Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 is inactivated by overexpression of MDM2 in about 10% of human tumors. However, p53 is inactivated by other mechanisms in the majority of tumors, raising the possibility that MDM2 may be irrelevant to transformation in most cases. However, MDM2 has been reported to have p53-independent functions, in cell cycle control, differentiation, cell fate determination, DNA repair, basal transcription, and other processes. Furthermore, MDM2 appears to contribute to the transformed phenotype in the absence of wild-type p53. Nevertheless, the number of studies is still limited, and the evidence in some cases does not unequivocally show that the functions are p53 independent. We will discuss the circuits of regulation involving MDM2 that do not directly concern p53. Hopefully, future work will consolidate our understanding of the p53-independent pathological functions of MDM2 and will lead to useful therapeutic interventions that target the majority of tumors.
Mol Cancer Res 2003 Dec
PMID:p53-independent functions of MDM2. 1470 86

We have used NMR to study the effects of peptide binding on the N-terminal p53-binding domain of human MDM2 (residues 25-109). There were changes in HSQC-chemical shifts throughout the domain on binding four different p53-derived peptide ligands that were significantly large to be indicative of global conformational changes. Large changes in chemical shift were observed in two main regions: the peptide-binding cleft that directly binds the p53 ligands; and the hinge regions connecting the beta-sheet and alpha-helical structures that form the binding cleft. These conformational changes reflect the adaptation of the cleft on binding peptide ligands that differ in length and amino acid composition. Different ligands may induce different conformational transitions in MDM2 that could be responsible for its function. The dynamic nature of MDM2 might be important in the design of anti-cancer drugs that are targeted to its p53-binding site.
J Mol Biol 2004 Feb 06
PMID:Binding of p53-derived ligands to MDM2 induces a variety of long range conformational changes. 1474 Dec 15

To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1-3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2-3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser(46) in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser(46) is involved in p53-dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.
Mol Cancer Ther 2004 Jan
PMID:Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo. 1474 79

The cellular stress response pathway regulated by the p53 tumor suppressor is critical to the maintenance of genomic integrity and to the prevention of oncogenic transformation. Intracellular levels of p53 are tightly regulated by an autoregulatory feedback loop comprised of p53 and MDM2. It might be predicted that disruption of this loop, either through p53 mutation or overexpression of MDM2, would be a negative prognostic marker for cancer development, likelihood of relapse, or response to therapy. In fact, although MDM2 overexpression is common in cancer, it can be both a positive and a negative predictor of outcome in different tumors, and its significance as a biomarker remains controversial. Data from a number of different tumor types are reviewed for the predictive significance of MDM2 expression, along with evidence for different mechanisms of MDM2 overexpression in these different tumors. In light of the biological complexities underlying the p53-MDM2 loop, it is, perhaps, not surprising that no simple paradigm exists that is generally applicable. Much work remains to be done to elucidate the basic mechanisms underlying the physical interactions between the two proteins, the role of protein modifications in altering those interactions, and also the genetic and transcriptional deregulations by which protein levels are altered in human cancers. Only in this way will truly biologically relevant predictive factors emerge.
Mol Cancer Res 2004 Jan
PMID:MDM2 and prognosis. 1475 40

MDM2 inhibits p53 transcriptional activity, favors its nuclear export, and stimulates its degradation. Inhibition of the p53-MDM2 interaction with synthetic molecules should therefore lead to both the nuclear accumulation and the activation of p53 followed by the death of the tumor cells from apoptosis. Inhibitors of the p53-MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type p53 in tumors. This review describes our current knowledge on the properties of the existing p53-MDM2 antagonists. Because the discovery of modulators of protein-protein interactions is an emerging field in drug discovery, the strategy used for designing inhibitors of the p53-MDM2 interaction could serve as an example for other protein interfaces.
Mol Cancer Res 2004 Jan
PMID:Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface. 1475 42

Alternative splicing has an important role in expanding protein diversity. An example of a gene with more than one transcript is the MDM2 oncogene. To date, more than 40 different splice variants have been isolated from both tumor and normal tissues. Here, we review what is known about the alteration of MDM2 mRNA expression, focusing on alternative splicing and potential functions of different MDM2 isoforms. We also discuss the progress that has been made in the development of antisense oligonucleotides targeted to MDM2 for use as a potential cancer therapy.
Mol Cancer Res 2004 Jan
PMID:MDM2 and its splice variant messenger RNAs: expression in tumors and down-regulation using antisense oligonucleotides. 1475 43

