7 research outputs found

    The effect of timing and composition of gestational weight gain in obese pregnant women on infant birth weight: A prospective cohort study.

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    Introduction: CK2 is a protein kinase implicated in several essential cellular processes, over-expressed in cancer and described to regulate insulin signaling cascade. Recently CK2 has been described to negatively regulate thermogenesis (Shinoda K et al, 2015, Cell Metabolism) and to inhibit insulin release (Rossi M et al, 2015, PNAS). Nevertheless, the role of CK2 in adipose tissue (AT) and its involvement in human obesity development and therapy has been poorly investigated. Methods: Our multi-disciplinary team performed biochemical analysis of signaling pathways by WB and in vitro kinase activity assays, and glucose handling studies using glucose uptake assay and IF in adipocyte cultures and glucose and insulin tolerance test in mice. Moreover we quantify CK2 expression/activity in human AT specimens of 27 obese patients, clinically characterized, in 12 obese patients underwent relevant weight loss and 11 normal-weight controls. Results: We proved that CK2 amount and activity were not influenced by insulin stimulation and that CK2 activity was efficiently inhibited by specific inhibitors, structurally unrelated. We worked with CX-4945, a CK2 inhibitor currently used in cancer clinical trials, using the minimal concentration (2.5 \u192 dM) and pre-treatment time (1hr) able to efficiently inhibit CK2 activity, avoiding any cytotoxic effect. Pharmacological inhibition of CK2 did not significantly affect in vitro adipogenic differentiation or expression profiling of mature adipocytes. Conversely, we showed that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. We compared CK2 expression and activity in different mouse tissues highlighted that white skeletal muscle fibres and liver contained the highest quantity of this kinase. CK2 was expressed more in brown AT than in white AT depots. We show that CK2 promotes insulin-signaling in mouse AT, liver and skeletal muscle and that in vivo acute treatment with CX-4945 impairs glucose- tolerance in mice. Studies in tissues of ob/ob and db/db mice highlights an up-regulation of CK2 expression and activity only in WAT. CK2 hyper-activation is strongly evident also in SAT and VAT of obese patients and weight loss obtained by bariatric surgery or hypocaloric diet reverts CK2 up-regulation to normal level. Conclusion: We show that CK2 is involved in insulin sensitivity, glucose handling and remodeling of WAT. Moreover we identify CK2 hyper-activation as a hallmark of human obesity, suggesting a new potential therapeutic target for metabolic diseases

    Therapeutic targeting of CK2 in acute and chronic leukemias

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    Phosphorylation can regulate almost every property of a protein and is involved in all fundamental cellular processes. Thus, proper regulation of phosphorylation events is critical to the homeostatic functions of cell signaling. Indeed, deregulation of signaling pathways underlies many human diseases, including cancer.[1] The importance of phosphorylation makes protein kinases and phosphatases promising therapeutic targets for a wide variety of disorders.[2] CK2, formerly known as casein kinase II, was discovered in 1954, [3] although only recently, and especially over the last two decades, it has become one of the most studied protein kinases, due to its ubiquity, pleiotropy and constitutive activity. In particular, appreciation of its pleiotropy has completely changed our vision of CK2 biology, from an ordinary cell homeostasis-maintaining enzyme to a master kinase potentially implicated in many human physiological and pathological events. CK2 is responsible for about 25% of the phosphoproteome,[4] as it catalyzes the phosphorylation of >300 substrates.[5] This partly explains the CK2 interconnected roles that underlie its involvement in many signaling pathways. However, CK2 prevalent roles are promotion of cell growth and suppression of apoptosis. Accordingly, several lines of evidence support the notion that CK2 is a key player in the pathogenesis of cancer. High levels of CK2 transcript and protein expression, as well as increased kinase activity are associated with the pathological functions of CK2 in a number of neoplasias.[6] It was only over the last decade, after extensive analyses in solid tumors, that basic and translational studies have provided evidence for a pivotal role of CK2 in driving the growth of different blood cancers as well, although the first report demonstrating increased CK2 expression in acute myelogenous leukemia (AML) dates back to 1985.[7] Since then, CK2 overexpression/activity has been demonstrated in other hematological malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). [8] With the notable exceptions of CML and pediatric ALL, many patients with leukemias still have a poor outcome, despite the development of protocols with optimized chemotherapy combinations. Insufficient response to first-line therapy and unsalvageable relapses present major therapeutic challenges. Moreover, chemotherapy, even if successful, could have deleterious long-term biological and psychological effects, especially in children.[9] Furthermore, CML patients can develop resistance to tyrosine kinase inhibitors (TKIs), while both primary chemoresistant and relapsed pediatric ALL cases still remain an unresolved issue.[9

    Deciphering the role of protein kinase CK2 in the maturation/stability of F508del-CFTR

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    F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2\u3b1' catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches

    Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

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    Casein kinase 2 (CK2) is a tetrameric protein kinase composed of 2 catalytic (α and α') and 2 regulatory β subunits. Our study provides the first molecular and cellular characterization of the different CK2 subunits, highlighting their individual roles in skeletal muscle specification and differentiation. Analysis of C2C12 cell knockout for each CK2 subunit reveals that: 1) CK2β is mandatory for the expression of the muscle master regulator myogenic differentiation 1 in proliferating myoblasts, thus controlling both myogenic commitment and subsequent muscle-specific gene expression and myotube formation; 2) CK2α is involved in the activation of the muscle-specific gene program; and 3) CK2α' activity regulates myoblast fusion by mediating plasma membrane translocation of fusogenic proteins essential for membrane coalescence, like myomixer. Accordingly, CK2α' overexpression in C2C12 cells and in mouse regenerating muscle is sufficient to increase myofiber size and myonuclei content via enhanced satellite cell fusion. Consistent with these results, pharmacological inhibition of CK2 activity substantially blocks the expression of myogenic markers and muscle cell fusion both in vitro in C2C12 and primary myoblasts and in vivo in mouse regenerating muscle and zebrafish development. Overall, our work describes the specific and coordinated functions of CK2 subunits in orchestrating muscle differentiation and fusogenic activity, highlighting CK2 relevance in the physiopathology of skeletal muscle tissue.-Salizzato, V., Zanin, S., Borgo, C., Lidron, E., Salvi, M., Rizzuto, R., Pallafacchina, G., Donella-Deana, A. Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity
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