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)

In the recent paper by Takaoka et al. (2003), the authors demonstrate that interferons-alpha and -beta stimulate p53 expression but not p53 activation. The increase in p53 expression translates into significant enhancement of apoptosis and reduction of chemotherapeutic dosages in vitro to destroy tumor cells. Furthermore, viral infections are also modulated by p53 in collaboration with interferons-alpha and -beta. These observations are significant and may lead to new paradigms for therapy if the high doses of interferon necessary to obtain the effects in vitro can be combined with more active interferons, interferons with minimal side effects, and/or novel delivery systems to target interferons directly to tumors.
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PMID:A dance between interferon-alpha/beta and p53 demonstrates collaborations in tumor suppression and antiviral activities. 1295 82

All members of the gamma-herpesvirus family encode genes capable of inhibiting apoptosis. Inhibition of a variety of types of apoptotic stimuli have been demonstrated for specific viral genes, including pathways induced by the immune system as well as internal pathways. Virally encoded genes inhibit the activation of caspase-8 by the TNF receptor and Fas; activate NF-kappaB to increase expression of antiapoptotic genes; inhibit interferon response; bind to p53, thereby blocking p53 dependent apoptosis; and interact with other pro- and antiapoptotic cellular genes. All gamma-herpesviruses also express viral homologues of cellular antiapoptotic genes, including one or two Bcl-2 homologues. The human gamma-herpesviruses encode genes that can inhibit apoptosis during both latent and lytic infection. During latent phase infection inhibition of apoptosis is likely important for persistence of the gamma-herpesviruses in the face of immune attack, but it is also required for maintenance of infected cells in culture. During lytic replication the virus inhibits apoptosis to prevent cell death before viral replication and spread occurs.
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PMID:Inhibition of apoptosis by the gamma-herpesviruses. 1295 51

PML is a tumor suppressor implicated in leukemia and cancer pathogenesis. PML epitomizes a multiprotein nuclear structure, the PML-nuclear body (PML-NB), whose proper formation and function depends on PML. Studies in knockout (KO) mice and cells unraveled an essential pleiotropic role for PML in multiple p53-dependent and -independent apoptotic pathways. As a result, Pml(-/-) mice and cells are protected from apoptosis triggered by a number of stimuli such as ionizing radiation, interferon, ceramide, Fas and TNF. It is becoming apparent that PML and the PML-NB act as molecular hubs for the induction and/or reinforcement of programmed cell death through a selective and dynamic regulation of proapoptotic transcriptional events. In addition, recent observations propose a role for PML in checkpoint responses upon DNA damage. Moreover, PML and the PML-NB have also been implicated in the control of genomic stability and DNA repair. Here, we will discuss the molecular mechanisms by which PML regulates these processes and the implication of these findings for cancer pathogenesis and therapy.
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PMID:Role of PML and the PML-nuclear body in the control of programmed cell death. 1466 83

Identification and characterization of multi-protein complexes is an important step toward an integrative view of protein-protein interaction networks that determine protein function and cell behavior. The limiting factor for identifying protein complexes is the method for their separation. Blue native PAGE (BN-PAGE) permits a high-resolution separation of multi-protein complexes under native conditions. To date, BN-PAGE has only been applicable to purified material. Here, we show that dialysis permits the analysis of multi-protein complexes of whole cellular lysates by BN-PAGE. We visualized different multi-protein complexes by immunoblotting including forms of the eukaryotic proteasome. Complex dynamics after gamma interferon stimulation of cells was studied, and an antibody shift assay was used to detect protein-protein interactions in BN-PAGE. Furthermore, we identified defined protein complexes of various proteins including the tumor suppressor p53 and c-Myc. Finally, we identified multi-protein complexes via mass spectrometry, showing that the method has a wide potential for functional proteomics.
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PMID:Two-dimensional Blue native/SDS gel electrophoresis of multi-protein complexes from whole cellular lysates: a proteomics approach. 1466 81

Hepatitis C virus (HCV) is a major etiologic agent for chronic hepatitis worldwide often leading to the development of cirrhosis and hepatocellular carcinoma. However, the mechanism for development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. HCV NS5A protein possesses many intriguing properties, including sequestration of p53 in the cytoplasm, downregulation of p21 protein, activation of STAT3, and inhibition of tumor necrosis factor-alpha-mediated apoptosis. Thus, we investigated whether this viral protein has oncogenic property in vivo. In the absence of an efficient cell culture system for virus growth and a suitable small animal model for HCV infection, transgenic FVB mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter or mouse major urinary promoter (MUP). The apoE promoter is constitutively expressed in liver, on the other hand, the MUP is developmentally regulated and expressed in the liver after birth. Reverse transcription polymerase chain reaction and Western blot analysis indicated establishment of HCV NS5A transgene expression in several lines from both groups of mice. Immunohistochemical studies suggested the presence of NS5A in the cytoplasm of hepatocytes. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a major histological change within the liver up to 24 months of age. Our results suggested HCV NS5A protein is not directly cytopathic or oncogenic in this FVB transgenic mouse model, although this viral protein promotes cell growth in vitro. These animals will be a valuable model of HCV immunopathology as well as for evaluation of siRNA, interferon and other cytokine therapies.
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PMID:Expression of hepatitis C virus non-structural 5A protein in the liver of transgenic mice. 1467 68

The interferon-inducible p200 (IFI-200) family of proteins is among the numerous gene products induced by interferons (IFNs), which are important regulators of cell growth, immunomodulation and host resistance to tumors and viral infections. The members of this family of proteins are highly homologous to one another and consist of five murine proteins including p202, p203, p204 and p205 as well as three human homologues; IFI-16, myeloid cell nuclear differentiation antigen (MNDA) and absent in melanoma (AIM) 2. They possess at least one copy of a conserved 200 amino-acid motif which exists in two types; the a and b domains. Most of the IFI-200 proteins also possess a domain in apoptosis and interferon response (DAPIN)/PYRIN domain, which is a conserved motif associated with protein-protein interactions in the regulation of apoptotic and inflammatory signaling pathways. The p200 proteins have been implicated in cell cycle regulation and differentiation based on their ability to interact with and modulate the activities of multiple transcriptional factors such as Rb and p53, and there are significant findings that link mutations in their genetic loci to the incidence of cancer. Here, we describe the structure and biological activities of these proteins, and discuss recent studies that describe their relevant roles in processes regulating cell proliferation and differentiation.
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PMID:The interferon-inducible p200 family of proteins: a perspective on their roles in cell cycle regulation and differentiation. 1475 31

Phage-peptide display is a versatile tool for identifying novel protein-protein interfaces. Our previous work highlighted the selection of phage-peptides that bind to specific isoforms of MDM2 protein and in this work we subjected the putative MDM2-binding proteins to phage-peptide display to expand further on putative protein interaction maps. One peptide that bound MDM2 had significant homology to members of the death-activated protein kinase (DAPK) family, an enzyme family of no known direct link to the p53 pathway. We examined whether a nuclear member of the DAPK family named DAPK3 or ZIP kinase had direct links to the p53 pathway. ZIP kinase was cloned, purified, and the enzyme was able to phosphorylate MDM2 at Ser166, a site previously reported to be modified by Akt kinase, thus demonstrating that ZIP kinase is a bona fide MDM2-binding protein. Native ZIP kinase fractions were then subjected to phage-peptide display and one ZIP kinase consensus peptide motif was identified in p21(WAF1). ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. Thus, although ZIP kinase consensus sites were then defined as containing a minimal RKKx(T/S) consensus motif, alternate contacts in ZIP kinase binding are implicated, since amino acid residues surrounding the phospho-acceptor site can effect the specific activity of the kinase. Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1), while the half-life of p21(WAF1[T145A]) is not effected by ZIP kinase. Thus, phage-peptide display identified an interferon-responsive protein kinase family as a novel modifier of two components of the p53 pathway, MDM2 and p21(WAF1), and underscores the utility of phage-peptide display for gaining novel insights into biochemical pathways.
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PMID:Phage-peptide display identifies the interferon-responsive, death-activated protein kinase family as a novel modifier of MDM2 and p21WAF1. 1500 56

DNA extracted from the skeletons of five equids discovered in a Pompeii stable and of a horse found in Herculaneum was investigated. Amino acid racemization level was consistent with the presence of DNA. Post-mortem base modifications were excluded by sequencing a 146 bp fragment of the 16S rRNA mitochondrial gene. Sequencing of a 370 bp fragment of mitochondrial (mt)DNA control region allowed the construction of a phylogenetic tree that, along with sequencing of nuclear genes (epsilon globin, gamma interferon, and p53) fragments, gave us the possibility to address some questions puzzling archaeologists. What animals-donkeys, horses, or crossbreeds-were they? And, given they had been evidently assigned to one specific job, were they all akin or were they animals with different mitochondrial haplotypes? The conclusions provided by molecular analysis show that the Pompeii remains are those of horses and mules. Furthermore one of the equids (CAV5) seems to belong to a haplotype, which is either not yet documented in the GenBank or has since disappeared. As its characteristics closely recall those of donkeys, which is the out group chosen to construct the tree, that appears to have evolved within the Equidae family much earlier than horses, this assumption seems to be nearer the truth.
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PMID:Genetic characterization of Pompeii and Herculaneum Equidae buried by Vesuvius in 79 AD. 1504 2

The ATM protein, which is mutated in the inherited disease ataxia telangiectasia (AT), is a key regulator of the cells' DNA damage response. AT cells also exhibit constitutive activation of transcriptional regulators such as p53, E2F, AP1, and NFkappaB. Inactivation of ATM may therefore alter the cells' transcriptional profile. ATM expression in HeLa cells was silenced with siRNA expressed from a plasmid based vector, generating a stable cell line, HeLaATM601. HeLaATM601 cells displayed minimal levels of ATM protein and had a 10-fold increase in sensitivity to ionizing radiation. DNA microarray analysis demonstrated that 35 genes were upregulated and five genes were downregulated in HeLaATM601 cells. Genes upregulated in the absence of ATM included interferon-response proteins, cell cycle regulators, integral membrane proteins, and adhesion and extracellular matrix proteins. Using real-time PCR, these genes were also upregulated in cells derived from AT patients. Inactivation of the ATM protein therefore has a significant impact on the transcriptional profile of the cell.
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PMID:Stable siRNA-mediated silencing of ATM alters the transcriptional profile of HeLa cells. 1509 73

We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXalpha1, alpha2, beta1, beta2, gamma1, and gamma2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXalpha and IFIXbeta, IFIXgamma isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXalpha1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchorage-dependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXalpha1 gene transfer suppressed the growth of already-formed tumors in a breast cancer xenograft model. IFIXalpha1 appears to suppress the growth of breast cancer cells in a pRB- and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21(CIP1), which leads to the reduction of the kinase activity of both Cdk2 and p34(Cdc2). Together, our results show that IFIXalpha1 possesses a tumor-suppressor activity and suggest IFIXalpha1 may be used as a therapeutic agent in cancer treatment.
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PMID:Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer. 1512 30


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