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.
J Mol Biol 2004 Mar 12
PMID:Phage-peptide display identifies the interferon-responsive, death-activated protein kinase family as a novel modifier of MDM2 and p21WAF1. 1500 56

Expanding on the possible protein interaction partners in a biochemical pathway is one key molecular goal in the post-genomic era. Phage peptide display is a versatile in vitro tool for mapping novel protein-protein interfaces and the advantage of this technique in expanding protein interaction maps is that in vitro manipulation of the bait protein conformational integrity can be controlled carefully. Phage peptide display was used to expand on the possible types of binding proteins for the conformationally responsive protein MDM2. Peptides enriched differ depending upon whether MDM2 is ligand-free, zinc-bound, or RNA-bound, suggesting that MDM2 conformational changes alter the type of peptide ligands enriched. Classes of putative/established MDM2-binding proteins identified by this technique included ubiquitin-modifying enzymes (F-box proteins, UB-ligases, UBC-E1) and apoptotic modifiers (HSP90, GAS1, APAF1, p53). Of the many putative MDM2 proteins that could be examined, the impact of HSP90 on MDM2 activity was studied, since HSP90 has been linked with p53 protein unfolding in human cancers. Zinc ions were required to reconstitute a stable MDM2-HSP90 protein complex. Zinc binding converted MDM2 from a monomer to an oligomer, and activated MDM2 binding to its internal RING finger domain, providing evidence for a conformational change in MDM2 protein when it binds zinc. Reconstitution of an HSP90-MDM2 protein complex in vitro stimulated the unfolding of the p53 tetramer. A p53 DNA-binding inhibitor purified from human cells that is capable of unfolding p53 at ambient temperature in vitro contains co-purifying pools of HSP90 and MDM2. These data highlight the utility of phage peptide display as a powerful in vitro method to identify regulatory proteins that bind to a conformationally flexible protein like MDM2.
J Mol Biol 2004 Mar 12
PMID:Expansion of protein interaction maps by phage peptide display using MDM2 as a prototypical conformationally flexible target protein. 1500 57

Osteosarcoma (OS) displays complex karyotypes with numerical changes as well as structural abnormalities suggesting that several oncogenes and tumor suppressor genes may be implicated in the biology of OS. The aim of our study was to investigate the possible implication of the molecular alterations of the G1 to S-phase checkpoint genes in the pathogenesis of OS. We analyzed samples from 29 patients and found molecular alterations of the RB and TP53 genes in 6 (21%) and 3 (10%) cases, respectively. Homozygous deletion of the INK4A/ARF locus and methylation of INK4A was detected in 3 (10%) and 2 (7%) cases, respectively. CDK4 and MDM2 co-amplification was observed in 1 case (3%). Cyclin D3 is differentially expressed in a greater proportion than D1- and D2-type cyclins. Cytogenetically, all cases had complex karyotypes being especially significant the losses of the chromosomes 4, 13, and 17. As a whole, 11 of 29 (38%) analyzed OS presented alterations in some of the analyzed G1 to S-phase checkpoint genes. These alterations were more frequently present in adults (P = 0.032). All patients with genetic alterations in the G1/S-phase checkpoint died during their clinical follow-up, whereas more than 53% of the remaining cases were alive in this period (P = 0.007). Hence, in the pathogenesis of human OS, deregulation of the G1/S checkpoint genes, especially RB, TP53, and INK4/ARF locus, plays an important role and defines a subgroup of patients with a poor outcome.
Diagn Mol Pathol 2004 Jun
PMID:Deregulation of the G1 to S-phase cell cycle checkpoint is involved in the pathogenesis of human osteosarcoma. 1516 9

This report describes a 49-year-old woman with a well-circumscribed nodule of liposarcoma. The patient noticed a soft, slowly growing mass at the right sural region. Both axial computed tomography and magnetic resonance imaging revealed a soft tissue tumor consisting of nonfatty lesion measuring 5 x 3 x 3 cm circumscribed by a 1-cm thickened fatty area. Histologically, the tumor was made of 2 distinct components: the inner component of the tumor was a classic myxoid liposarcoma with numerous lipoblasts; the outer component was a lipoma-like lesion consisting of mature adipocytes without atypical nuclei. Immunohistochemically, MDM2 overexpression was observed and p53 immunophenotype was negative in both components. Molecular analysis revealed that type 1 TLS/ CHOP fusion gene transcript, characteristic of myxoid/round cell liposarcoma, was detected in both areas.
Diagn Mol Pathol 2004 Jun
PMID:Myxoid liposarcoma with adipocytic maturation: detection of TLS/CHOP fusion gene transcript. 1516 10


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