CK2 kinase activity but not its binding to CK2 promoter regions is implicated in the regulation of CK2α and CK2β gene expressions

Lupp, Sarah; Gumhold, Catalina; Ampofo, Emmanuel; Montenarh, Mathias; Rother, Karen

doi:10.1007/s11010-013-1782-8

Cited by 8 publications

(6 citation statements)

References 67 publications

(71 reference statements)

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“…Interestingly, deletion of CK2α resulted in a significant reduction in Csnk2a2 and Csnk2b mRNA expression upon activation, demonstrating a dependence of the expression of these subunits on the activity of CK2α. This finding provides evidence that CK2 may regulate its own expression in T cells, as demonstrated previously in a cancer cell line (23). Further, CK2α protein was undetectable in CK2α −/− CD4 + T cells.…”

Section: Resultssupporting

confidence: 87%

CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1

Gibson

Yang

Yan

et al. 2018

The Journal of Immunology

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Growing evidence demonstrates that the highly conserved serine/threonine kinase CK2 promotes Th17 cell differentiation while suppressing the generation of Foxp3 regulatory T cells (Tregs); however, the exact mechanism by which CK2 regulates the Th17/Treg axis remains unclear. CK2 can be composed of three distinct subunits: two catalytic subunits, CK2α and CK2α', and the regulatory subunit CK2β. We generated mice that lack the major catalytic subunit of CK2, CK2α, specifically in mature T cells using the distal Lck-Cre (CK2α). Importantly, CK2α deficiency resulted in a significant decrease in the overall kinase activity of CK2. Further, CK2α deficiency resulted in a significant defect in Th17 cell polarization and a reciprocal increase in Tregs both in vitro and in vivo in the context of autoimmune neuroinflammation. The transcription factor forkhead box protein O1 (FoxO1) directly inhibits Th17 cell differentiation and is essential for the generation of Tregs. CK2α CD4 T cells exhibit less phosphorylated FoxO1 and a corresponding increase in the transcription of FoxO1-regulated genes. Treatment of CK2α CD4 T cells with the FoxO1 inhibitor AS1842856 or short hairpin RNA knockdown of FoxO1 is sufficient to rescue Th17 cell polarization. Through use of a genetic approach to target CK2 kinase activity, the current study provides evidence of a major mechanism by which CK2 regulates the Th17/Treg axis through the inhibition of FoxO1.

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Section: Resultssupporting

confidence: 87%

CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1

Gibson

Yang

Yan

et al. 2018

The Journal of Immunology

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“…In general, there is little data on the regulation of CK2 gene expression, and presumably both genetic and epigenetic mechanism may be involved. A number of studies show that regulation of CK2 transcription happens at the promoter level for CK2α and CK2β [43] , [44] , [45] . However, there is no data on whether CK2 genes themselves are controlled by epigenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mining CK2 in Cancer

2014

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Cancer is a leading cause of death worldwide. Cancer cells proliferate uncontrollably and, many cases, spread to other parts of the body. A protein historically involved in cancer is protein kinase CK2. CK2 is a serine-threonine kinase that has been involved in cell growth, cell proliferation and cell apoptosis. CK2 functions as an oncogene when overexpressed in mouse tissues, and can synergize with known oncogenes, such as ras, to induce cell transformation in cells in culture. CK2, typically the CK2α protein, is found elevated in a number of human tumors. However, we have little information on CK2α' and CK2β proteins, and scarce information on CK2 gene transcript expression. Here, we explore the expression of CK2 transcripts in primary tumor tissues using the database Oncomine in the six cancers with the highest mortality in the U.S.A. In addition, we studied the correlation between CK2 expression and overall survival using the Kaplan-Meier Plotter database in breast, ovarian, and lung cancers. We found widespread upregulation in the expression of CK2 genes in primary tumor tissues. However, we found underexpression of CK2α' transcripts in some tumors, increased CK2β transcripts in some invasive tumors, and deregulation of CK2 transcripts in some tumor precursors. There was also correlation between CK2 expression levels and patient survival. These data provides additional evidence for CK2 as a biomarker for cancer studies and as a target for cancer therapy.

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“…42,47 The increased activity of CK2 in cancer is most likely due to transcription of the genes that encode its catalytic and regulatory subunits. 48,49 CK2 directly phosphorylates Ikaros at multiple serine/threonine residues, resulting in impaired Ikaros function. [20][21][22] Here we show that elevated CK2 activity in B-ALL results in impaired Ikaros function as a transcriptional regulator of cell cycle and PI3K-promoting genes.…”

Section: Discussionmentioning

confidence: 99%

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

Song

Gowda

Pan

et al. 2015

Blood

159

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• Ikaros controls cellular proliferation by repressing genes that regulate cell cycle progression and the PI3K pathway in leukemia.• CK2 inhibitor restores Ikaros tumor suppressor function in high-risk B-ALL with IKZF1 deletion and has a strong therapeutic effect in vivo.Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele. (Blood. 2015;126(15):1813-1822 Introduction Ikaros (IKZF1) activity is essential for normal hematopoiesis and immune development. [1][2][3][4] Ikaros knockout mice have severely impaired hematopoiesis, 5-7 whereas mice with the heterozygous loss of Ikaros develop T-cell leukemia. 8 In humans, impaired Ikaros activity due to the deletion or inactivating mutation of a single IKZF1 allele results in high-risk B-cell leukemia that is resistant to treatment.9-14 Ikaros regulates transcription of target genes via chromatin remodeling. [15][16][17] Ikaros activity is controlled through multiple mechanisms. Mouse studies suggest that the transcription of IKZF1 during normal hematopoiesis is regulated by a complex network. 18 However, Ikaros protein is expressed at high levels in most hematopoietic cells, and posttranslational modifications are hypothesized to play a critical role in regulating Ikaros activity. 19 Several groups have shown that phosphorylation, [19][20][21][22][23][24] sumoylation, 25 and ubiquitination 22 can regulate Ikaros function as a transcriptional repressor. However, the role of posttranslational modification in the regulation of Ikaros tumor suppressor activity in leukemia is unknown.Despite extensive global analyses of Ikaros DNA binding in normal murine hematopoietic cells, 26-28 the molecular mechanisms by which Ikaros exerts its tumor suppressor effects in human leukemia ...

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CK2 kinase activity but not its binding to CK2 promoter regions is implicated in the regulation of CK2α and CK2β gene expressions

Cited by 8 publications

References 67 publications

CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1

CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1

Mining CK2 in Cancer

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

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