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

p53 is an allosterically regulated protein with a latent DNA-binding activity. Posttranslational modification of a carboxy-terminal regulatory site in vitro, by casein kinase II and protein kinase C, can activate the sequence-specific DNA-binding function of the wild-type protein. The latent form of p53 is produced in a variety of eukaryotic and prokaryotic cell lines, including E. coli, Sf9 insect cells, and C6 cells, indicating that the activation of p53 in vivo is rate-limiting. In addition, phosphorylation of p53 at the protein kinase C site and activation in vivo correlate with the loss of reactivity of active p53 protein to the carboxy-terminal antibody, PAb421. These results suggest that two highly conserved protein kinases modify polypeptide structure through a common biochemical mechanism and that different enzymatic pathways may channel information into the carboxy-terminal regulatory site of p53, allosterically activating its function as a tumor suppressor.
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PMID:Regulation of the cryptic sequence-specific DNA-binding function of p53 by protein kinases. 758 70

Aberrant cyclin expression has been implicated in oncogenesis in a number of human cancers. Since altered function of regulators of cyclin-dependent kinase (CDK) activity other than cyclins, in particular CDK inhibitors, might play a similar role in oncogenesis, we examined the expression and regulation of the CDK inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer cell lines. Both the INK4 and INK4B genes were homozygously deleted in 3 cell lines, while INK4 alone was deleted in 2 cell lines. A further 2 cell lines displayed loss of an allele at this locus, and in 1 of these the remaining allele contained a mis-sense mutation within the coding region of the p16INK4 protein. The majority of cell lines examined, including 2 normal mammary epithelial cell strains, expressed low levels of INK4 mRNA and low or undetectable levels of INK4B mRNA. However, INK4 mRNA was expressed at high levels in 5 cell lines, and this was associated with deletion or inactivation of the retinoblastoma susceptibility gene product pRB but not with mutation of TP53. No deletions of the WAF1/CIP1 gene were observed, but WAF1/CIP1 mRNA levels were reduced in cell lines with TP53 mutation. Transfection of a p16INK4 expression vector into MDA-MB-231 cells lacking the INK4 gene failed to produce any p16INK4-expressing cell lines, suggesting that such cells were selected against in continuous culture. Despite the frequent deletion of INK4 in breast cancer cell lines, no evidence was obtained for INK4 deletions in DNA from 45 primary breast carcinomas. Thus, homozygous deletion of the INK4 gene appears to be a rare event in primary breast cancer.
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PMID:Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. 759 Dec 70

Mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase are ubiquitous kinases conserved from fungi to mammals. Their activity is regulated by phosphorylation on both threonine and tyrosine, and they play a crucial role in the regulation of proliferation and differentiation. We report here the cloning of the murine p44 MAP kinase (extracellular signal-regulated kinase 1) gene, the determination of its intron/exon boundaries, and the characterization of its promoter. The gene spans approximately eight kilobases (kb) and can be divided into nine exons and eight introns, each coding region exon containing from one to three of the highly conserved protein kinase domains. Primer extension analysis reveals the existence of two major start sites of transcription located at -183 and -186 base pairs (bp) as well as four discrete start sites for transcription located at -178, -192, -273, and -292 bp of the initiation of translation. However, the start site region lacks TATA-like sequences but does contain initiator-like sequences proximal to the major start sites obtained by primer extension. 1 kb of the promoter region has been sequenced. It contains three putative TATA boxes far upstream of the main start sites region, one AP-1 box, one AP-2 box, one Malt box, one GAGA box, one half serum-responsive element, and putative binding sites for Sp1 (five), GC-rich binding factor (five), CTF-NF1 (one), Myb (one), p53 (two), Ets-1 (one), NF-IL6 (two), MyoD (two), Zeste (one), and hepatocyte nuclear factor-5 (one). To determine the sites critical for the function of the p44 MAPK promoter, we constructed a series of chimeric genes containing variable regions of the 5'-flanking sequence of p44 MAPK gene and the coding region for luciferase. Activity of the promoter, measured by its capacity to direct expression of a luciferase reporter gene, is strong, being comparable with the activity of the Rous sarcoma virus promoter. Progressive deletions of the approximately 1 kb (-1200/-78) promoter region allowed us to define a minimal region of 186 bp (-284/-78) that has maximal promoter activity. Within this context, deletion of the AP-2 binding site reduces by 30-40% the activity of the promoter. Further deletion of this minimal promoter that removes the major start sites (-167/-78) surprisingly preserves promoter activity. This result implicates a major role of this region that contains the Sp1 sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The mouse p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1) gene. Genomic organization and structure of the 5'-flanking regulatory region. 759 46

