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https://www.readbyqxmd.com/read/29649512/14-3-3-protein-directly-interacts-with-the-kinase-domain-of-calcium-calmodulin-dependent-protein-kinase-kinase-camkk2
#1
Katarina Psenakova, Olivia Petrvalska, Salome Kylarova, Domenico Lentini Santo, Dana Kalabova, Petr Herman, Veronika Obsilova, Tomas Obsil
BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca2+ /calmodulin-dependent kinase (CaMK) family involved in adiposity regulation, glucose homeostasis and cancer. This upstream activator of CaMKI, CaMKIV and AMP-activated protein kinase is inhibited by phosphorylation, which also triggers an association with the scaffolding protein 14-3-3. However, the role of 14-3-3 in the regulation of CaMKK2 remains unknown. METHODS: The interaction between phosphorylated CaMKK2 and the 14-3-3γ protein, as well as the architecture of their complex, were studied using enzyme activity measurements, small-angle x-ray scattering (SAXS), time-resolved fluorescence spectroscopy and protein crystallography...
April 9, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29540272/association-of-low-dietary-folate-intake-with-lower-camkk2-gene-methylation-adiposity-and-insulin-resistance-in-obese-subjects
#2
Omar Ramos-Lopez, Mirian Samblas, Fermin I Milagro, M Angeles Zulet, Maria L Mansego, Jose I Riezu-Boj, J Alfredo Martinez
Folate deficiency has been putatively implicated in the onset of diverse metabolic abnormalities, including insulin resistance, by altering epigenetic processes on key regulatory genes. The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is involved in the regulation of critical metabolic processes such as adiposity and glucose homeostasis. This study hypothesized associations between low folate intakes and lower methylation levels of the CAMKK2 gene, with the presence of metabolic alterations in subjects with obesity...
February 2018: Nutrition Research
https://www.readbyqxmd.com/read/29499303/chemerin-suppresses-neuroinflammation-and-improves-neurological-recovery-via-camkk2-ampk-nrf2-pathway-after-germinal-matrix-hemorrhage-in-neonatal-rats
#3
Yixin Zhang, Ningbo Xu, Yan Ding, Yiting Zhang, Qian Li, Jerry Flores, Mina Haghighiabyaneh, Desislava Doycheva, Jiping Tang, John H Zhang
Chemerin, an adipokine, has been reported to reduce the production of pro-inflammatory cytokines and neutrophil infiltration. This study investigated the role of Chemerin and its natural receptor, ChemR23, as well as its downstream mediator calmodulin-dependent protein kinase kinase 2 (CAMKK2) /adenosine monophosphate-activated protein kinase (AMPK) /Nuclear factor erythroid 2-related factor 2 (Nrf2) following germinal matrix hemorrhage (GMH) in neonatal rats, with a specific focus on inflammation. GMH was induced by intraparenchymal injection of bacterial collagenase (0...
February 27, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29431615/glut12-promotes-prostate-cancer-cell-growth-and-is-regulated-by-androgens-and-camkk2-signaling
#4
Mark A White, Efrosini Tsouko, Chenchu Lin, Kimal Rajapakshe, Jeffrey M Spencer, Sandi R Wilkenfeld, Sheiva S Vakili, Thomas L Pulliam, Dominik Awad, Fotis Nikolos, Rajasekhara Reddy Katreddy, Benny Abraham Kaipparettu, Arun Sreekumar, Xiaoliu Zhang, Edwin Cheung, Cristian Coarfa, Daniel E Frigo
Despite altered metabolism being an accepted hallmark of cancer, it is still not completely understood which signaling pathways regulate these processes. Given the central role of androgen receptor (AR) signaling in prostate cancer, we hypothesized that AR could promote prostate cancer cell growth in part through increasing glucose uptake via the expression of distinct glucose transporters. Here, we determined that AR directly increased the expression of SLC2A12, the gene that encodes the glucose transporter GLUT12...
February 5, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29428485/polymorphisms-in-p2x4r-and-camkk2-may-affect-tnf%C3%AE-production-implications-for-a-role-in-hiv-associated-sensory-neuropathy
#5
Jessica Gaff, Samuel Halstrom, Suzanna El Temple, Svetlana Baltic, Peter Kamerman, Patricia Price
Polymorphisms in P2X4R and CAMKK2 associate with susceptibility to HIV-associated sensory neuropathy (HIV-SN) - a condition likely mediated by TNFα. As single nucleotide polymorphisms (SNPs) and haplotypes of CAMKK2, and a neighbouring gene P2X4R, mark susceptibility to HIV-SN in South Africans living with HIV, we examined the relationship between P2X4R and CAMKK2 genotypes and TNFα production. Peripheral blood mononuclear cells from 129 healthy donors were stimulated with killed Escherichia coli, and concentrations of soluble TNFα were assessed...
