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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 plays an essential role in cellular growth control. Some of its distinct biological functions are regulated by interaction with cellular proteins. We have previously (Wagner et al., 1994) shown that p53 binds to the regulatory subunit of protein kinase CK2. Using C-terminal protein fragments of p53 we now demonstrate that the region between amino acids 287 and 340 on the polypeptide chain of p53 is critical for binding of p53 to the beta-subunit of CK2. Neither phosphorylation at the p34cdc2 site (aa315) nor at the CK2 site (aa392) is necessary for binding of p53 to the beta-subunit of CK2. Using deletion mutants of the beta-subunit of CK2 we also show that an internal region between amino acids 72 and 149 of the beta-subunit of CK2 is necessary for binding to p53. Thus, this study defines new functional regions on the polypeptide chains of p53 and of protein kinase CK2.
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PMID:Mapping of the interaction sites of the growth suppressor protein p53 with the regulatory beta-subunit of protein kinase CK2. 747 15

The protein kinase CK2 is an ubiquitous serine-threonine kinase found in all eukaryotic cells. Although well characterized on a biochemical ground, its role and regulation in the intact cell are not clearly understood. Its possible implication in the control of cell proliferation has been examined by several different approaches. (i) Immunocytochemical detection of CK2 revealed that whereas the signal was evenly distributed throughout cycle arrested cells in primary culture, it accumulates rapidly (30-90 min) in the nuclear compartment in cells stimulated to grow. (ii) CK2 biosynthesis is activated as an early response to growth factors in quiescent cells. The neo-synthesized kinase accumulates as the cells progress through the G1 phase. This growth factor-activated biosynthesis concerns in parallel the two kinase subunits. (iii) The kinase is activated in vitro by polyamines, which are increased in cells challenged by growth factors. Spermine binds to a specific domain of the beta subunit of CK2. (iv) In addition to phosphorylation CK2 forms a molecular complex with p53, a major negative regulator of the cell cycle. The complex was demonstrated in intact cells and reconstituted in vitro (Kd 70 nM) with purified components and shown to require the beta subunit and to result in the inhibition of p53 DNA-annealing activity. These observations suggest that CK2 and p53 may play a coordinated role in the cell response to mitogenic stimuli.
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PMID:[Has protein kinase CK2 a role in the intracellular mitogenic signalling?]. 764 67

Unlike most Ser/Thr protein kinases which recognize phosphoacceptor sites specified by basic residues, protein kinase CK2 is extraordinarily acidophilic in nature. By combining the analysis of more than 100 CK2 natural phosphorylation sites with the kinetic behaviour of a large number of model peptide substrates, it can be concluded that although the most crucial specificity determinant is an acidic residue (Glu, Asp, TyrP, or SerP) at position +3, additional acidic residues at positions spanning from -2 to +7 (and probably farther) also act as positive specificity determinants for CK2, whereas basic residues at these positions, prolyl residue at position +1, and a bulky hydrophobic doublet at position +1 and +2, are powerful negative determinants. It also appears that the nature of the acidic determinants may variably influence their effect depending on the position occupied: Thus, multiple aspartic acids are, in general, determinants as good as, or even better, than an equivalent number of glutamic acids; an individual Asp at position +3 flanked by Glu residues is ineffective; and phosphorylated residues appear to be much more effective if adjacent to the target residue (positions -2 to +2). In some instances, the local determinants alone are insufficient to account for the phosphorylation efficiency of the substrate which is greatly improved by the overall protein conformation, as illustrated by the examples of CK2 beta-subunit and protein p53, the latter exhibiting no consensus sequence around its phosphorylation site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Substrate specificity of protein kinase CK2. 773 14

