Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor gene belongs to a small family of related proteins that includes two other members, p63 and p73. Phylogenetic and functional studies suggest that p63 and p73 are ancient genes that have essential roles in normal development, whereas p53 seems to have evolved more recently to prevent cell transformation. In mammalian cells, a plethora of proteins have been found to specifically regulate p53 activity. The genome of the fish Fugu rubripes has been recently published. It is the second vertebrate genome for which the entire sequence is now available. Phylogenetic studies are essential in order to analyse and define signalling pathways important for cell cycle regulation. The presence or absence of a critical member in any pathway can shed light about the evolution of these pathways. The Fugu genome databank has been analysed for several members of the p53 network, including p53, p63 and p73. A good conservation of the network that regulates p53 stability and apoptosis has been found. We also discovered that some cofactors that cooperate with p53 for apoptosis are also well conserved and belong to multigene families not detected in the human genome.
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PMID:Data mining the p53 pathway in the Fugu genome: evidence for strong conservation of the apoptotic pathway. 1290 91

The tumour suppressor activity of p53 plays a major role in limiting abnormal proliferation, and inactivation of the p53 response is becoming increasingly accepted as a hallmark of cancer. In contrast, both p63 and p73, which are close relatives of p53, are rarely mutated in tumour cells. At a theoretical level, therapeutic approaches that reinstate p53 activity, or augment p63 and p73, provide plausible and potentially efficacious routes towards new cancer treatments. Equally important is the clinical need to increase the efficacy of conventional anti-cancer drugs. Incapacitating the p53 response to limit the side effects in healthy cells may be one approach towards increasing the therapeutic window of many current anti-cancer drugs. Nevertheless, while cancer drug discovery focussed on p53 is an exciting and realistic possibility, translating this concept into a clinical setting is likely to be challenging.
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PMID:Drug discovery and the p53 family. 1459 32

The transcription factor and tumour suppressor p53 and its two homologues p63 and p73 form a family of proteins. p63 and p73 show much greater molecular complexity than p53 because they are expressed both as multiple alternatively spliced C-terminal isoforms, and as N-terminally deleted, dominant-negative proteins that show reciprocal functional regulation. In addition, several other factors, such as post-translational modifications and specific and common family regulatory proteins, result overall in subtle modulation of their biological effects. Although all p53, p63 and p73 family members are regulators of the cell cycle and apoptosis, the developmental abnormalities of p73- and p63-null mice do not show enhanced tumour susceptibility of p53 knockouts, suggesting that complex regulatory processes modulate the functional effects of this family of proteins.
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PMID:Functional regulation of p73 and p63: development and cancer. 1465 98

The TP73 gene, first identified in 1997, encodes the p73 protein, a p53 tumour suppressor homologue. The lack of mutations in the TP73 gene in cancers and the developmentally abnormal phenotype of the TP73 knockout mouse suggest a different function for TP73 gene derived proteins. An alternative promoter in the third intron of the TP73 gene, which produces a transcription deficient and dominant negative protein (DeltaNp73), produces increased complexity in the function of p73 proteins. Functional studies of transcriptionally active (TAp73; regulated by the first promoter) and DeltaNp73 (regulated by the second promoter) show that the TP73 gene encodes both a candidate tumour suppressor (TAp73) and an oncogene (DeltaNp73), with pro-apoptotic and anti-apoptotic properties, respectively. This "two in one" gene architecture leads us to make an in silico search for other probable promoter regions and transcription start sites in different introns of the TP73 gene. To identify such regulatory regions, we have analysed the genomic structure of human and mouse TP73 genes. We have found introns 1 and 4 to be extremely large and relatively conserved in size in mouse and human, in addition to intron 3, which includes the DeltaNp73 promoter. We have further characterized these introns by transcription factor binding motifs, transcription initiation sites, open reading frames, and splicing using six programs that can successfully identify the already characterized promoters. Our results suggest the presence of a candidate 2 kbp genomic DNA in the first intron of human TP73 gene, harbouring 2 putative promoter regions, together with a similar region within intron 1 of the mouse gene.
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PMID:p73: in silico evidence for a putative third promoter region. 1469 57

Since its discovery in 1979, many studies have reported that the p53 tumour suppressor protein could be expressed in the form of products smaller than those predicted by the full-length amino-acid sequence. These products differ from full-length p53 in their N- or C-terminal regions, but generally conserve the central, DNA-binding domain. They appear to be expressed at rather low levels and to be restricted to particular cell types and/or physiological circumstances, suggesting that they play very narrow and specific roles. Several mechanisms have been proposed to explain their timely occurrence, including alternative splicing, internal initiation of translation or proteolytic cleavage. A precise assessment of the various 'p53 isoforms' reveals striking similarities with several isoforms of the p53 homologous proteins p63 or p73, suggesting that regulated production of specific, N- or C-terminal variants may be a 'trademark' of all family members. In this review, we summarize the published evidence on the structure, mode of production, expression and function of the p53 isoforms, and discuss their properties in the light of recent data on the structure and function of p63/p73 isoforms.
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PMID:p53 protein variants: structural and functional similarities with p63 and p73 isoforms. 1473 98

