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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the importance of oncogenes and tumor suppressor genes in bladder carcinogenesis, we determined the status of the expression of the MDM-2 and p53 genes and genetic alterations in the p53 gene in five bladder carcinoma cell lines and one kidney urothelial carcinoma cell line. Overexpression of MDM-2 mRNA was observed in three bladder carcinoma cell lines, J82, SCaBER, and BFTC-905. Amplification of the MDM-2 gene was not detected in any of the six cell lines by southern analysis. The deletion in the p53 gene was observed in J82, and point mutation was detected in J82 and BFTC-909, the kidney urothelial carcinoma cell line. In contrast, no mutations were found in codons 12, 13, and 61 in the Ha-ras and Ki-ras genes in these six cell lines. These results indicate that alterations in the p53-regulated pathway are important in bladder carcinogenesis.
Mol Carcinog 1995 Jul
PMID:Overexpression of MDM-2 mRNA and mutation of the p53 tumor suppressor gene in bladder carcinoma cell lines. 761 20

To assess the generality of the hypothesis that murine double-minute-2 (MDM-2) gene amplification complements the absence of p53 mutation during tumor development, we analyzed 143 murine tumors induced by a variety of carcinogenic agents in two different mouse strains. Only three of 143 tumors showed p53 genetic alterations and none showed MDM-2 amplification, indicating the existence of alternative pathways that permit tumor cells to bypass p53-MDM-2 control.
Mol Carcinog 1994 Jan
PMID:Absence of MDM-2 gene amplification in experimentally induced tumors regardless of p53 status. 829 84

Wild-type p53 plays a crucial role in the control of apoptosis following ionizing radiation (IR); conversely, mutant p53 is associated with IR resistance. Although wild-type p53 is expressed in virtually all neuroblastoma tumors, treatment failures secondary to inadequate local control with radiotherapy are a problem in patients with advanced stage disease. This apparent paradox is the focus of our interest. The Shep-1 neuroblastoma cell line is highly resistant to IR. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. The induced p53 is functional as p53-responsive genes (Waf-1 and MDM-2) are appropriately induced following IR. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. These findings demonstrate that p53 overexpression renders Shep-1 cells IR-sensitive and suggest that large quantities of exogenous p53 can overcome the factors inhibiting p53-mediated, IR-induced apoptosis.
Mol Genet Metab 1998 Oct
PMID:Role of p53 in the regulation of irradiation-induced apoptosis in neuroblastoma cells. 978 7

Numerous miniature inverted repeat transposable elements (MITEs) are present in the rice genome but their transposition mechanisms are unknown. In this report, we present evidence that two novel MITE families may have arisen from Mutator-related transposable elements and thus may use a transposition mechanism similar to that of Mutator elements. Two families of novel MITEs, namely, MDM-1 and MDM-2, were identified by searching for MITEs nested with Kiddo, a previously identified MITE family. MDM-1 and MDM-2 bear hallmarks of Mutator elements, such as long terminal inverted repeats (LTIRs), 9-bp target-site duplications (TSDs), and putative transposase binding sites. Strikingly, the MDM-1 family has a 9-bp terminus identical to that of a rice Mutator-like element ( MULE-9) and the MDM-2 family has an 8-bp terminus identical to that of the maize autonomous Mutator element MuDR. A putative transposase homologous to MURA protein is identified for the MDM-2 family. Thus, these two novel MITE families, with a total copy number of several hundred in rice, are designated Mutator-derived MITEs ( MDMs). Interestingly, sequence decay analysis of MDM families revealed a number of insertion site duplications (ISDs) in the alignment gaps, and widespread historical nesting events are proposed to account for the existence of these ISDs. In addition to its value for discovering new MITEs, the nesting analysis approach used in this study simultaneously identifies MITE insertion polymorphisms.
J Mol Evol 2003 Mar
PMID:MDM-1 and MDM-2: two mutator-derived MITE families in rice. 1261 29

Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that is caused by a small deletion in the giant elastic muscle protein titin. Homozygous mdm/mdm mice develop a progressive muscular dystrophy, leading to death at approximately 2 months of age. We surveyed the transcriptomes of skeletal muscles from 24 day old homozygous mdm/mdm and +/+ wild-type mice, an age when MDM animals have normal passive and active tensions and sarcomeric structure. Of the 12488 genes surveyed (U74 affymetrix array), 75 genes were twofold to 30-fold differentially expressed, including CARP (cardiac ankyrin repeat protein), ankrd2/Arpp (a CARP-like protein) and MLP (muscle LIM protein), all of which associate with the titin filament system. The four genes most strongly affected (eightfold to 30-fold change) were all members of the CARP-regulated Nkx-2.5-dependent signal pathway, and CARP mRNA level was 30-fold elevated in MDM skeletal muscle tissues. The CARP protein overexpressed in MDM became associated with the I-band region of the sarcomere. The mdm mutation excises the C-terminal portion of titin's N2A region, abolishing its interaction with p94/calpain-3 protease. Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of CARP and loss of p94/calpain-3. These changes were absent from the following control tissues (1). cardiac muscles from homozygous mdm/mdm animals, (2). skeletal and cardiac muscle from heterozygous mdm/+ animals, and (3). dystrophic muscles from MDX mice. Thus, the altered composition of the titin N2A complex is specific for the titin-based skeletal muscular dystrophy in MDM.
J Mol Biol 2004 Feb 06
PMID:Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling. 1474 Dec 10

It has been developed an HIV type 1 transgenic rat model (HIV-1 Tg Rat) which contains a gag-pol-deleted HIV-1 provirus regulated by the viral LTR promoter. Although it harbors a non infectious provirus, efficient viral expression occurs in different tissues and disease manifestations as well as immune-response alterations and pathologies similar to humans can be observed. Regulation of HIV-1 expression is influenced by various cellular factors and it is well known that macrophages are one of the major reservoir of HIV-1 infection and a vehicle for virus spread to other tissues. Purpose of our work was to establish an antigen presenting cells (monocyte-derived macrophages, MDM) ex vivo model from these HIV-1 transgenic rats. This model can be used to study function of HIV-infected MDM and their behavior like HIV-1 reservoir. Ultimately, these studies may be helpful in defining approaches to control HIV-1 spread.
Mol Immunol 2004 Aug
PMID:Establishment of an ex vivo model of monocytes-derived macrophages differentiated from peripheral blood mononuclear cells (PBMCs) from HIV-1 transgenic rats. 1530 60

Abnormal activation of CXCR 4 during inflammatory/infectious states may lead to neuronal dysfunction or damage. The major goal of this study was to determine the coupling of CXCR 4 to p53-dependent survival pathways in primary neurons. Neurons were stimulated with the HIV envelope protein gp120(IIIB) or the endogenous CXCR 4 agonist, SDF-1 alpha. We found that gp120 stimulates p53 activity and induces expression of the p53 pro-apoptotic target Apaf-1 in cultured neurons. Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1. Moreover, gp120 neurotoxicity is markedly reduced by the p53-inhibitor, pifithrin-alpha. The viral protein also regulates p53 phosphorylation and expression of other p53-responsive genes, such as MDM 2 and p21. Conversely, SDF-1 alpha, which can promote neuronal survival, increases p53 acetylation and p21 expression in neurons. Thus, the stimulation of different p53 targets could be instrumental in determining the outcome of CXCR 4 activation on neuronal survival in neuro-inflammatory disorders.
Mol Cell Neurosci 2005 Sep
PMID:Regulation of neuronal P53 activity by CXCR 4. 1600 38

The small-molecule compound pifithrin-alpha (PFT-alpha) has been reported to inhibit p53 function and protect against a variety of genotoxic agents. We show here that PFT-alpha is unstable in tissue culture medium and is rapidly converted to its condensation product PFT-beta. Both compounds showed limited solubility with PFT-alpha precipitating out of tissue culture medium at concentrations >30 micromol/L. PFT-alpha and -beta exhibited cytotoxic effects in vitro towards two human wild-type p53-expressing tumor cell lines, A2780 ovarian and HCT116 colon (IC(50) values for both cell lines were 21.3 +/- 8.1 micromol/L for PFT-alpha and 90.3 +/- 15.5 micromol/L for PFT-beta, mean +/- SD, n = 4). There was no evidence of protection by clonogenic assay with either compound in combination with ionizing radiation. Indeed, there was some evidence that PFT-alpha enhanced cytotoxicity, particularly at higher concentrations of PFT-alpha. Neither compound had any effect on p53, p21, or MDM-2 protein expression following ionizing radiation exposure and there was no evidence of any abrogation of p53-dependent, ionizing radiation-induced cell cycle arrest. Similarly, there was no evidence of cellular protection, or of effects on p53-dependent gene transcription, or on translation of MDM-2 or p21 following UV treatment of these human tumor cell lines. In addition, there was no effect on p53 or p21 gene transactivation or p38 phosphorylation after UV irradiation of NIH-3T3 mouse fibroblasts. In conclusion, neither PFT-alpha nor -beta can be regarded as a ubiquitous inhibitor of p53 function, and caution should be exercised in the use of these agents as specific p53 inhibitors.
Mol Cancer Ther 2005 Sep
PMID:An evaluation of the ability of pifithrin-alpha and -beta to inhibit p53 function in two wild-type p53 human tumor cell lines. 1617 29

