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

The human leukemia cell line, HL60 is very sensitive to various apoptotic stimuli and p53-null. The death-related cysteine proteases of the caspases family play a central role in the execution phase of apoptosis, and we recently reported the importance of serine protease activation in camptothecin-induced apoptotic endonuclease activation in HL60 cells. In the present study, we investigated the role of caspases (ICE/CED-3-related cysteine proteases) and serine proteases in cell death induced by the topoisomerase I inhibitor, camptothecin, in HL60 cells and in a cell-free system. We found that CPP32 is activated during camptothecin-induced apoptosis, and that N-benzyloxycarbony-Val-Ala-Asp (O-methyl) -fluoromethyketone (Z-VAD-fmk), a cell permeable caspase inhibitor blocks all features of apoptosis: morphological changes, cleavage of caspase 3 (CPP32/Yama/Apopain) and poly(ADP-ribose) polymerase, lamin B degradation and DNA fragmentation. However, Z-VAD-fmk and two other ICE/CED-3 inhibitors, YVAD-CHO and DEVD-CHO, were inactive in a cell-free system reconstituted from nuclei of untreated HL60 cells and cytosol from camptothecin-treated cells, suggesting that caspases are not required for endonuclease activation or lamin B cleavage in the cell-free system. By contrast, the serine protease inhibitors, 3,4-dichloroisocoumarin (DCI) and L-1-chloro-3-(4-tosylamido)-4-phenyl-2-butanone tosyl-L-phenylalanine chloromethyl ketone (TPCK), abolished the apoptosis-associated biochemical changes induced by camptothecin both in whole cells and in a cell-free system. DCI also inhibited CPP32 cleavage. Taken together, these results suggest that in HL60 cells, both CPP32 and serine proteases are activated in camptothecin-induced apoptosis.
 ...
PMID:Camptothecin-induced apoptosis in p53-null human leukemia HL60 cells and their isolated nuclei: effects of the protease inhibitors Z-VAD-fmk and dichloroisocoumarin suggest an involvement of both caspases and serine proteases. 926 76

Alterations of the p53 gene have been extensively investigated in a wide variety of human malignancies. However, data on childhood malignant solid tumors are still limited. Mutations of the p53 gene on exons 5 through 8 were examined in 82 childhood malignant solid tumors by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of these mutations was confirmed by direct sequencing. The 82 tumors examined included neuroblastomas (n = 44), Wilms' tumors in = 13), hepatoblastomas (n = 11), rhabdomyosarcomas (n = 10), extraosseus Ewing sarcomas (n = 2), undifferentiated sarcoma of the liver (n = 1), and fibrosarcoma (n = 1). Two sarcoma samples were identified as having point mutations. One was a rhabdomyosarcoma with a missense mutation at codon 273, substituting histidine (His) for arginine (Arg). Another was an undifferentiated sarcoma of the liver with a missense mutation at codon 245, substituting serine (Ser) for glycine (Gly). No mutations were detected among neuroblastomas, Wilms' tumors, or hepatoblastomas. The two sarcomas with mutations were localized tumors. Both patients who had these tumors are disease free for 8 and 5 years after treatment, respectively. The overall incidence of p53 mutations was low (2.4%, 2 of 82). However, the incidence, when calculated for sarcomas, was higher at 14.3% (2 of 14). These data indicate that p53 mutations are generally uncommon in childhood malignant solid tumors examined. However, in some childhood sarcomas, p53 mutations appear to have a causative role in the development of these tumors.
 ...
PMID:Mutation analysis of p53 gene in childhood malignant solid tumors. 926 65