The completion of the Drosophila genome sequencing project [Science 287 (2000) 2185] has reconfirmed the fruit fly as a model organism to study human disease. Comparison studies have shown that two thirds of genes implicated in human cancers have counterparts in the fly [Curr. Opin. Genet. Dev. 11 (2001) 274; J. Cell Biol. 150 (2000) F23], including the tumour suppressor, p53. The suitability of the fruit fly to study the function of the tumour suppressor p53 is further exemplified by the lack of p53 family members within the fly genome, i.e., no homologues to p63 and p73 have been identified. Hence, there is no redundancy between family members greatly facilitating the analysis of p53 function. In addition, studying p53 in Drosophila provides an opportunity to learn about the evolution of tumour suppressors. Here, we will discuss what is known about Drosophila p53 in relation to human p53.
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PMID:Of flies and men; p53, a tumour suppressor. 1516 98

p63 and p73 share significant structural and functional homologies with the tumour suppressor p53. Unlike the p53 gene, both encode for several isoforms which vary in their NH2 and COOH termini with variable and, in part, opposed biological functions. The objective of the present study was to analyse the expression profiles of p53 family members in squamous cell carcinomas of the head and neck (HNSCC) and their alterations caused by exposure to the clinically active drug cisplatin. Using multiplex RT-PCR combined with the Southern technique, we determined transcription of p53 family members in 10 established HNSCC cell lines. In the majority of HNSCC, p53 and different p63/p73 isoforms were expressed with cell-line-specific patterns for composition and intensity of transcript expression. Exposure to cisplatin caused multiple alterations in the p63 and p73 profiles suggesting a complex regulation which may influence the sensitivity to chemotherapy.
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PMID:p53, p63 and p73 expression in squamous cell carcinomas of the head and neck and their response to cisplatin exposure. 1560 18

In the present study, we have investigated mechanisms of transcriptional co-operation between proteins that belong to the tumour suppressor p53 and Sp (specificity protein) families of transcription factors. Such mechanisms may play an important role in the regulation of genes containing binding sites for both classes of transcription factors in their promoters. Two of these genes were analysed in the present study: the cyclin-dependent kinase inhibitor p21Cip1 gene and the PUMA (p53-up-regulated mediator of apoptosis) gene. We found that Sp1 and Sp3, but not Sp2, co-operate functionally with p53, p73 and p63 for the synergistic transactivation of the p21Cip1 promoter in Drosophila Schneider SL2 cells that lack endogenous Sp factors. We also found that Sp1 strongly transactivated the PUMA promoter synergistically with p53, whereas deletion of the Sp1-binding sites abolished the transactivation by p53. Using p53 mutant forms in GST (glutathione S-transferase) pull-down assays, we found that the C-terminal 101 amino acids of p53, which include the oligomerization and regulatory domains of the protein, are required for the physical interactions with Sp1 and Sp3, and that deletion of this region abolished transactivation of the p21Cip1 promoter. Utilizing truncated forms of Sp1, we established that p53 interacted with the two transactivation domains A and B, as well as the DNA-binding domain. Our findings suggest that Sp factors are essential for the cellular responses to p53 activation by genotoxic stress. Understanding in detail how members of the p53 and Sp families of transcription factors interact and work together in the p53-mediated cellular responses may open new horizons in cancer chemotherapy.
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PMID:Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. 1579 Mar 10

Inactivation of p53 and p73 is known to promote thyroid cancer progression. We now describe p63 expression and function in human thyroid cancer. TAp63alpha is expressed in most thyroid cancer specimens and cell lines, but not in normal thyrocytes. However, in thyroid cancer cells TAp63alpha fails to induce the target genes (p21Cip1, Bax, MDM2) and, as a consequence, cell cycle arrest and apoptosis occur. Moreover, TAp63alpha antagonizes the effect of p53 on target genes, cell viability and foci formation, and p63 gene silencing by small interfering (si) RNA results in improved p53 activity. This unusual effect of TAp63alpha depends on the protein C-terminus, since TAp63beta and TAp63gamma isoforms, which have a different arrangement of their C-terminus, are still able to induce the target genes and to exert tumour-restraining effects in thyroid cancer cells. Our data outline the existence of a complex network among p53 family members, where TAp63alpha may promote thyroid tumour progression by inactivating the tumour suppressor activity of p53.
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PMID:The p53-homologue p63 may promote thyroid cancer progression. 1632 35

The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of deltaNp73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. DeltaNp73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and deltaNp73 in human carcinogenesis.
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PMID:Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. 1639 24


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