The ornithine decarboxylase inhibitor, difluoromethylornithine, inhibits casein kinase II activity, c-Myc expression and normal human keratinocyte proliferation

Praskova, Maria; Kalenderova, Silvia; Miteva, Ljubka; Poumay, Yves; Mitev, В.

doi:10.1007/s00403-001-0278-7

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…We have previously demonstrated that CK2 kinase activity is increased in both ODC-overexpressing keratinocytes and in the skin of K6/ODC transgenic mice (38). The abrogation of this response by the ODC inhibitor R-difluoromethylornithine (DFMO) is in agreement with other studies demonstrating a similar downregulation of CK2 activity in DFMOtreated adult human keratinocytes (39) as well as xenotransplanted colorectal neoplasias (40). We also observed an increased CK2 kinase activity in ODC-overexpressing cells that appeared to be disconcordant with static levels of CK2 protein in the cytosol (38).…”

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confidence: 90%

A Novel Protein Kinase CK2 Substrate Indicates CK2 Is Not Directly Stimulated by Polyamines in Vivo

et al. 2006

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The activity of the protein kinase (CK2) is enhanced in vitro by the binding of polyamines to the CK2beta regulatory subunit. The overexpression of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, also elevates CK2 kinase activity in primary keratinocytes and tissues of K6/ODC transgenic mice. In an effort to better characterize the mechanisms by which polyamines may affect CK2 in vivo, we constructed a transfectable CK2 substrate cDNA consisting of the enhanced green fluorescence protein appended with a canonical CK2 phosphorylation sequence (EGFP-S). In contrast to unmodified EGFP, the EGFP-S protein was extensively phosphorylated by CK2, and this phosphorylation was stimulated by the polyamine spermine in a dose-dependent manner. The in vivo phosphorylation of EGFP-S was examined in cell lines which inducibly express either wild-type CK2 holoenzyme or a CK2 holoenzyme which contains activating mutations in the polyamine-binding region of its CK2beta regulatory subunit. Neither the overexpression of ODC in either cell line nor the mutation of the CK2beta subunit conferred an increase in CK2 kinase activity as measured by the in vivo phosphorylation of EGFP-S. Rather, our data indicate that polyamines increase total CK2 kinase activity through increases in steady-state levels of both CK2alpha and CK2beta subunits. The overexpression of ODC resulted in a 3-fold increase in steady-state levels of both exogenous and endogenous CK2 transcripts but did not increase the half-life of wild-type or mutated CK2 protein. These data suggest that the regulation of intracellular CK2 by the polyamines may occur through mechanisms distinct from the direct stimulation of CK2 by polyamines in vitro as previously described.

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A Novel Protein Kinase CK2 Substrate Indicates CK2 Is Not Directly Stimulated by Polyamines in Vivo

et al. 2006

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“…While we have shown that the pseudophosphorylation of residues T102 and T126 makes at best a small contribution to E1-importin interactions in the context of S109D, all three of these residues must now be reevaluated in conjunction with S90, S94, S95, and S100. Residues S94, S95, and S100 are all predicted to be phosphorylated by CKII, which is also known to be involved in the regulation of keratinocyte proliferation (46).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Import of Bovine Papillomavirus Type 1 E1 Protein Is Mediated by Multiple Alpha Importins and Is Negatively Regulated by Phosphorylation near a Nuclear Localization Signal

