Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oncogene product MDM2 can be phosphorylated by protein kinase CK2 in vitro 0.5-1 mol of phosphate were incorporated per mol MDM2 protein. The catalytic subunit of protein kinase CK2 (alpha-subunit) catalyzed the incorporation of twice as much phosphate into the MDM2 protein as it was obtained with the holoenzyme. Polylysine stimulated MDM2 phosphorylation by CK2 holoenzyme threefold in contrast to the alpha-subunit-catalyzed MDM2 phosphorylation which was reduced by about 66% when polylysine was added. Full length p53, but also a peptide representing a C-terminal fragment of the tumor suppressor gene product p53 (amino acids 264-393 which also harbors the CK2beta interaction site at amino acids 287-340) mimicked the polylysine effect in all respects, ie. stimulation of phosphate incorporation by CK2 holoenzyme and inhibition in the presence of the catalytic CK2 alpha-subunit. Stimulation by p53(264-393) was on the average close to twofold and inhibition in the case of the alpha-subunit-catalyzed MDM2 phosphorylation was about 40%. Phosphorylation of MDM2 by CK2 holoenzyme in the presence of the p21(WAF1/CIP1), known to be a potent inhibitor of cyclin-dependent protein kinases, also led to a significant reduction of phosphate incorporation into MDM2 indicating that p21(WAF1/CIP1) does not exclusively inhibit cell cycle kinases. Furthermore, these data add new insight into the autoregulatory loop which include p21(WAF1/CIP1), MDM2 protein, CK2 and p53.
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PMID:The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation. 917 66

Some of the numerous functions of the growth suppressor protein p53 are regulated by its interaction with viral and cellular proteins. C-terminal sequences of p53 are implicated in binding to the regulatory beta-subunit of protein kinase CK2. Using a p53-specific DNA binding element we found that the beta-subunit of CK2 inhibited the DNA binding of p53 whereas the alpha-subunit had no influence. The CK2 holoenzyme consisting of two alpha- and two beta-subunits led to a supershift in DNA binding of p53 similar to the p53-specific monoclonal antibody PAb421 as well as the C-terminus of p53. Thus, our results showed an individual role of the free beta-subunit of CK2 on the DNA binding activity of p53.
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PMID:Regulation of the DNA binding of p53 by its interaction with protein kinase CK2. 918 Feb 77

The yeast tms1 gene was originally identified as a multi-copy suppressor of a lethal growth arrest caused by expression of a tumour mutant cDNA of p53 in fission yeast. The tms1 gene product (Tms1) was found to form stable complexes with p53 in yeast and in vitro; using purified recombinant proteins, the interaction was mapped to the C-terminal region of p53. This part is known to be modified by several protein kinases resulting in a transition of p53 from a latent to an activated state capable of transactivating various cellular genes involved in growth suppression or apoptosis. Since there is evidence for an evolutionary conservation of a Tms1-related protein in mammals, the effect of the phosphorylation status of the C-terminus of p53 on Tms1/p53 complex formation in vitro has been investigated. Whereas mutants changing the cdc2 phosphorylation site at position 315 of human p53 had only little effect on Tms1/p53 complex formation, we found that mutants involving the protein kinase CK2 site at position 392 showed a significantly decreased relative affinity for the Tms1 protein. The same result was obtained by using a C-terminal fragment of p53 which was phosphorylated by purified protein kinase CK2, suggesting that the complex formation of p53 with cellular C-terminal binding proteins like Tms1 impairs regulation by phosphorylation.
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PMID:Phosphorylation mutants of p53 show differential complex formation with putative dehydrogenase Tms1 of fission yeast. 934

Protein kinase CK2 is a ubiquitous protein kinase responsible for the phosphorylation of Ser and Thr residues specified by acidic side chains in many proteins, including several key enzymes, growth factor receptors, transcription factors and cytoskeletal proteins. The holoenzyme is composed of two catalytic and two regulatory subunits, the latter having antagonistic roles. CK2 is constitutively active and its targeting seems to be modulated through association with a variety of cellular proteins (e.g. heat shock protein 90 and p53). CK2 is abnormally elevated in proliferating and neoplastic tissues and recent studies suggest that mice overexpressing CK2 develop leukemia. Specific inhibitors of CK2, currently being developed, may have therapeutic potential.
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PMID:Protein kinase CK2. 936 31

In vivo p53 is multiply phosphorylated by different protein kinases suggesting a central role for phosphorylation in modulating p53 function. In addition, p53 was found to be associated with two protein kinases, p34cdc2 and protein kinase CK2. Here we report the precise mapping of the interaction sites of p53-p34cdc2 complexes. The p34cdc2 binding site on human p53 maps to one distinct C-terminal site LQIRGRERFE (aa 330-339) close to the corresponding phosphorylation site at serine 315. In order to test whether phosphorylation of p53 might influence the binding of p53 to p34cdc2 phosphorylation mutants of the C-terminus of p53, which mimick permanent phosphorylation, were tested on their ability to bind to p34cdc2 in vitro. Substitution of serine 315 (the p34cdc2 phosphorylation site) with aspartic acid had only little effect on complex formation whereas an exchange of serine 392 (the protein kinase CK2 phosphorylation site) to aspartic acid resulted in a significant reduced relative binding affinity of p53 to p34cdc2. The same result was obtained when the C-terminus of p53 was phosphorylated by purified protein kinase CK2 prior to examination of complex formation. In addition, the specificity of the complex formation has been checked by competition experiments with full length p53 proteins and the influence of cyclin B on complex formation was examined.
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PMID:Fine mapping and regulation of the association of p53 with p34cdc2. 946 49