February 8, 2018: Human Immunology
https://www.readbyqxmd.com/read/29358691/re-analysis-of-public-genetic-data-reveals-a-rare-x-chromosomal-variant-associated-with-type-2-diabetes
#6
Sílvia Bonàs-Guarch, Marta Guindo-Martínez, Irene Miguel-Escalada, Niels Grarup, David Sebastian, Elias Rodriguez-Fos, Friman Sánchez, Mercè Planas-Fèlix, Paula Cortes-Sánchez, Santi González, Pascal Timshel, Tune H Pers, Claire C Morgan, Ignasi Moran, Goutham Atla, Juan R González, Montserrat Puiggros, Jonathan Martí, Ehm A Andersson, Carlos Díaz, Rosa M Badia, Miriam Udler, Aaron Leong, Varindepal Kaur, Jason Flannick, Torben Jørgensen, Allan Linneberg, Marit E Jørgensen, Daniel R Witte, Cramer Christensen, Ivan Brandslund, Emil V Appel, Robert A Scott, Jian'an Luan, Claudia Langenberg, Nicholas J Wareham, Oluf Pedersen, Antonio Zorzano, Jose C Florez, Torben Hansen, Jorge Ferrer, Josep Maria Mercader, David Torrents
The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males...
January 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29316249/the-mitochondrial-atp-synthase-is-a-shared-drug-target-for-aging-and-dementia
#7
Joshua Goldberg, Antonio Currais, Marguerite Prior, Wolfgang Fischer, Chandramouli Chiruta, Eric Ratliff, Daniel Daugherty, Richard Dargusch, Kim Finley, Pau B Esparza-Moltó, José M Cuezva, Pamela Maher, Michael Petrascheck, David Schubert
Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain...
April 2018: Aging Cell
https://www.readbyqxmd.com/read/29314250/inhibition-of-camkk2-enhances-fracture-healing-by-stimulating-indian-hedgehog-signaling-and-accelerating-endochondral-ossification
#8
Justin N Williams, Anuradha Valiya Kambrath, Roshni B Patel, Kyung Shin Kang, Elsa Mével, Yong Li, Ying-Hua Cheng, Austin J Pucylowski, Mariah A Hassert, Michael J Voor, Melissa A Kacena, William R Thompson, Stuart J Warden, David B Burr, Matthew R Allen, Alexander G Robling, Uma Sankar
Approximately 10% of all bone fractures do not heal, resulting in patient morbidity and healthcare costs. However, no pharmacological treatments are currently available to promote efficient bone healing. Inhibition of Ca2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) reverses age-associated loss of trabecular and cortical bone volume and strength in mice. In the current study, we investigated the role of CaMKK2 in bone fracture healing and show that its pharmacological inhibition using STO-609 accelerates early cellular and molecular events associated with endochondral ossification, resulting in a more rapid and efficient healing of the fracture...
January 3, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29290103/mechanisms-of-thermal-adaptation-and-evolutionary-potential-of-conspecific-populations-to-changing-environments
#9
Zhongqi Chen, Anthony P Farrell, Amanda Matala, Shawn R Narum
Heterogeneous and ever-changing thermal environments drive the evolution of populations and species, especially when extreme conditions increase selection pressure for traits influencing fitness. However, projections of biological diversity under scenarios of climate change rarely consider evolutionary adaptive potential of natural species. In this study, we tested for mechanistic evidence of evolutionary thermal adaptation among ecologically divergent redband trout populations (Oncorhynchus mykiss gairdneri) in cardiorespiratory function, cellular response and genomic variation...
February 2018: Molecular Ecology
https://www.readbyqxmd.com/read/29277967/induction-of-autophagy-and-autophagy-dependent-apoptosis-in-diffuse-large-b-cell-lymphoma-by-a-new-antimalarial-artemisinin-derivative-sm1044
#10
Chunyan Cheng, Tao Wang, Zhiqun Song, Lijun Peng, Mengqing Gao, Olivier Hermine, Sophie Rousseaux, Saadi Khochbin, Jian-Qing Mi, Jin Wang
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II...
February 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29249655/the-plag1-gdh1-axis-promotes-anoikis-resistance-and-tumor-metastasis-through-camkk2-ampk-signaling-in-lkb1-deficient-lung-cancer
#11
Lingtao Jin, Jaemoo Chun, Chaoyun Pan, Avi Kumar, Guojing Zhang, Youna Ha, Dan Li, Gina N Alesi, Yibin Kang, Lu Zhou, Wen-Mei Yu, Kelly R Magliocca, Fadlo R Khuri, Cheng-Kui Qu, Christian Metallo, Taofeek K Owonikoko, Sumin Kang
Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance...