Bian

Rosas-Acosta

et al. 2007

J Virol

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Papillomavirus DNA replication occurs in the nucleus of infected cells and requires the viral E1 protein, which enters the nuclei of host epithelial cells and carries out enzymatic functions required for the initiation of viral DNA replication. In this study, we investigated the pathway and regulation of the nuclear import of the E1 protein from bovine papillomavirus type 1 (BPV1). Using an in vitro binding assay, we determined that the E1 protein interacted with importins ␣3, ␣4, and ␣5 via its nuclear localization signal (NLS) sequence. In agreement with this result, purified E1 protein was effectively imported into the nucleus of digitonin-permeabilized HeLa cells after incubation with importin ␣3, ␣4, or ␣5 and other necessary import factors. We also observed that in vitro binding of E1 protein to all three ␣ importins was significantly decreased by the introduction of pseudophosphorylation mutations in the NLS region. Consistent with the binding defect, pseudophosphorylated E1 protein failed to enter the nucleus of digitonin-permeabilized HeLa cells in vitro. Likewise, the pseudophosphorylation mutant showed aberrant intracellular localization in vivo and accumulated primarily on the nuclear envelope in transfected HeLa cells, while the corresponding alanine replacement mutant displayed the same cellular location pattern as wild-type E1 protein. Collectively, our data demonstrate that BPV1 E1 protein can be transported into the nucleus by more than one importin ␣ and suggest that E1 phosphorylation by host cell kinases plays a regulatory role in modulating E1 nucleocytoplasmic localization. This phosphoregulation of nuclear E1 protein uptake may contribute to the coordination of viral replication with keratinocyte proliferation and differentiation.Papillomaviruses are the etiological agents involved in several human cancers such as cervical cancer, anogenital cancer, skin cancer, and cancers of the oral cavity, the larynx, and the esophagus (68). In addition to their importance in clinical disease, papillomaviruses have provided a valuable model system for analyzing the mechanisms regulating eukaryotic DNA replication. The viral E1 protein is the largest open reading frame and is highly conserved among all papillomaviruses, maintaining its size, amino acid composition, and location in the viral genome with respect to other early genes. The E1 protein is expressed during the early stage of virus infection in order to maintain the viral DNA as an episome. The multifunctional E1 protein recognizes and binds to the viral origin of replication in combination with the viral protein E2, recruits host cell replication proteins to the origin, and initiates DNA replication via its ATP-dependent helicase activity (60, 61).Papillomavirus infection is established in the basal layer of the epithelium, and the complex viral life cycle is coordinated with the differentiation state of the epithelium (13, 14). There are three distinct modes of viral DNA replication: (i) transient amplification, which occurs immediately upon ...

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“…α-Difluoromethylornithine (DFMO), which is an ODC inhibitor, leads to an abrogation of this response (Praskova et al 2002). Increased ODC expression and polyamine levels act not only to increase CK2 activity and protein levels, but also to redistribute CK2 subunits within the cell.…”

Section: Activators Of Protein Kinase Ck2mentioning

confidence: 99%

Cellular regulators of protein kinase CK2

Montenarh

2010

Cell Tissue Res

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Protein phosphorylation is a key regulatory post-translational modification and is involved in the control of many cellular processes. Protein kinase CK2, formerly known as casein kinase II, which is a ubiquitous and highly conserved protein serine/threonine kinase, plays a central role in the control of a variety of pathways in cell proliferation, transformation, apoptosis and senescence. An understanding of the regulation of such a central protein kinase would greatly help our comprehension of the regulation of many pathways in cellular regulation. A number of reviews have addressed the detection, the development, and the characterization of inhibitors of CK2. The present review focuses on possible natural regulators of CK2, i.e. proteins and other cellular factors that bind to CK2 and thereby regulate its activity.

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The ornithine decarboxylase inhibitor, difluoromethylornithine, inhibits casein kinase II activity, c-Myc expression and normal human keratinocyte proliferation

Cited by 6 publications

References 24 publications

A Novel Protein Kinase CK2 Substrate Indicates CK2 Is Not Directly Stimulated by Polyamines in Vivo

A Novel Protein Kinase CK2 Substrate Indicates CK2 Is Not Directly Stimulated by Polyamines in Vivo

Nuclear Import of Bovine Papillomavirus Type 1 E1 Protein Is Mediated by Multiple Alpha Importins and Is Negatively Regulated by Phosphorylation near a Nuclear Localization Signal

Cellular regulators of protein kinase CK2

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