In the majority of cervical cancers, DNAs of high-risk mucosotpropic human papillomaviruses (HPVs), such as type 16, are maintained so as to express two viral proteins, E6 and E7, suggesting an essential importance to carcinogenesis. The high-risk HPV E6 proteins are known to inactivate p53 tumor suppressor protein but appear to have an additional, molecularly unknown function(s). In this study, we demonstrate that these E6 proteins can bind to the second PDZ domain of the human homologue of the Drosophila discs large tumor suppressor protein (hDLG) through their C-terminal XS/TXV/L (where X represents any amino acid, S/T serine or threonine, and V/L valine or leucine) motif. This finding is similar to the interaction between the adenomatous polyposis coli gene product and hDLG. E6 mutants losing the ability to bind to hDLG are no longer able to induce E6-dependent transformation of rodent cells. These results suggest an intriguing possibility that interaction between the E6 protein and hDLG or other PDZ domain-containing proteins could be an underlying mechanism in the development of HPV-associated cancers.
 ...
PMID:Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. 932 58

Upon activation, cell surface death receptors, Fas/APO-1/CD95 and tumor necrosis factor receptor-1 (TNFR-1), are attached to cytosolic adaptor proteins, which in turn recruit caspase-8 (MACH/FLICE/Mch5) to activate the interleukin-1 beta-converting enzyme (ICE)/CED-3 family protease (caspase) cascade. However, it remains unknown whether these apoptotic proteases are generally involved in apoptosis triggered by other stimuli such as Myc and p53. In this study, we provide lines of evidence that a death protease cascade consisting of caspases and serine proteases plays an essential role in Myc-mediated apoptosis. When Rat-1 fibroblasts stably expressing either s-Myc or c-Myc were induced to undergo apoptosis by serum deprivation, a caspase-3 (CPP32)-like protease activity that cleaves a specific peptide substrate, Ac-DEVD-MCA, appeared in the cell lysates. Induction of s-Myc- and c-Myc-mediated apoptotic cell death was effectively prevented by caspase inhibitors such as Z-Asp-CH2-DCB and Ac-DEVD-CHO. Furthermore, exposing the cells to a serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), also significantly inhibited s-Myc- and c-Myc-mediated apoptosis and the appearance of the caspase-3-like protease activity in vivo. However, AEBSF did not directly inhibit caspase-3-like protease activity in the apoptotic cell lysates in vitro. Together, these results indicate that caspase-3-like proteases play a critical role in both s-Myc- and c-Myc-mediated apoptosis and that caspase-3-like proteases function downstream of the AEBSF-sensitive step in the signaling pathway of Myc-mediated apoptosis.
 ...
PMID:A functional role for death proteases in s-Myc- and c-Myc-mediated apoptosis. 934 38

DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, the oncoprotein MDM2, in vivo and in vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by DNA-PK (or other protein kinases with similar specificity) in response to DNA damage.
 ...
PMID:DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. 936 41

Casein kinase I is a family of serine/threonine protein kinases common to all eukaryotes. In yeast, casein kinase I homologues have been linked to the regulation of growth, DNA repair and cell division. In addition, their subcellular localization to membraneous structures and the nucleus is essential for function. In higher eukaryotes, there exist seven genetically distinct isoforms: (alpha), ss, (gamma)1, (gamma)2, (gamma)3, (delta) and (epsilon). Casein kinase I(alpha) exhibits a cell cycle-dependent subcellular localization including an association with cytosolic vesicular structures and the nucleus during interphase, and the spindle during mitosis. casein kinase I has also been shown to modulate critical regulators of growth and DNA synthesis/repair in mammalian cells such as SV40 large T antigen and p53. These results suggest that casein kinase I may be involved in processes similar to those ascribed to the yeast casein kinase I homologues. To define a role for casein kinase I(alpha) in cell cycle regulation, the mouse oocyte was utilized because of its well-defined cell cycle and ease of micromanipulation. Immunofluorescence studies from meiosis I of maturation to the first zygotic cleavage demonstrated that the kinase was associated with structures similar to those previously reported. Microinjection of casein kinase I(alpha) antibodies at metaphase II-arrest and G2 phase, had no effect on the completion of second meiosis or first division. However, microinjection of these antibodies during the early pronucleate phase prior to S-phase onset blocked uptake of the kinase into pronuclei and interfered with proper and timely cell cycle progression to first cleavage. These results suggest that the kinase regulates the progression from interphase to mitosis during the first cell cycle.
 ...
PMID:A casein kinase I isoform is required for proper cell cycle progression in the fertilized mouse oocyte. 936 78

