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)

We now understand neoplastic transformation to be the consequence of multiple acquired genetic alterations. The combination of these acquired changes confer the various phenotypes that constitute the clinical features of cancer. Although only rare human cancers derive from a viral etiology, the study of DNA tumor viruses that transform rodent and human cells has led to a greater understanding of the molecular events that program the malignant state. In particular, investigation of the viral oncoproteins specified by the Simian Virus 40 Early Region (SV40 ER) has revealed critical host cell pathways, whose perturbation play an essential role in the experimental transformation of mammalian cells. Recent work has re-investigated the roles of two SV40 ER oncoproteins, the large T antigen (LT) and the small t antigen (ST), in human cell transformation. Co-expression of these two oncoproteins, together with the telomerase catalytic subunit, hTERT, and an oncogenic version of the H-Ras oncoprotein, suffices to transform human cells. LT inactivates two key tumor suppressor pathways by binding to the retinoblastoma protein (pRB) and p53. The ability of ST to transform human cells requires interactions with PP2A, an abundant family of serine-threonine phosphatases. Here we review recent developments in our understanding of how these two viral oncoproteins facilitate human cell transformation.
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PMID:SV40 early region oncoproteins and human cell transformation. 1264 5

Electrospray tandem mass spectrometry (ESI-MS/MS) was combined with biomolecular interaction analysis (BIA) to develop a method of direct protein identification after real-time analysis of protein protein interactions. Using this method, called BIA-MS/MS, we detected multiple p53-interacting proteins in whole tissue extracts from human placenta and liver. Peptide sequencing revealed three proteins whose interaction with p53 had not been previously reported: a cyclin-dependent kinase inhibitor p57/Kip2, a serine/threonine protein phosphatase PP1C, and hemoglobin. Using our system, unambiguous sequence information can be obtained at the femto- to picomole level after repeating the recovery procedure five times. Furthermore, the association and dissociation constants are easily determined by kinetic analysis. This system provides a powerful tool for analyzing complex biological materials in a simple but highly specific and sensitive manner.
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PMID:Identification of novel p53-binding proteins by biomolecular interaction analysis combined with tandem mass spectrometry. 1266 91

p53 has a role in many cellular processes through the transcriptional regulation of target genes. PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases. Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter. PAC1 transcription is induced in response to serum deprivation and oxidative stress, which results in p53-dependent apoptosis, but not in response to gamma-irradiation, which causes cell cycle arrest. Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation. Moreover, activation of p53 significantly inhibits MAP kinase activity. We conclude that, under specific stress conditions, p53 regulates transcription of PAC1 through a new p53-binding site, and that PAC1 is necessary and sufficient for p53-mediated apoptosis. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes.
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PMID:PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. 1267 51

p73 transcription factors are members of the p53 family and participate in developmental processes and DNA damage response. p73 expression was shown to be regulated during the cell cycle, suggesting that p73 might play a role in cell growth and might be a target for cyclin-dependent kinases. Consistent with this hypothesis, we discovered that p73 interacts physically with various cyclins (A, B, D, and E). Furthermore, cyclin A/CDK1/2, cyclin B/CDK1/2, and cyclin E/CDK2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. A specific antibody directed against phosphorylated Thr86 showed that this site is phosphorylated in vivo and that such phosphorylation is regulated in a cell cycle-dependent manner. Thr86 phosphorylation is induced during S phase and is maximal in the G2/M phase. Accordingly inhibitors of cell growth, such as p16 and serum starvation, reduce Thr86 phosphorylation. Finally, we found that cyclin-dependent kinase (CDK)-dependent Thr86 phosphorylation represses the ability of p73 to induce endogenous p21 expression. Our results demonstrate that p73 proteins are targets of CDK complexes and that phosphorylation on Thr86 by CDKs regulates p73 functions.
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PMID:Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73. 1267 26