Central to the role of p53 in cell regulation are its sequence-specific interactions with genes that control the cell cycle and apoptosis. p53 response elements contain two or more copies of a somewhat promiscuous consensus sequence: 5'-XXXC(A,T)(T,A)GYY-3' (where X is a purine and Y is a pyrimidine) (ref. 3). The sequence-specific DNA-binding region of p53 resides in its central conserved region. Although this region itself is not known to be phosphorylated, the amino and carboxy termini of human p53 contain sites for phosphorylation by several protein kinases. We have examined the role of cyclin-dependent kinase (Cdk) shown previously to phosphorylate human p53 at serine 315 (ref. 5). We report here that p53 is efficiently and selectively phosphorylated by S and G2/M Cdks. Such phosphorylation markedly stimulates sequence-specific DNA binding by p53 and also causes a distinctive conformational change in p53 as revealed by partial protease analysis. Strikingly, Cdk phosphorylation also confers binding-site preference on p53. These data suggest a potential regulatory mechanism of p53 activity.
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PMID:Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases. 759 41

p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate with Cdk7/cyclin H. Overexpression of P21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is greatly enhanced by cyclin binding. This property is shared by the structurally related inhibitor p27, suggesting a common biochemical mechanism for inhibition. With respect to Cdk2 and Cdk4 complexes, p27 shares the inhibitory potency of p21 but has slightly different kinase specificities. In normal diploid fibroblasts, the vast majority of active Cdk2 is associated with p21, but this active kinase can be fully inhibited by addition of exogenous p21. Reconstruction experiments using purified components indicate that multiple molecules of p21 can associate with Cdk/cyclin complexes and inactive complexes contain more than one molecule of p21. Together, these data suggest a model whereby p21 functions as an inhibitory buffer whose levels determine the threshold kinase activity required for cell cycle progression.
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PMID:Inhibition of cyclin-dependent kinases by p21. 762 5

Post-translational modification of a carboxyl-terminal negative regulatory domain in vitro by either casein kinase II or protein kinase C allosterically activates the latent sequence-specific DNA binding function of p53. Reported here is a biochemical approach to determine the types of signaling pathways and enzymes that are involved in p53 activation in cells. Using a novel chromatographic method, we have been able to separate three distinct biochemical forms of p53 that have been synthesized in vivo; two are in an activated state, and one is in a latent state for sequence-specific DNA binding. The two activated forms of p53 appear to be controlled individually by either a constitutive or a UV-inducible signaling pathway. p53 lacking the COOH-terminal casein kinase II site (p53 delta 4) was characterized biochemically and used to determine the affects of deletion of the casein kinase II motif on the production of the two activated forms of p53 in vivo. As observed with full-length p53, the production of two distinct chromatographic forms of activated p53 delta 4 occurs in vivo, indicating that p53 activation can occur through a casein kinase II-independent pathway and suggesting that two other factors are involved in activation of p53 in vivo.
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PMID:Two distinct signaling pathways activate the latent DNA binding function of p53 in a casein kinase II-independent manner. 762 29

