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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although p53 is known to have dual functions as a transcriptional activator and repressor, there has not been an example where both p53-activating and -repressing elements reside within one target promoter. Previous work from this laboratory defined two different p53 response elements, termed P1 and P2, located at nucleotide positions -70 and -707, respectively, in the rat bradykinin B2 receptor promoter. In this study, through manipulation of the DNA sequence and context, we demonstrate opposing roles for P1 and P2 as transcriptional activator and repressor, respectively. Deletion of P1 abrogates p53-mediated activation. P1 maintains its role as an activator upon relocation to the P2 site and activates transcription from a heterologous promoter construct. Thus, P1 is a bona fide positive p53-response element. In contrast, deletion of P2 enhances P1-induced activation. P2 represses transcription when substituted for P1 or when relocated midway between P1 and P2. P2-mediated repression is sequence-dependent, because it is reversed to activation when P2 is substituted by the P1 or p53 consensus sequences. Moreover, site-directed mutagenesis that converts P2 to a higher affinity p53-binding site results in transcriptional activation rather than repression. Surprisingly, P2 strongly activates a heterologous promoter. Thus, P2-mediated transcriptional repression is both sequence- and context-dependent. Investigations into the mechanisms of P2-mediated repression indicate that it is trichostatin-insensitive and unaffected by CBP or mutation of the minimal repression C-terminal domain of p53. However, gel shift assays suggest that p53 competes with other transcriptional activators for binding to overlapping binding sequences within the P2 element. In conclusion, this study provides a rare example of a transcription factor having two divergent functional effects that are sequence- and context-dependent. The interplay of P1 and P2 may be important in the regulation of bradykinin B2 receptor gene expression in response to inflammatory stress and during development.
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PMID:Two functionally divergent p53-responsive elements in the rat bradykinin B2 receptor promoter. 1279 84

While the p53 homologue p73 has been found to be involved in tumorigenesis, the molecular mechanisms involved in this function are still not fully evident. The presence of two distinct promoters allows the formation of two proteins with opposite effects: while TA-p73 shows pro-apoptotic effects, DeltaN-p73 has an evident anti-apoptotic function. The relative expression of the two proteins is in fact related to the prognosis of several cancers. Since both p73 and p63, the other member of the same family, share the ability to interact with each other, it is important to understand the mechanisms that control the degradation and stability of both proteins, and their relative isoforms. p73 and p63 stability is regulated not only by protein modifications (phosphorylation, acetylation) but also by its degradation in the proteasome. To this end, the interaction with Mdm2, p300/CBP, and SUMO-1 are discussed in details.
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PMID:p73 and p63 protein stability: the way to regulate function? 1455 34

The tumor suppressor p53-related p73 shares significant amino-acid sequence identity with p53. Like p53, p73 recognizes canonical p53 DNA-binding sites and activates p53-responsive target genes and induces apoptosis. Moreover, transcription coactivator p300/CBP binds to and coactivates with both p53 and p73 in stimulating the expression of their target genes. Here, we report that coactivator PCAF binds to p73. The N-terminal transactivation domain (TAD) and the conserved oligomerization domain (OD) of p73 are both required for its interaction with PCAF. Conversely, PCAF's HAT-domain is required for and both the N-terminal region and Bromo domain enhance binding of PCAF to p73. Significantly, PCAF stimulates p73-mediated transactivation, and binding of PCAF to p73 is necessary for p73's transactivation activity. PCAF-specific siRNA dramatically reduces p73-mediated transactivation. Stimulation of p73-mediated transactivation by PCAF requires the HAT domain of PCAF and the p53-binding site within the p21 promoter. In vivo, coexpression of wild-type, but not HAT-deficient PCAF with p73beta markedly increases p21 expression. Furthermore, cotransfection of PCAF and p73 leads to increased apoptosis and reduced colony formation. Collectively, these data suggest that p73 recruit PCAF to specific promoters to activate the transcription of p73 target genes.
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PMID:PCAF is a coactivator for p73-mediated transactivation. 1461 55

Promyelocytic leukemia nuclear bodies (PML-NBs) are discrete interchromosomal macromolecular structures. The integrity of this dynamic nuclear subcompartment critically depends on the presence of the name-giving PML protein. Among the permanent or transient residents of PML-NBs are various regulatory proteins, including Sp100, CBP, pRb, HIPK2, RAD51 and p53. PML-NBs are frequently targeted by viral infections, as a number of different RNA and DNA viruses, including herpesviruses, adenoviruses, papovaviruses, papillomaviruses and arenaviruses, cause changes in PML-NBs. Viruses interfere with PML-NB in two ways: 1) some viral proteins can associate with PML-NB proteins and/or lead to the destruction and lysis of this subnuclear compartment, thus aiding viral gene expression and disabling the host's innate immunity; 2) the parental genomes of some nuclear-replicating DNA viruses associate preferentially with PML-NBs, which presumably serves to assist in viral gene expression or replication. Here we feature the different viral strategies leading to the hijacking of PML-NBs and discuss the consequences for the immune response.
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PMID:Viruses as hijackers of PML nuclear bodies. 1462 29

Our manipulation of the nonsense-mediated decay pathway in microsatellite unstable colon cancer cell lines identified the p300 gene as a potential tumor suppressor in this subtype of cancer. Here, we have demonstrated that not only the p300 gene but also the highly homologous cAMP-response element-binding protein (CREB) binding protein (CBP) gene together are mutated in >85% of microsatellite instability (MSI)+ colon cancer cell lines. A limited survey of primary tumors with MSI+ shows that p300 is also frequently mutated in these cancers, demonstrating that these mutations are not consequences of in vitro growth. The mutations in both genes occur frequently in mononucleotide repeats that generate premature stop codons. Reintroduction of p300 into MSI colon cancer cells could only be supported in the presence of an inactivated CBP gene, suggesting the idea that one or the other function must be inactivated for cancer cell viability. p300 is known to acetylate p53 in response to DNA damage, and when MSI+ cells null for p300 activity are forced to reexpress exogenous p300 cells show slower growth and a flatter morphology. p53 acetylation is increased upon reexpression of p300, suggesting that MSI+ cells constitutively activate the DNA damage response pathway in the absence of DNA-damaging agents. In support of this hypothesis, c-ABL kinase, which is also activated in response to DNA damage, shows higher levels of basal kinase activity in MSI+ cells. These observations suggest that there is a selective growth/survival advantage to mutational inactivation of p300/CBP in cells with inactivated mismatch repair capabilities.
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PMID:A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. 1473 95

Simian virus (SV) 40 large T antigen can both induce tumors and inhibit cellular differentiation. It is not clear whether these cellular changes are synonymous, sequential, or distinct responses to the protein. T antigen is known to bind to p53, to the retinoblastoma (Rb) family of tumor suppressor proteins, and to other cellular proteins such as p300 family members. To test whether SV40 large T antigen inhibits cellular differentiation in vivo in the absence of cell cycle induction, we generated transgenic mice that express in the lens a mutant version of the early region of SV40. This mutant, which we term E107KDelta, has a deletion that eliminates synthesis of small t antigen and a point mutation (E107K) that results in loss of the ability to bind to Rb family members. At embryonic day 15.5 (E15.5), the transgenic lenses show dramatic defects in lens fiber cell differentiation. The fiber cells become post-mitotic, but do not elongate properly. The cells show a dramatic reduction in expression of their beta- and gamma-crystallins. Because CBP and p300 are co-activators for crystallin gene expression, we assayed for interactions between E107KDelta and CBP/p300. Our studies demonstrate that cellular differentiation can be inhibited by SV40 large T antigen in the absence of pRb inactivation, and that interaction of large T antigen with CBP/p300 may be enhanced by a mutation that eliminates the binding to pRb.
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PMID:Inhibition of lens fiber cell morphogenesis by expression of a mutant SV40 large T antigen that binds CREB-binding protein/p300 but not pRb. 1474 45

