Joining the cell survival squad: an emerging role for protein kinase CK2

Ahmed, Khalil; Gerber, Delphine; Cochet, Claude

doi:10.1016/s0962-8924(02)02279-1

Cited by 361 publications

(309 citation statements)

References 60 publications

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“…More specifically, Casein Kinase 2, a serine/threonine kinase that associates with CD5 in thymocytes [37], was shown to play a crucial role in cell survival and apoptosis [61]. In this context, CD5 À/À CD4 1 T cells, as well as CD4 1 T lymphocytes that express a Casein Kinase 2 binding/ Figure 9.…”

Section: Discussionmentioning

confidence: 99%

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg). Analysis of CD5 À/À mice showed a significant increase in the percentage and absolute numbers of CD4 1 CD25 1 Foxp3 1 thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5 À/À mice showed reduced cellularity due to increased apoptosis, which preferentially affected naïve T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5 À/À nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5 À/À naïve T cells but not CD5 À/À nTreg showed lower levels of p-Akt. Finally, CD5 À/À nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4 1 CD25 À naïve thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.Key words: CD5 . Development . Treg . Signaling . Thymocyte IntroductionThe maintenance of immunological self-tolerance is a fundamental property of the immune system besides the clearance of pathogenic agents. Central and peripheral mechanisms exist to ensure the elimination or inactivation of potentially harmful autoreactive T cells. Negative selection in the thymus induces the deletion of most self-reactive T-cell clones during T-cell development [1]. However, some autoreactive T cells escape from clonal deletion and need to be controlled by peripheral mechanisms including peripheral T-cell deletion by activation-induced cell death [2], T-cell anergy [3] and T-cell-mediated suppression [4].Recently, non-deletional mechanisms of central tolerance have been re-evaluated, such as the development of thymus-derived Treg [5]. These cells are currently known as ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg), which represent a small population (5-10%) of peripheral CD4 1 T cells and are characterized by high levels of surface CD25 and by the expression of Foxp3, a transcription factor, identified as a key regulator of nTreg development and function [6]. In addition, nTreg also express activation markers such 2233as CTLA-4, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, OX40 and CD103 [7,8]. nTreg were first studied for their role in maintaining self-tolerance [9], preventing autoimmune diseases [10] and the development of harmful immunopathological responses [11]. However, nTreg can also participate in modulating adaptive immunity to viruses, bacteria and parasites affecting favorably or detrimentally the outcome of immune responses to infections [12,13].The mechanisms of suppression used by Treg...

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Section: Discussionmentioning

confidence: 99%

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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“…The heterotetramer holoenzyme exists as a 2 b 2 , aa 0 b 2 , or a 0 2 b 2 tetramers. 23 A 1:1 stochiometry of the a and b subunits is required for optimal CK2 activity. The a catalytic subunit is stimulated by the b regulatory subunit, which undergoes autophosphorylation.…”

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confidence: 99%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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“…Moreover, binding of P1 on A CK2b subunit-interacting peptide induces p53-dependent cell apoptosis V Martel et al CK2b did not change the phosphorylation of Engrailed and CDC25B, two protein substrates that are exclusively targeted by the canonical CK2 holoenzyme (Maizel et al, 2002;Theis-Febvre et al, 2003). Mounting evidence indicates that CK2 is required for cell viability and plays a critical role in apoptotic signal transduction (Ahmed et al, 2002;Pinna, 2002;Unger et al, 2004). Accordingly, we have observed that the viability of several mammalian cell types was strongly inhibited upon GFP-P1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Protein kinase CK2 (formerly casein kinase II) is a multifunctional protein kinase that has crucial roles in cell differentiation, proliferation and survival (Ahmed et al, 2002;Litchfield, 2003). The enzyme is described as a multi-subunit protein kinase that is generated by the association of two catalytic subunits a or a 0 with a dimer of b regulatory subunits leading to the idea that CK2 functions as a stable heterotetrameric complex.…”

Section: Introductionmentioning

confidence: 99%

“…However, this traditional view has been challenged by the evidence for naturally occurring free monomeric CK2a (Dobrowolska et al, 1992;Stigare et al, 1993;Heriche et al, 1997) and for an unbalanced expression of CK2 subunits in different mammalian tissues (Stalter et al, 1994;Pinna and Meggio, 1997;Guerra et al, 1999b;Ghavidel and Schultz, 2001;Keller et al, 2001). Moreover, the marked elevation of CK2 enzymatic activity in various solid tumors is suspected to result in the suppression of cellular apoptosis, aiding tumor resistance to radiation and anticancer drug treatments (Guerra and Issinger, 1999;Ahmed et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

Martel

Filhol

Colas³

et al. 2006

Oncogene

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Joining the cell survival squad: an emerging role for protein kinase CK2

Cited by 361 publications

References 60 publications

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Role for casein kinase 2 in the regulation of HIF‐1 activity

p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

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Joining the cell survival squad: an emerging role for protein kinase CK2

Cited by 361 publications

References 60 publications

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Role for casein kinase 2 in the regulation of HIF‐1 activity

p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling