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 gene p53 encodes a transcriptional activator of genes involved in growth arrest, DNA repair and apoptosis. Loss of p53 function contributes to tumour development in vivo. The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product. Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumour development. To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 and p53 and obtained progeny homozygous for both p53 and mdm2 null alleles. Rescue of the mdm2-/- lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.
 ...
PMID:Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. 747 26

The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells. Overexpression of Mdm2 can immortalize primary cultures of rodent fibroblasts. Human MDM2 is amplified in 30-40% of sarcomas, and is overexpressed in leukaemic cells. The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53-mediated transregulation of gene expression. Because Mdm2 expression increases in response to p53, Mdm2-p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell. We have created Mdm2-null and Mdm2/p53-null mice to determine whether Mdm2 possesses developmental functions in addition to the ability to complex with p53, and to investigate the biological role of Mdm2-p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 and p53 develop normally and are viable. These results suggest that a critical role of Mdm2 in development is the regulation of p53 function.
 ...
PMID:Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. 747 27

Cellular responses following DNA damage are ubiquitous in the biological world. In response to DNA damage, cell cycle checkpoints are activated, which delay cell cycle progression and most likely serve to allow time for repair. One important checkpoint in mammalian cells, activated in the G1 phase of the cell cycle, is dependent on the p53 tumor suppressor gene product. While p53 is responsible for inducing G1 arrest, the product of the MDM2 gene is believed to alleviate the arrest, allowing continuation of the cell cycle after a transient delay. Inasmuch as MDM2 and WAF1/CIP1 are transactivated by p53, while MDM2 binds to and modulates the activity of p53, a "feedback loop" is thus created. This pathway has been highly conserved in mammalian cells, but its presence outside of vertebrates is unknown. By using human MDM2 and WAF1/CIP1 cDNA probes, and monoclonal antibodies to p53 and Mdm2, we demonstrate in insect cell lines evidence for the existence of p53-, MDM2-, and WAF1/CIP1-like molecules and a p53-regulated pathway following treatment by DNA-damaging agents.
 ...
PMID:Induction of p53-, MDM2-, and WAF1/CIP1-like molecules in insect cells by DNA-damaging agents. 769 55

Inactivation of tumour-suppressor genes leads to deregulated cell proliferation and is a key factor in human tumorigenesis. Both p53 and retinoblastoma genes are frequently mutated in human cancers, and the simultaneous inactivation of RB and p53 is frequently observed in a variety of naturally occurring human tumours. Furthermore, three distinct DNA tumour virus groups--papovaviruses, adenoviruses and human papillomaviruses--transform cells by targeting and inactivating certain functions of both the p53 and retinoblastoma proteins. The cellular oncoprotein, Mdm2, binds to and downmodulates p53 function; its human homologue, MDM2, is amplified in certain human tumours, including sarcomas and gliomas. Overproduction of Mdm2 is both tumorigenic and capable of immortalizing primary rat embryo fibroblasts. Here we show that MDM2 interacts physically and functionally with pRB and, as with p53, inhibits pRB growth regulatory function. Therefore, both pRB and p53 can be subjected to negative regulation by the product of a single cellular protooncogene.
 ...
PMID:Interaction between the retinoblastoma protein and the oncoprotein MDM2. 779 4

The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.
 ...
PMID:The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia. 792 16

Loss of or mutations in p53 protein have been shown to decrease both radio- and chemosensitivity. The present study assessed the p53 gene status, ability to arrest in G1 of the cell cycle, the functionality of the p53 transduction pathway, and apoptosis following treatment with radiation in a series of drug-resistant human breast cancer cells to determine whether p53 alterations occur during the development of drug resistance. We used 13 sublines derived from MCF-7, ZR75B, and T47D cells, which were resistant to doxorubicin, paclitaxel, vinblastine, cisplatin, etoposide, and amsacrine. Eleven of 12 drug-resistant sublines retained the parental p53 gene status, as determined by sequence analysis and functional yeast assay; only one subline was found to have acquired a mutation in the p53 gene. The MCF-7 TH subline was found to both acquire mutated p53 and to have major changes in p53 protein expression and function. In 12 other drug-resistant sublines, the G1 checkpoint was conserved or only slightly impaired. A normal accumulation of p53, p21Cip1/Waf1, and Mdm2 proteins and hypophosphorylation of Rb protein occurred in response to radiation with only small differences noted in the kinetics of p53 and p21Cip1/Waf1 induction. Increased susceptibility to apoptosis was found in the ZR75B drug-resistant sublines, whereas no evidence for apoptosis was observed in the ZR75B, MCF-7, and T47D parentals and the MCF-7 and T47D drug-resistant sublines. This effect could not be explained by alterations in bcl-2 or bax expression. Our results demonstrate that alterations in: (a) p53 gene status; (b) ability to arrest in G1; (c) induction of p53 protein and p53-dependent genes; and (d) decreased activation of apoptosis is not a requirement for the onset of drug resistance. The function of p53 appears to be dissociated from drug resistance in our model system.
 ...
PMID:Normal p53 status and function despite the development of drug resistance in human breast cancer cells. 856 78