The tumor suppressor protein p53 is phosphorylated at a C-terminal residue (serine 386 in mouse p53) by the protein kinase CK2. Phosphorylation by CK2 activates the specific DNA binding function of p53 and stimulates its ability to suppress cellular growth. Previous reports have suggested that phosphorylation of p53 at the CK2 site is stimulated in cells expressing the large tumor antigen (T antigen) of simian virus 40 (SV40). To test this idea, we have expressed a C-terminal p53 "mini-protein" which comprises amino acids 154-387 of mouse p53 and therefore lacks the heavily phosphorylated N-terminus. In addition, the serine 309 phosphorylation site (targeted by cyclin-dependent kinases) has been mutated to encode alanine. We have expressed the p53 mini-protein in mammalian cells and shown by phosphopeptide mapping that it is phosphorylated at a single physiological phosphorylation site, serine 386. Using this mini-protein as a cellular target for CK2, we have shown that phosphorylation of p53 by CK2 is not affected by the presence of T antigen. The p53 mini-protein is likely to be a useful tool with which to probe the regulation of p53 phosphorylation by CK2 in response to other factors which influence cell growth.
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PMID:A novel system to investigate the phosphorylation of the p53 tumor suppressor protein by the protein kinase CK2. 773 30

The effect of cis-diaminedichloroplatinum(II) (cisplatin) on the induction of p53 and protein kinase CK2 activity was studied in the mouse teratocarcinoma cell line F9. Treatment of the cells with the chemotherapeutic agent cisplatin led to the detection of p53 3 h after addition of the drug. F9 cell extracts treated with and without cisplatin were analyzed by ion exchange chromatography for protein kinase CK2 alpha/beta subunits and p53 distribution. The following results were obtained: (a) in crude extracts of cisplatin-treated cells, CK2 activity was sometimes reduced by as much as 50%; (b) after separation by anionic exchange chromatography (MA7Q, BioRad) of the crude cellular extracts from cisplatin-treated cells, lower CK2 activity was found in the peak fractions confirming the results obtained with crude cellular extracts; (c) besides the detection of CK2 alpha subunit by immunostaining, we have detected, at a concentration of approximately 200 mM NaCl, a protein of approximately 46 kDa which reacted with the CK2 alpha-specific antibody. This fraction was devoid of CK2 activity; and (d) cisplatin-treated cells exhibited p53 protein, which was mostly eluting ahead but also partly together with CK2 holoenzyme.
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PMID:Characterization of protein kinase CK2 protein subunits and p53 in F9 teratocarcinoma cells in the absence and presence of cisplatin. 773 33

Using a new series of p53 mutants targeting the conserved regions we have analysed the relationship of various activities of the protein. Mdm-2 and human papillomavirus (HPV) E6, two proteins which interact with and abrogate p53 function, were shown to bind independently. Deletion of the conserved regions of the protein in which most of the naturally occurring mutations are found (boxes II-V) abrogated transcriptional activity and the ability to interact with E6, supporting the importance of this DNA binding domain to these activities. Nevertheless, these mutants retained the ability to interact with mdm2. One mutant, deleted of all the C-terminal sequences, showed loss of mdm2 binding, E6 binding and transcriptional activity. More subtle mutations within the C-terminus of the protein, including alterations of the cdc2 and CKII phosphorylation sites, had no effect on the transcriptional trans-activation, mdm-2 or E6 binding functions, indicating that phosphorylation of these sites is not essential for these activities. Deletion of conserved box I sequences abolished the interaction with mdm-2 without loss of transcriptional activation or transformation suppressor activity, suggesting that mdm-2 is not a downstream effector of p53 function.
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PMID:Interaction of p53 with MDM2 is independent of E6 and does not mediate wild type transformation suppressor function. 805 35

In the present study, we examined the sufficiency of SV40 T antigen (Tag) binding to pRB and p53 to substitute for alterations in RB and TP53 at all stages of human uroepithelial cell (HUC) transformation in vitro. Two independent SV40 immortalized HUCs (SV-HUC and SV-HUC/CK2) and 17 independent derivative carcinogen-induced or spontaneous tumors (T-SV-HUCs and T-SV-HUC/CK2) representing different stages of urothelial tumorigenesis were examined. Although five of 17 T-SV-HUCs and SV-HUC/CK2 and its derivative tumor showed 13q chromosome deletion and loss of heterozygosity (LOH), this did not reflect functional loss of pRB because Tag/pRB binding was unaltered and sequencing showed a normal RB gene in all these tumors. No genetic alterations involving 17p or TP53 were detected in any tumors in this study using the same techniques. These results indicate that Tag/pRB and Tag/p53 binding apparently abrogate requirements for/or a selective advantage of RB and TP53 mutations in HUC tumorigenic transformation and progression, as well as in HUC immortalization. These data also provide new evidence that more than one suppressor gene may be located on chromosome 13q.
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PMID:Role of SV40 T antigen binding to pRB and p53 in multistep transformation in vitro of human uroepithelial cells. 824 58