Thymic epithelial tumours are broadly classified into thymomas and thymic carcinomas. Although both tumours occasionally show invasive growth, they exhibit different clinical and biological findings. The oncogene and anti-oncogene in thymic epithelial tumours have not been evaluated fully. We investigated the expression of p53 protein by immunohistochemical analysis using the anti-p53 polyclonal antibody (CM-1) in 17 thymomas and 19 thymic carcinomas. We also examined p53 gene (exon 5-8) mutation in 18 thymic carcinomas by using polymerase chain reaction-single-strand conformation polymorphism methods and direct sequencing. Of the thymoma cases, only one invasive thymoma showed focal nuclear staining. Fourteen of the 19 thymic carcinomas (74%) showed nuclear staining. Point mutations of the p53 gene were recognized in only 2 of the 18 thymic carcinomas (11%). One was the mutation C to T transition in the first letter of codon 222 in exon 6, which results in the amino acid substitution from proline to serine. Another was a silent mutation. p53 protein accumulation is highly frequent in thymic carcinomas but not in thymomas, and gene mutation is uncommon in thymic carcinomas.
 ...
PMID:High frequency of p53 protein expression in thymic carcinoma but not in thymoma. 937 84

The function of the tumor suppressor protein p53 is modulated by post-translational events, primarily by phosphorylation. p53 is phosphorylated at multiple sites by a variety of protein kinases depending on the cellular environment. It has been suggested that serine 34 of mouse p53 is specifically phosphorylated by a stress-activated protein kinase in response to ultraviolet radiation. Since serine 34 is a major site of phosphorylation of mouse p53 in vivo and its specific protein kinase is still not definitively identified yet, we have examined the c-Jun N-terminal kinase 1 (JNK1) activity on p53 by expressing JNK1 in 293T cells. We show here that activated JNK1 phosphorylates mouse p53 specifically at serine 34 in vitro, while a dominanant-negative JNK1 mutant does not phosphorylate p53. More importantly, JNK1 associates with p53 in vivo, with or without activation, confirming that JNK1 is indeed a p53 kinase. Interestingly, activated JNK2 and JNK3 also phosphorylate serine 34 of mouse p53. Furthermore, JNK2 and JNK3 also associate with p53 in vivo, indicating that not only JNK1, but also JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Phosphorylation of p53 by JNKs may play an important role in nuclear signal transduction in response to environmental stress or tumorigenic agents.
 ...
PMID:JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases. 939 73

Data are presented demonstrating that DNA damage leads to specific post-translational modifications of p53 protein. Using two-dimensional peptide mapping of in vivo radiolabeled p53 tryptic phosphopeptides, recombinant truncated p53 protein, and synthetic p53 tryptic peptides, a unique p53 phosphopeptide was identified after exposure of ML-1 cells to ionizing irradiation. This peptide represents the first 24 amino acids of p53 and contains three phosphorylated serine residues. A specific p53 phosphopeptide antibody identified serine-15 as one of the two serines in p53 that becomes phosphorylated following DNA damage induced by either ionizing irradiation (IR) or ultraviolet (UV) irradiation in multiple cell types. IR-induced phosphorylation of p53 does not affect the kinetics of p53 binding to or dissociating from DNA as assessed by electrophoretic mobility-shift assays. However, p53 phosphorylation induced by DNA damage correlates with enhanced transcription of downstream p53 target genes. Low levels of phosphoserine-15 p53 are detectable within 6 hr after IR in AT cells, whereas lymphoblasts from normal individuals exhibit this modification within 1 hr. In contrast, phosphorylation of p53 on serine-15 is similar in normal and AT cells after UV irradiation. Our results indicate that p53 is phosphorylated in response to DNA damage, that this de novo phosphorylation may be involved in the subsequent induction and activation of p53, and that although ATM affects the kinetics of p53 phosphorylation after IR, it is not absolutely required for phosphorylation of p53 on serine-15.
 ...
PMID:DNA damage induces phosphorylation of the amino terminus of p53. 940 38

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.
 ...
PMID:Fine mapping and regulation of the association of p53 with p34cdc2. 946 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>