The p53 tumour-suppressor guards the genome in response to genotoxic stress by transcriptional regulation of genes involved in cell-cycle control, DNA replication, repair and apoptosis such as p21, GADD45, bax and mdm2 (Cox and Lane, 1995). Mdm2 is classically considered to be an inhibitor of p53, that forms an auto-regulatory loop (Momand et al., 1992; Oliner et al., 1993; Wu et al., 1993; Chen et al., 1994; Chen and Levine, 1995). It immortalises cells containing wild type p53 and transforms them together with Ras (Finlay, 1993). We show that, in the absence of p53, mdm2 confers a growth advantage to cells (i.e. "transforms" them) and can overcome a G1 cell-cycl arrest induced by p107, a member of the pRb tumour-suppressor family (Adams and Kaelin, 1995). The minimum "transforming" and p107 inhibiting region of Mdm2 corresponds to its p53 binding domain. p53 inhibits transformation by Mdm2, apparently without requiring transcription. p53 can be considered to be a suppressor of Mdm2, a positive effector of the cell cycle. Mdm2 over-expression in tumours is reminiscent of p53 mutations with gain of function, in that Mdm2 both transforms cells and inhibits p53 activity.
 ...
PMID:MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. 857 Jan 97

The effect of excess mdm2 on p53-mediated apoptosis was investigated in two human-derived cell lines, H1299 and HeLa. In H1299 cells, overexpression of mdm2 resulted in effective protection from apoptosis. This protective effect was seen only under conditions allowing the formation of p53-Mdm2 complexes. In contrast, excess mdm2 failed to abolish p53-mediated apoptosis in HeLa cells, despite a complete abrogation of p53-dependent sequence-specific transcriptional activation (SST). These data strongly support the contention that SST is dispensable for at least some types of p53-mediated apoptosis. Further, they suggest that one of the roles of mdm2 may be to modulate the apoptotic activity of p53, in a manner which is dictated by the pathway through which p53 induced apoptosis in a given cell type
 ...
PMID:Cell type-specific inhibition of p53-mediated apoptosis by mdm2. 861 83

The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression. Recently, Mdm2 has been found to bind several other proteins that function to regulate cell cycle progression, including the E2F-1/DP1 transcription factor complex and the retinoblastoma tumor-suppressor protein. To determine whether Mdm2 plays a role in cell cycle control or tumorigenesis that is distinct from its ability to modulate p53 function, we have examined and compared both the in vitro growth characteristics of p53-deficient and Mdm2/p53-deficient fibroblasts, and the rate and spectrum of tumor formation in p53-deficient and Mdm2/p53-deficient mice. We find no difference between p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts either in their rate of proliferation in culture or in their survival frequency when treated with various genotoxic agents. Cell cycle studies indicate no difference in the ability of the two cell populations to enter S phase when treated with DNA-damaging agents or nucleotide antimetabolites, and p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts exhibit the same rate of spontaneous immortalization following long-term passage in culture. Finally, p53-deficient mice and Mdm2/p53-deficient mice display the same incidence and spectrum of spontaneous tumor formation in vivo. These results demonstrate that deletion of Mdm2 has no additional effect on cell proliferation, cell cycle control, or tumorigenesis when p53 is absent.
 ...
PMID:The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2. 894 68

The p53 tumor suppressor gene is a key target for inactivation in human cancer. One of the main biological functions of the p53 protein is the positive regulation of apoptosis in response to signals such as genomic damage and the aberrant activation of certain oncogenes. A transient transfection assay was utilized in order to study the mechanism and regulation of p53-mediated apoptosis in human cancer cells. It was found that the sequence specific transcriptional activation (SST) function of p53 is essential for apoptosis in certain cell types, but not in others. This implies the existence of at least two distinct mechanisms for p53-mediated apoptosis, one requiring the activation of specific target genes, and the other being SST-independent. Typically, both mechanisms may be triggered simultaneously, and their cooperation may be required for maximal apoptotic effects. In addition, in cells lacking the function of the Rb tumor suppressor, the apoptotic activity of p53 could be inhibited by reconstitution of active Rb. p53-mediated apoptosis could also be inhibited by the protein encoded by the mdm2 oncogene. The latter inhibition required the formation of complexes between the Mdm2 protein and p53, and operated only on SST-dependent apoptosis but not SST-independent apoptosis. Together, the data imply that p53 induces apoptosis through the activation of multiple biochemical pathways, and that the efficiency of the process is dictated by the cellular context.
 ...
PMID:p53-mediated apoptosis: mechanisms and regulation. 895 Apr 66


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