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

We have previously demonstrated that cells from patients with ataxia-telangiectasia (A-T) fail to show initial delay at several cell cycle checkpoints post-irradiation. In addition a defect in the induction of p53 by ionizing radiation was evident. We demonstrate here that the radiation signal transduction pathway operating through p53, its target gene WAF1, cyclin-dependent kinases and the retinoblastoma (Rb) protein is defective in A-T cells. The defective p53 induction after ionizing radiation, observed previously in A-T cells, was also reflected at the functional level using p53-DNA binding activity, transactivation and transfection with wild type p53. Correction of the defect at the G1/S checkpoint was observed when wild type p53 was constitutively expressed in A-T cells. Exposure of control cells to radiation gave rise to p53 induction and as a consequence increased expression of WAF1 mRNA and protein, but A-T cells were defective in this response. As expected the WAF1 response in irradiated control cells resulted in an inhibition of cyclin-dependent kinase activity including cyclin E-cdk2, which plays an important role in the transition from G1 to S phase. No inhibition of cyclin-dependent kinase activity was observed in A-T cells correlating with the delayed WAF1 response. On the contrary an enhancement of cyclin-dependent kinase activity was seen in A-T cells post-irradiation. An accumulation of the hypophosphorylated form of Rb protein occurred in irradiated control cells compatible with the G1/S phase delay observed in these cells after exposure to radiation. In unirradiated A-T cells the amount of Rb protein was much higher compared to controls and it was mainly in the hyperphosphorylated (functionally inactive) form. In addition, accumulation of the hypophosphorylated form of Rb in A-T cells post-irradiation was defective, consistent with the lack of cell cycle arrest. Thus the failure of the G1/S checkpoint in A-T cells after exposure to ionizing radiation is consistent with a defective radiation signal transduction pathway operating through p53.
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PMID:Nature of G1/S cell cycle checkpoint defect in ataxia-telangiectasia. 765 23

D-type cyclins and cyclin-dependent kinase (cdk-4) are likely involved in regulating passage of cells through the G1 phase of the cell cycle. A decrease in the proportion of cells in G1, a relatively radiation-sensitive phase of the cell cycle, should result in increased resistance to ionizing radiation; however, the effect of such overexpression on X-ray-induced G1-phase arrest is not known. Radiation survival curves were obtained at a dose rate of either 8 cGy/min or 1 Gy/min for subclones of the IL-3-dependent hematopoietic progenitor cell line 32D cl 3 expressing transgenes for either cyclin-D1, D2 or D3 or cdk-4. We compared the results to those with overexpression of the transgene for Bcl-2, whose expression enhances radiation survival and delays apoptosis. Cells overexpressing transgenes for each D-type cyclin or Bcl-2 had an increased number of cells in S phase compared to parent line 32D cl 3; however, overexpression of cdk-4 had no effect on cell cycle distribution. Cell death resulting from withdrawal of IL-3 was not affected by overexpression of cyclins D1 and D3 but was delayed by overexpression of D2, cdk-4 or Bcl-2. Flow cytometry 24 h after 5 Gy irradiation demonstrated that overexpression of each G1-phase regulatory transgene decreased the proportion of cells at the G1/S-phase border. Western analysis revealed induction of cyclin-D protein levels by irradiation, but no change in the levels of cdk-4, p53 or p21. There was no significant change in the D0, but a significant increase in the n for cyclin-D or cdk-4 transgene-overexpressing clones at 1 Gy/min (P < 0.017). At a lower dose rate of 8 cGy/min, the n for cyclin or cdk-4-overexpressing clones was also increased (P < 0.07). Thus overexpression of cyclin-D or cdk-4 in hematopoietic cells induces detectable effects on hematopoietic cell radiation biology including a broadening of the shoulder on the radiation survival curve and a decrease in radiation-induced G1/S-phase arrest.
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PMID:Inhibition of G1-phase arrest induced by ionizing radiation in hematopoietic cells by overexpression of genes involved in the G1/S-phase transition. 765 61

This review focuses on genes that have a proven or presumed role in the genesis of astrocytic tumors. A common theme in glioblastoma is the amplification of genes that code for growth factor receptors of the protein-tyrosine kinase family (epidermal growth factor receptor, platelet-derived growth factor receptor-alpha, met). The majority of glioblastomas also have alterations in genes that encode factors that are involved in cyclin-dependent kinase activity, which is a critical step in G1-S transition in the cell cycle. These alterations include deletions of negative regulatory elements (TP53, CDKN2, MTS2) and amplification of positive factors (MDM2, CDK4). In addition, there are loci on chromosomes 10 and 19q that seem to be involved in tumor progression.
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PMID:Molecular genetics of human glioma. 765 23


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