 27, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28550454/oncogenic-roles-of-the-pi3k-akt-mtor-axis
#18
Masahiro Aoki, Teruaki Fujishita
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP...
May 28, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28538732/cps1-maintains-pyrimidine-pools-and-dna-synthesis-in-kras-lkb1-mutant-lung-cancer-cells
#19
Jiyeon Kim, Zeping Hu, Ling Cai, Kailong Li, Eunhee Choi, Brandon Faubert, Divya Bezwada, Jaime Rodriguez-Canales, Pamela Villalobos, Yu-Fen Lin, Min Ni, Kenneth E Huffman, Luc Girard, Lauren A Byers, Keziban Unsal-Kacmaz, Christopher G Peña, John V Heymach, Els Wauters, Johan Vansteenkiste, Diego H Castrillon, Benjamin P C Chen, Ignacio Wistuba, Diether Lambrechts, Jian Xu, John D Minna, Ralph J DeBerardinis
Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal...
June 1, 2017: Nature
https://www.readbyqxmd.com/read/28533555/scopolin-ameliorates-high-fat-diet-induced-hepatic-steatosis-in-mice-potential-involvement-of-sirt1-mediated-signaling-cascades-in-the-liver
#20
Ahyoung Yoo, Vikram P Narayan, Eun Young Hong, Wan Kyunn Whang, Taesun Park
The present study aimed to investigate whether scopolin exhibits beneficial effects on high-fat diet (HFD)-induced hepatic steatosis in mice. The involvement of sirtuin 1 (SIRT1) as a molecular target for scopolin was also explored. Scopolin decreased the Km of SIRT1 for p53 and nicotinamide adenine dinucleotide without altering Vmax in a cell-free system. Scopolin alleviated oleic acid-induced lipid accumulation and downregulation of SIRT1 activity in HepG2 cells, and these beneficial effects of scopolin were abolished in the presence of SIRT1 inhibitor...
May 22, 2017: Scientific Reports
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