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation. Here we demonstrate that CK2alpha transgenic mice partially or completely deficient in p53 develop thymic lymphomas at a markedly accelerated rate when compared to p53-deficient mice lacking the transgene. Lymphomas originating from CK2alpha transgenic mice that are heterozygous for p53 generally lose the wild type p53 allele, indicating that loss of p53 is an important step in tumor progression. Moreover, though lymphomas occur as early as 3 weeks of age in the transgenic mice that are nullizygous for p53, they are still monoclonal, indicating that additional stochastic mutations are required for their development. These lymphomas express high levels of myc mRNA and frequently ectopically express Lmo-2, a transcription factor involved in human T cell acute lymphocytic leukemia. The p53-null CK2alpha transgenic lymphomas grow rapidly but are highly prone to apoptosis, suggesting that transformation occurs through synergistic dysregulation of cell cycle control induced by misexpression of CK2 and loss of function of p53.
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PMID:p53 deficiency and misexpression of protein kinase CK2alpha collaborate in the development of thymic lymphomas in mice. 966 28

Using the murine teratocarcinoma cell line F9 we investigated the influence of serum stimulation and cisplatin treatment on the p53, CK2, MDM2 levels. Both treatments led to an increase of p53, though with different kinetics; the other proteins investigated were not affected. We present direct evidence by immunoprecipitation for an association of protein kinase CK2 holoenzyme (alpha2beta2), p53, and the ribosomal protein L5. The results suggest complexes between the CK2 holoenzyme and p53 but also p53/CKbeta complexes. Furthermore we provide evidence for the existence of high molecular mass complexes of CK2 in vivo. This is the first evidence that, under physiological conditions, protein kinase CK2 does not exist solely as a heterotetramer, but predominantly in association with other proteins.
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PMID:p53 and the ribosomal protein L5 participate in high molecular mass complex formation with protein kinase CK2 in murine teratocarcinoma cell line F9 after serum stimulation and cisplatin treatment. 973 62

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with a wide range of substrates, many of which are involved in cell cycle regulation. CK2 activity is elevated in a variety of human tumors and we have used a transgenic mouse model to demonstrate that dysregulated expression of CK2 can induce lymphoma. Thus, CK2 fulfills the definition of an oncogene: A mutated, dysregulated, or mis-expressed gene that contributes to cancer in a dominant fashion. CK2 cooperates in transforming cells with other lymphoid oncogenes such as myc and tal-1, and here we show cooperativity with loss of the tumor suppressor gene p53. To understand more about the physiological and pathological role of CK2, we are cloning the murine CK2alpha' cDNA and gene. CK2alpha' will be used to generate transgenic and knockout mice and the regulatory elements for gene expression will be analyzed.
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PMID:Murine protein kinase CK2: gene and oncogene. 1009 94

p53 is one of the most powerful negative regulators of growth. To manage this in an efficient way it has to interact with a set of different cellular proteins. Most contacts with the cellular environment occur in the N- or the C-terminal domain of the protein. Since we previously found that p53 binds to the regulatory beta-subunit of CK2 we now analyzed N- and C-terminal domains of p53 separately for the binding of protein kinase CK2, an enzyme which seems to have a certain importance for proliferation processes. With different overlay assays we could map the binding domain of protein kinase CK2 to a sequence between amino acids 325-344, a region which coincides with the interaction domain of some other p53 binding proteins. We also found that the regulatory beta-subunit of protein kinase CK2 binds independent of the catalytic alpha-subunit to this C-terminal domain of p53.
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PMID:Protein kinase CK2 interacts with a multi-protein binding domain of p53. 1009 99

The p53 tumour suppressor protein is regulated by several mechanisms including multisite phosphorylation. One of the protein kinases which has an established role in regulating p53 function is the protein kinase CK2. The regulation by CK2 occurs both through interaction of p53 with CK2 itself (the regulatory beta subunit) and phosphorylation at the penultimate residue of p53, serine 386 (murine p53). Strikingly, this phosphorylation event controls several independent functions of p53 including site-specific DNA binding, strand renaturation, transcriptional repression and the anti-proliferative function of p53. However, CK2 is a constitutively-active enzyme and therefore the mechanism by which the phosphorylation of p53 at serine 386 is itself regulated, or indeed the question as to whether phosphorylation of this site is regulated at all, remains unresolved. In this paper we provide evidence that serine 386 is highly resistant to dephosphorylation in cultured cells, even though this site can be dephosphorylated in vitro by recombinant protein phosphatase 1. These data suggest that, once phosphorylated at the CK2 site, a p53 molecule remains in this modified form throughout its lifespan. To address the issue of whether the level of serine 386 phosphorylation may be regulated through controlling the subcellular compartmentalisation of p53 and CK2, we examined the subcellular localisation of p53 and CK2alpha in C57MG cells and Rat-1 fibroblasts by immunofluorescence staining. Both proteins were present in the cytoplasm and enriched in the nucleus, with minor variations in the intensity of subcellular location over the course of the cell cycle. Similarly, activation of p53 by UV irradiation or DNA damage-inducing drugs had no effect on either the localisation or levels of CK2alpha, even although significant nuclear p53 accumulation was observed. A striking observation arising from these studies was the intense staining of CK2alpha with the centrosomes, suggesting a potentially important role for this kinase in microtubule formation and/or chromosomal segregation.
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PMID:Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. 1009 8


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