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  • Although CK phosphorylated Msn as well

    2019-11-08

    Although CK2 phosphorylated Msn4 as well as Msn2 (Fig. 1A), the two CK2-dependent phosphorylation sites in Msn2 are not conserved in Msn4. Thus, Msn2 and Msn4 might be differently regulated by CK2-dependent phosphorylation. Msn2 and Msn4, which have 41% identity and similarity in size and amino Phosphatase Inhibitor Cocktail 3 (100X in DMSO) composition, are often considered as functionally redundant transcription factors [5], [6], [36]. However, Msn2 and Msn4 are dissimilar in regulating a subset of target genes, and show different expression and phosphorylation patterns in response to stressful conditions [2], [37]. PKA-dependent phosphorylation sites are partially conserved between Msn2 and Msn4, and only Msn2, but not Msn4, has PKA-dependent oscillatory behavior, shuttling repeatedly between the nucleus and cytoplasm [38]. In summary, our study has revealed that CK2 positively regulates Msn2 activity in a phosphorylation-dependent manner in response to H2O2, and lactic acid, and glucose starvation. These findings shed light on the crucial role for CK2 as a central regulator administering not only growth-related but also stress-related responses to ensure proper cellular adaptation and survival in response to environmental fluctuations. In addition, we newly demonstrated that lactic acid induces nuclear accumulation and activation of Msn2, and its CK2-dependent activation is essential for cell survival in response to lactic acid. These findings might provide information to develop lactic acid-tolerant yeast strain for industrial applications. The following are the supplementary data related to this article.
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    Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (NRF-2015R1A2A2A01005429).
    Introduction Vessel occlusion following neointima development restricts the therapeutic potential of peripheral and coronary artery bypass grafts, and percutaneous coronary interventions. Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal compartment greatly facilitates the formation of restenotic lesions via both contributing to its occlusive mass and serving as a foundation for superimposed, accelerated atherosclerosis [1], [2]. Intervening with modulators of VSMC proliferation is hence considered a pragmatic approach in designing preventative therapies against vein graft degeneration and in-stent restenosis. Protein kinase CK2 is a ubiquitously expressed and highly pleiotropic enzyme implicated in a diverse range of cellular functions including such indices as cell cycle progression, viability and motility [3]. Aberrant activity has predictably been associated with malignant transformation and aggressive tumour growth, with T-cell lymphomas [4], non-small cell lung cancer [5], prostate cancer [6], and tumors of the head, neck, mammary gland and kidney [7], [8], [9] being documented examples. Emodin, DRB, DDZ and TBB, both naturally derived and synthetic inhibitors of CK2, have been reported to induce cell cycle arrest in isolated VSMCs [10], [11], [12], though in consideration of the promiscuity of these compounds this action could not be solely ascribed to suppression of CK2 activity. The proline-rich homeodomain (PRH), also referred to as haematopoietically expressed homeobox (Hex/Hhex), is a multifunctional transcription factor critical for embryonic and tissue development - notably of the haematopoietic and vascular lineages [13], [14], [15]. PRH can operate as either a potent facilitator or inhibitor of cellular proliferation dependent on context; though in adult epithelial and vascular tissues, is most often reported to mediate cell cycle arrest and exhibit tumour suppressor properties [14], [16], [17], [18]. Our previous studies have reported that protein kinase CK2-dependent phosphorylation of PRH at residues Ser163 and Ser177 abrogates DNA-binding potential and transcriptional regulation activity, reduces nuclear retention and lowers stability via directing PRH for proteasome-mediated proteolysis [19], [20]. By this action, CK2 alleviates PRH-mediated suppression of cell cycle progression in human leukaemic myeloid K562 cells [19]. We hypothesize therefore that inhibition of CK2 leads to suppression of VSMC proliferation via PRH. This hypothesis contradicts what was postulated by Sekiguchi and colleagues, where it was proposed that PRH facilitates neointima formation by participating in the de-differentiation of medial VSMC [21].