Lysine acetylation of the tumor suppressor protein p53 in response to a wide variety of cellular stress signals is required for its activation as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report that the conserved bromo-domain of the transcriptional coactivator CBP (CREB binding protein) binds specifically to p53 at the C-terminal acetylated lysine 382. This bromodomain/acetyl-lysine binding is responsible for p53 acetylation-dependent coactivator recruitment after DNA damage, a step essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21 in G1 cell cycle arrest. We further present the three-dimensional nuclear magnetic resonance structure of the CBP bromodomain in complex with a lysine 382-acetylated p53 peptide. Using structural and biochemical analyses, we define the molecular determinants for the specificity of this molecular recognition.
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PMID:Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. 1475 70

CBP can function as a tumor suppressor, but the mechanisms that govern oncogenesis in its absence are unknown. Here we show that CBP inactivation in mouse thymocytes leads to lymphoma. Although CBP has been implicated in the transactivation functions of p53, development of these tumors does not seem to involve loss of p53 activity. CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2, two oncoproteins that can promote p27Kip1 proteolysis. Reduction of p27Kip1 by introduction of a p27Kip1-null allele into CBP knockout mice accelerates lymphomagenesis and seems to obviate the requirement for Skp2 and cyclin E upregulation. These data suggest that CBP loss mediates lymphomagenesis in cooperation with a mechanism that reduces p27Kip1 abundance.
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PMID:Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. 1499 93

The transcriptional co-activator CBP [CREB (cAMP-response-element-binding protein)-binding protein] and its paralogue p300 play a key role in the regulation of both activity and stability of the tumour suppressor p53. Degradation of p53 is mediated by the ubiquitin ligase MDM2 (mouse double minute protein) and is also reported to be regulated by CBP/p300. Direct protein-protein interaction between a central domain of MDM2 and the TAZ1 (transcriptional adaptor zinc-binding domain) [C/H1 (cysteine/histidine-rich region 1)] domain of p300 and subsequent formation of a ternary complex including p53 have been reported previously. We expressed and purified the proposed binding domains of HDM2 (human homologue of MDM2) and CBP, and examined their interactions using CD spectroscopy. The binding studies were extended by using natively purified GST (glutathione S-transferase)-p300 TAZ1 and GST-p53 fusion proteins, together with in vitro translated HDM2 fragments, under similar solution conditions to those in previous studies, but omitting added EDTA, which causes unfolding and aggregation of the zinc-binding TAZ1 domain. Comparing the binding properties of the known TAZ1 interaction partners HIF-1alpha (hypoxia-inducible factor 1), CITED2 (CBP/p300-interacting transactivator with glutamic- and aspartic-rich tail) and STAT2 (signal transducer and activator of transcription 2) with HDM2, our data suggest that TAZ1 in its native state does not serve as a specific recognition domain of HDM2. Rather, unfolded TAZ1 and HDM2 proteins have a high tendency to aggregate, and non-specific protein complexes are formed under certain conditions.
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PMID:The CBP/p300 TAZ1 domain in its native state is not a binding partner of MDM2. 1527 Jul

The p53 tumour suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress. However, p53 is a short-lived protein and its activity is maintained at low levels in normal cells. Numerous studies indicate that CBP/p300-mediated acetyl-transferase activity is critical for its role in both catalysing p53 acetylation and activating p53-mediated function during stress response. Interestingly, two additional regulators have also been identified in the p53 acetylation pathway. PID/MTA2 is a p53-interacting protein that induces p53 deacetylation by recruiting the HDAC1 complex. Subsequent work has also identified Sir2alpha, a NAD-dependent histone deacetylase that can attenuate p53 transcriptional activity through deacetylation. The prominence of deacetylase activity on p53 certainly raises the defining question of its physiological purpose. It is likely that deacetylation proxides a quick acting mechanism to stop p53 function once transcriptional activation of target genes is no longer needed. We present data indicating that both HDAC1 and Sir2alpha are critical for p53-dependent stress response. Furthermore, we also try to define the functional consequence of p53 acetylation at the molecular level. Finally, we propose a model regarding the differential roles of HDAC1 and Sir2alpha in the regulation of p53 function.
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PMID:Dynamics of the p53 acetylation pathway. 1517 Dec 55


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