January 4, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29156711/multiple-regulatory-aspects-of-histone-methyltransferase-ezh2-in-pb-induced-neurotoxicity
#12
Wei-Zhen Xue, Xiaozhen Gu, Yulan Wu, Danyang Li, Yi Xu, Hui-Li Wang
Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2 , NGFR and CaMKK2 , genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29133590/genotoxic-damage-activates-the-ampk-%C3%AE-1-isoform-in-the-nucleus-via-ca-2-camkk2-signaling-to-enhance-tumor-cell-survival
#13
Diana Vara-Ciruelos, Madhumita Dandapani, Alexander Gray, Ejaife O Egbani, A Mark Evans, D Grahame Hardie
Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+ /calmodulin-dependent kinase, CaMKK2...
February 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29038536/hydrogen-sulphide-treatment-increases-insulin-sensitivity-and-improves-oxidant-metabolism-through-the-camkkbeta-ampk-pathway-in-pa-induced-ir-c2c12-cells
#14
Xubo Chen, Xueyan Zhao, Fazhang Lan, Tao Zhou, Hua Cai, Haiying Sun, Weijia Kong, Wen Kong
Studies have reported attenuation of insulin resistance (IR) by improving phosphorylation of the insulin signalling pathway. However, the upstream molecular signalling pathway is still elusive. In this study, Western blot was used to evaluate the phosphorylation level of the insulin signalling pathway and the AMPK pathway. 2-NBDG was used to evaluate glucose uptake. Ca2+ imaging was used to assess change of intracellular Ca2+ concentration. We found that NaHS enhanced the intracellular Ca2+ concentration and glucose uptake and activated the insulin signalling cascade in a palmitic acid (PA)-induced IR model in C2C12 cells...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038020/the-ca-2-camkk2-axis-mediates-the-telbivudine-induced-upregulation-of-creatine-kinase-implications-for-mechanism-of-antiviral-nucleoside-analogs-side-effect
#15
Long Jianfei, Wang Min, Ma Chunlai, Chen Bicui, Zhang Jiming, Wang Bin
Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and β-actin), oxidative stress, intracellular Ca2+ levels, Ca2+ -related signaling pathway (CaMKK2/AMPK), and Ca2+ -related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs)...
December 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28981105/calcium-calmodulin-dependent-kinase-kinase-2-regulates-hematopoietic-stem-and-progenitor-cell-regeneration
#16
Luigi Racioppi, William Lento, Wei Huang, Stephanie Arvai, Phuong L Doan, Jeffrey R Harris, Fernando Marcon, Helder I Nakaya, Yaping Liu, Nelson Chao
Hematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28924233/pharmacological-inhibition-of-camkk2-with-the-selective-antagonist-sto-609-regresses-nafld
#17
Brian York, Feng Li, Fumin Lin, Kathrina L Marcelo, Jianqiang Mao, Adam Dean, Naomi Gonzales, David Gooden, Suman Maity, Cristian Coarfa, Nagireddy Putluri, Anthony R Means
Binding of calcium to its intracellular receptor calmodulin (CaM) activates a family of Ca(2+)/CaM-dependent protein kinases. CaMKK2 (Ca(2+)/CaM-dependent protein kinase kinase 2) is a central member of this kinase family as it controls the actions of a CaMK cascade involving CaMKI, CaMKIV or AMPK. CaMKK2 controls insulin signaling, metabolic homeostasis, inflammation and cancer cell growth highlighting its potential as a therapeutic target for a variety of diseases. STO-609 is a selective, small molecule inhibitor of CaMKK2...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28778081/multiple-regulatory-aspects-of-histone-methyltransferase-ezh2-in-pb-induced-neurotoxicity
#18
Wei-Zhen Xue, Xiaozhen Gu, Yulan Wu, Danyang Li, Yi Xu, Hui-Li Wang
Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28737528/genetic-variants-of-increased-waist-circumference-in-psychosis
#19
Dzana S Hukic, Urban Ösby, Eric Olsson, Agneta Hilding, Claes-Göran Östenson, Harvest F Gu, Ewa Ehrenborg, Gunnar Edman, Martin Schalling, Catharina Lavebratt, Louise Frisén
OBJECTIVE: We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference. PATIENTS AND METHODS: We analyzed the association in (i) a case-case model in which patients with schizophrenia spectrum disorder with increased waist circumference (≥80 cm for women and ≥94 cm for men) (n=534) were compared with patients with normal waist circumference (<80 cm for women; <94 cm for men) (n=124), and in (ii) a case-control model in which schizophrenia spectrum disorder patients with increased waist circumference or irrespective of waist circumference were compared with population-derived controls (n=494) adjusted for age, sex, fasting glucose, smoking, and family history of diabetes...
December 2017: Psychiatric Genetics
https://www.readbyqxmd.com/read/28634229/akt-activation-by-ca-2-calmodulin-dependent-protein-kinase-kinase-2-camkk2-in-ovarian-cancer-cells
#20
Angela M Gocher, Gissou Azabdaftari, Lindsey M Euscher, Shuhang Dai, Loukia G Karacosta, Thomas F Franke, Arthur M Edelman
Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (β) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3)...
August 25, 2017: Journal of Biological Chemistry
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