Curcumin, an active yellow pigment of turmeric and curry, possesses anti-inflammatory, antioxidative and anticarcinogenic properties. Analysis of its structure revealed the presence of beta-diketone moiety and phenolic hydroxy groups that were believed to contribute to antioxidation. And vanillin, ferulic acid and a dimer of curcumin were identified as the curcumin-derived radical reaction products. In addition to antioxidation, curcumin could also induce apoptosis by targeting mitochondria, affecting p53-related signaling and blocking NF-kappaB activation. To further dissect its anticarcinogenic mechanisms, a number of curcumin targets were identified. These included the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine/threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine kinases. This review will summarize our current knowledge on how these important proteins are affected by curcumin, and hopefully, may provide a whole picture illustrating how the chemopreventive and antitumorigenic effect of curcumin is achieved.
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PMID:The molecular mechanisms for the antitumorigenic effect of curcumin. 1267 37

PLK (polo-like kinase), the human counterpart of polo in Drosophila melanogaster and of CDC5 in Saccharomyces cerevisiae, belongs to a family of serine/threonine kinases. It is intimately involved in spindle formation and chromosome segregation during mitosis. The purpose of this study was to determine whether PLK1 is overexpressed in primary colorectal cancer specimens as compared with normal colon mucosa and to assess its relation to other kinases as a potential new tumor marker. In the present study, immunohistochemical analyses were performed of PLK1 expression in 78 primary colorectal cancers as well as 15 normal colorectal specimens. Furthermore, we examined the relationship between other kinases, Aurora-A and Aurora-C, and PLK1 expression. In normal colon mucosa, some crypt cells showed weakly positive staining for PLK1 in 13 out of 15 cases, the remaining cases being negative. Elevated expression of PLK1 was observed in 57 (73.1%) of the colorectal cancers, statistically significant associations being evident with pT (primary tumor invasion) (P=0.0006, Mann-Whitney U test), pN (regional lymph nodes) (P=0.008, chi2 test) and the Dukes' classification (P=0.0005, Mann-Whitney U test). Mean proliferating cell nuclear antigen-labeling index was 52.3%, with a range of 24.1% to 77.3%. Values for lesions with high and low PLK1 expression were 54.7+/-10.3% (mean+/-SD) and 45.9+/-11.9% (P=0.002, Student's t test). PLK1 was significantly associated with Aurora-A, but PLK1 staining was more diffuse and extensive than for Aurora-A or Aurora-C. Interestingly, PLK1 overexpression was significantly associated with p53 accumulation in colorectal cancers. Our results suggest overexpression of PLK1 might be of pathogenic, prognostic and proliferative importance, so that this kinase might have potential as a new tumor marker for colorectal cancers.
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PMID:Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. 1270 89

Aurora kinases representing a novel family of serine/threonine kinases have been identified as key regulators of the mitotic cell division process. The three members of this kinase family, identified so far, referred to as Aurora-A, Aurora-B and Aurora-C kinases, are close homologues of the prototypic yeast Ipll and Drosophila aurora kinases, which are known to be involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation processes. All three members of the mammalian kinase family have a catalytic domain that is highly conserved with a short C-terminal domain and an N-terminal domain of varying sizes. Following their discovery about five years ago, extensive research has focused on understanding the biological roles of these kinases and elucidation of their pathways, which regulate cell proliferation and maintenance of normal cellular phenotypes. Significant interest in the subject was generated since all three Aurora kinases family members were reported to be overexpressed in many human cancers, and elevated expression has been correlated with chromosomal instability and clinically aggressive disease in some instances. Ectopic overexpression of one member of the family, Aurora-A, was shown to induce oncogenic transformation in cells. Unlike most other putative oncogenes identified, so far, members of this kinase family are expressed and active at the highest level during G2-M phase of the cell cycle. Aurora kinases are localized at the centrosomes of interphase cells, at the poles of the bipolar spindle and in the midbody of the mitotic apparatus. Substrates identified for the Aurora-A and Aurora-B kinases, include a kinesin-like motor protein, spindle apparatus proteins, histone H3 protein, kinetochore protein and the tumor suppressor protein p53. Identification of Aurora kinases as RasGAP Src homology 3 domain binding protein, also implicates these kinases as potential effectors in the Ras pathway relevant to oncogenesis. Abnormal elevated expression of Aurora kinases detected in human cancer cells could help explain the underlying biological mechanisms responsible for the development of many cellular phenotypes associated with malignant cells. Identification of these mechanisms offers the possibility of designing novel targeted therapies for cancer in the future.
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PMID:The Aurora kinases: role in cell transformation and tumorigenesis. 1288 18