Direct evidence of tumour seeding in distant organs at the time of surgery for gastric cancer is not available. An immunocytochemical assay for epithelial cytokeratin protein may fill this gap since it is a feature of epithelial cells that would not normally be present in bone marrow. The bone marrow of 46 patients with primary gastric cancer was examined for tumour cells, using immunocytochemical techniques and antibody reacting with cytokeratin, a component of the intracytoplasmic network of intermediate filaments. The monoclonal antibody CK2 recognises a single cytokeratin polypeptide (human cytokeratin no. 18) commonly present in epithelial cells. The expression of tumour-suppressor genes p53 and RB for the primary lesion was also determined using the monoclonal antibodies PAb 1801 and 3H9 respectively, and the proliferating activity was determined by the Ki-67 antigen labelling index for MIB-1 antibody staining. Of these 46 patients, 15 (32.6%) presented with cytokeratin-positive cells at the time of primary surgery. The positive findings were related to the undifferentiated tissue type and to the prominent depth of invasion, but not to other clinicopathological factors. In 2 of 15 (13.3%) patients, the depth of invasion was limited to the mucosa. The metastatic potential to bone marrow did not relate to expressions of p53 and RB genes, or to the proliferating activity of MIB-1 staining for the primary lesion of gastric cancer. As tumour cells in bone marrow are indicative of the general disseminative capability of an individual tumour, this technique may be useful for identifying patients at high risk of metastasis from a gastric tumour.
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PMID:Cytokeratin-positive cells in bone marrow for identifying distant micrometastasis of gastric cancer. 855 89

Considerable effort is currently being devoted to understand the functions of protein p53, a major regulator of cell proliferation. The protein p53 has been reported to catalyse the annealing of complementary DNA or RNA strands. We report that this activity is inhibited in the presence of the serine/threonine protein kinase CK2. It is shown that this inhibition can be explained by the occurrence of a high-affinity molecular association between p53 and CK2. The molecular complex involves an interaction between the C-terminal domain of p53 and the beta subunit of the oligomeric kinase. Accordingly, the isolated alpha subunit of the kinase was without effect. In addition, after phosphorylation by CK2, phosphorylated p53 lost its DNA annealing activity. Because the C-terminal domain of p53 is both involved in the association with CK2 and phosphorylated by it, our results suggest that either protein-protein interaction or phosphorylation of this domain might control the base pairing of complementary sequences promoted by p53 in processes related to DNA replication and repair.
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PMID:Casein kinase 2 inhibits the renaturation of complementary DNA strands mediated by p53 protein. 864 26

p21WAF1/CIP1 which belongs to a class of regulatory proteins that interact with cyclin dependent kinases is a potent inhibitor of these kinases. The inhibition of the cyclin dependent kinases induces an arrest of cells in the G phase of the cell cycle. In addition p21WAF1/CIP1 associates with PCNA and inhibits DNA replication. Here, we show that p21WAF1/CIP1 binds to the regulatory beta-subunit of protein kinase CK2 but not to the catalytic alpha-subunit. Binding of p21WAF1/CIP1 down regulates the kinase activity of CK2 with respect to the phosphorylation of the beta-subunit of CK2, casein and the C-terminus of p53. This study demonstrates a new binding partner for the regulatory beta-subunit of protein kinase CK2 which regulates the activity of the holoenzyme.
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PMID:p21WAF1/CIP1 interacts with protein kinase CK2. 871 Mar 78


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