Aims-To investigate the immunohistochemical expression of MDM-2 protein in comparison with that of p53 protein in nasopharyngeal carcinomas.Methods-Formalin fixed, paraffin wax embedded tissue from 59 cases of nasopharyngeal carcinoma was stained by immunohistochemistry for MDM-2 and p53 proteins.Results-The tumours were divided histologically into seven cases of keratinising nasopharyngeal carcinoma (KNPC), 14 cases of non-keratinising nasopharyngeal carcinoma (NKNPC), and 38 cases of undifferentiated nasopharyngeal carcinoma (UNPC). MDM-2 nuclear expression was observed in 0/7 KNPC, 1/14 NKNPC, and 11/38 UNPC. p53 nuclear expression was observed in 1/7 KNPC, 2/14 NKNPC, and 15/38 UNPC. Parallel MDM-2 and p53 expression was found in 12 cases (11 UNPC and one NKNPC). Discordant MDM-2-/p53 + expression was found in six cases (four UNPC, one NKNPC, and one KNPC), and absence of expression of both proteins in the remaining 41 cases.Conclusions-Expression of MDM-2 and p53 proteins may be associated with the level of tumour cell differentiation in nasopharyngeal carcinoma. Simultaneous expression of MDM-2/p53 in a proportion of UNPC suggests that MDM-2 protein may be responsible for stabilisation of p53 protein in these cases, in view of the previous demonstration of the p53 gene in germ line configuration. This could be important in the pathogenesis of these cases, since MDM-2 may deregulate the p53 dependent growth suppressive pathway. Discordant MDM-2-/p53 + expression in a few cases of nasopharyngeal carcinoma may reflect stabilisation of p53 protein by other proteins, or p53 mutations unable to activate MDM-2.
Clin Mol Pathol 1995 Dec
PMID:MDM-2 protein expression in nasopharyngeal carcinomas. Comparative study with p53 protein expression. 1669 32

The mussel Mytilus trossulus can develop a neoplasia of the haemolymph, which occurs with high frequency (up to 40%) in nature. Associated with this disease are pro-apoptotic tumor-suppressor protein p53 isoforms, which are highly conserved between molluscs and vertebrates. The vertebrate wildtype p53 protein is maintained at low levels by the MDM2 protein in non-stressed cells to prevent undesired apoptosis. Identification of a putative invertebrate MDM-like homolog suggests early evolution of this mechanism of p53 regulation. The M. trossulus MDM homolog consists of a conserved NH(2)-terminal p53 binding domain, an acidic domain with highly conserved phosphorylation sites, and a highly conserved C-terminal RING-finger Zn-binding domain. Although BLAST queries predict this homologue to be more similar to vertebrate MDM2 than to MDM4, phylogenetic analysis suggests that it may be an ancestral form to both vertebrate MDM genes. Using yeast-two-hybrid assays and pull-down assays, we show that this molluscan MDM is able to bind to its p53 counterpart. We also show that MDM expression levels are directly correlated with p53 expression levels in healthy and in neoplastic haemocytes, but not with other p53 isoforms or with the proto-oncogene RAS. The combination of expression levels of five gene transcripts (p53, mdm, ras, Np63/73, and TAp63/73) is significantly correlated with late-stage haemic neoplasia in M. trossulus.
Comp Biochem Physiol B Biochem Mol Biol 2010 Aug
PMID:An invertebrate mdm homolog interacts with p53 and is differentially expressed together with p53 and ras in neoplastic Mytilus trossulus haemocytes. 2041 99


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