Dual-specificity phosphatase 5 (DUSP5), a VH1-like enzyme that hydrolyses nuclear substrates phosphorylated on both tyrosine and serine/threonine residues, has a potential role in deactivation of mitogen- or stress-activated protein kinases. Using cDNA-microarray technology, we found that the expression of DUSP5 mRNA was dramatically increased by exogenous p53 in U373MG, a p53-mutant glioblastoma cell line. Transcription of DUSP5 was also remarkably activated by endogenous p53 in response to DNA damage in colon-cancer cells (p53+/+) that contained wild-type p53, but not in p53-/- cells. Chromatin-immunoprecipitation (ChIP) and reporter assays demonstrated that endogenous p53 protein would bind directly to the promoter region of the DUSP5 gene, implying p53-dependent transcriptional activity. Overexpression of DUSP5 suppressed the growth of several types of human cancer cells, in which Erk1/2 was significantly dephosphorylated. If, as the results suggest, DUSP5 is a direct target of p53, it represents a novel mechanism by which p53 might negatively regulate cell-cycle progression by downregulating mitogen- or stress-activated protein kinases.
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PMID:Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. 1294 6

HIPK2 is a member of a novel family of nuclear serine-threonine kinases identified through their ability to interact with the Nkx-1.2 homeoprotein. The physiological role of these kinases is largely unknown, but we have recently reported on the involvement of HIPK2 in the induction of apoptosis of tumor cells after UV stress through p53 phosphorylation and transcriptional activation. Here, we demonstrate that the chemotherapeutic drug cisplatin increases HIPK2 protein expression and its kinase activity, and that HIPK2 is involved in cisplatin-dependent apoptosis. Indeed, induction of HIPK2 and of cell death by cisplatin are efficiently inhibited by the serine-threonine kinase inhibitor SB203580 or the transduction of HIPK2-specific RNA-interfering molecules. HIPK2 gene silencing efficiently reduces the p53-mediated transcriptional activation of apoptotic gene promoters as well as apoptotic cell death after treatment with cisplatin. These findings, along with the involvement of p53 phosphorylation at serine 46 (Ser46) in the transcriptional activation of apoptotic gene promoters, suggest a critical role for HIPK2 in triggering p53-dependent apoptosis in response to the antineoplastic drug cisplatin.
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PMID:Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. 1472 69

Alkylphospholipids (ALKs) are a novel class of antitumor agents with an unknown mechanism of action. The first ALK tested in the clinic, miltefosine, has been approved recently in Europe for the local treatment of patients with cutaneous metastasis. Perifosine, the only available oral ALK, is being studied currently in human cancer clinical trials. We have shown previously that perifosine induces p21(waf1/cip1) in a p53-independent fashion and that induction of p21(waf1/cip1) is required for the perifosine-induced cell cycle arrest because cell lines lacking p21(waf1/cip1) are refractory to perifosine. In this report, we investigated the mechanism by which perifosine induces p21(waf1/cip1) protein expression. We observed that perifosine induces the accumulation of p21(waf1/cip1) mRNA without affecting p21(waf1/cip1) mRNA stability. Using several p21(waf1/cip1) promoter-driven luciferase reporter plasmids, we observed that perifosine activates the 2.4-kb full-length p21(waf1/cip1) promoter as well as a p21 promoter construct lacking p53-binding sites, suggesting that perifosine activates the p21(waf1/cip1) promoter independent of p53. The minimal p21 promoter region required for perifosine-induced p21 promoter activation contains four consensus Sp1-binding sites. Mutations in each particular Sp1 site block perifosine-induced p21(waf1/cip1) expression. Moreover, we showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. These results represent a novel mechanism by which alkylphospholipids modulate transcription, and may contribute to the discovery of new signal transduction pathways crucial for normal and neoplastic cell cycle control.
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PMID:Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1. 1474 93


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