Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse skin carcinogenesis represents one of the best models for the understanding of malignant transformation, including the multistage nature of tumor development. The retinoblastoma gene product (pRb) plays a critical role in cell cycle regulation, differentiation, and inhibition of oncogenic transformation. In epidermis, Rb-/- deletion leads to proliferation and differentiation defects. Numerous evidences showed the involvement of the retinoblastoma pathway in this model. However, the actual role of pRb is still unknown. To study the possible involvement of pRb in keratinocyte malignant transformation, we have carried out two-stage chemical skin carcinogenesis on Rb(F19/F19) (thereafter Rb+/+) and Rb(F19/F19);K14Cre (thereafter Rb-/-) animals. Unexpectedly, we found that Rb-/- mice developed fewer and smaller papillomas than the Rb+/+ counterparts. Moreover, the small size of the pRb-deficient tumors is associated with an increase in the apoptotic index. Despite this, pRb-deficient tumors display an increased conversion rate to squamous cell carcinomas. Biochemical analyses revealed that these characteristics correlate with the differential expression and activity of different pathways, including E2F/p19arf/p53, PTEN/Akt, c-jun NH2-terminal kinase/p38, and nuclear factor-kappaB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis.
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PMID:Unexpected roles for pRb in mouse skin carcinogenesis. 1626 87

The p14 alternate reading frame (ARF) tumor suppressor plays a central role in cancer by binding to mdm2 (Hdm2 in humans) and enhancing p53-mediated apoptosis following DNA damage and oncogene activation. It is unclear, however, how ARF initiates its involvement in the p53/mdm2 pathway, as p53 and mdm2 are located in the nucleoplasm, whereas ARF is largely nucleolar in tumor cells. We have used immunofluorescence and coimmunoprecipitation to examine how the subnuclear distribution and protein-protein interactions of ARF change immediately after DNA damage and over the time course of the DNA damage response in human tumor cells. We find that DNA damage disrupts the interaction of ARF with the nucleolar protein B23(nucleophosmin) and promotes a transient p53-independent translocation of ARF to the nucleoplasm, resulting in a masking of the ARF NH2 terminus that correlates with the appearance of ARF-Hdm2 complexes. The translocation also results in an unmasking of the ARF COOH terminus, suggesting that redistribution disrupts a nucleolar interaction of ARF involving this region. By 24 hours after irradiation, DNA repair has ceased and the pretreatment immunofluorescence patterns and complexes of ARF have been restored. Although the redistribution of ARF is independent of p53 and likely to be regulated by interactions other than Hdm2, ARF does not promote UV sensitization unless p53 is expressed. The results implicate the nucleolus and nucleolar interactions of the ARF, including potentially novel interactions involving its COOH terminus as sites for early DNA damage and stress-mediated cellular events.
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PMID:DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. 1626 6

[[trans-PtCl(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+) (BBR 3464) is a 4+ cationic trinuclear platinum drug that has undergone phase II clinical trials in the treatment of ovarian and lung cancers. The chemical structure of BBR 3464 is distinct from that of clinically used agents such as cisplatin and oxaliplatin. As a consequence, the modes of DNA binding and the structures of BBR 3464 DNA adducts are also structurally distinct from those formed by cisplatin and oxaliplatin. Previous chemical and spectroscopic measurements on BBR 3464 had elucidated a significant noncovalent contribution to DNA binding. To examine this effect further, the biological activity of two BBR 3464 analogs that bind DNA only through noncovalent interactions was investigated in this study, and their cellular effects were compared with those caused by the "parent" drug. The compounds were [[trans-PtL(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](n+), with L = NH(3), n = 6 for compound I, and L = H(2)N(CH(2))(6)NH(3), n = 8 for compound II. All compounds induce caspase-dependent apoptosis in both primary mast cells and transformed mastocytomas, although with a smaller IC(50) value in the transformed cells. In cells deficient in either the tumor suppressor proteins p53 or Bax, apoptosis was least affected in the case of II, but in all cases the effect of p53 deficiency was greater than that of Bax. Surprisingly, cellular uptake was actually enhanced for the more highly charged compounds, resulting in significant (micromolar) cyotoxicity for II. Cellular accumulation was enhanced in mastocytomas over primary mast cells, suggesting a mechanism for enhancement of tumor cell selectivity.
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PMID:Biological consequences of trinuclear platinum complexes: comparison of [[trans-PtCl(NH3)2]2mu-(trans-Pt(NH3)2(H2N(CH2)6-NH2)2)]4+ (BBR 3464) with its noncovalent congeners. 1627 7

The p53 tumor suppressor is a modular transcription factor that determines cellular outcome (cell cycle arrest and DNA repair vs. apoptosis) in response to stress signals. The two p53 homologues, p63 and p73 play an important role in development but also act as tumor suppressors. The p53 family members are highly homologous in the activation domain (AD), the DNA-binding domain (DBD) and the tetramerization domain (TD) but differ in the C-terminus. Indeed, the p53 C-terminus contains a basic domain (BD) whereas p63/p73 have a sterile alpha motif (SAM) domain and an inhibitory domain (ID). In addition to the full-length proteins, the p53 family genes produce multiple isoforms truncated at the NH2- and/or C-terminus. Importantly, every functional domain is a determinant in the transactivation of specific target genes by the p53 family members. Distinct post-translational modifications and interactions with cofactors further modulate the transcriptional activity of the p53 family members in response to particular stress signals. Therefore, divergence in the composition of the p53 family proteins is responsible for the diversity of p53 family functions.
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PMID:Structural basis for gene activation by p53 family members. 1629 21

p63, a member of the p53 family of transcription factors, is known to be involved in epithelial development. However, its role in tumorigenesis is unclear. Contributing to this uncertainty, the TP63 locus can express multiple gene products from two different promoters. Utilization of the upstream promoter results in expression of the TAp63 variant with an activation domain similar to p53. In contrast, the NH2-terminally deleted (DeltaN) p63 variant, transcribed from a cryptic promoter in intron 3, lacks such an activation domain. Thus, the TAp63 and DeltaNp63 variants possess a wide ranging ability to up-regulate p53 target genes. Consequentially, the disparity in transactivation potential between p63 variants has given rise to the hypothesis that the DeltaNp63 variant can serve as oncoprotein by opposing the activity of the TAp63 variant and p53. However, recent studies have revealed a transcriptional activity for DeltaNp63. This study was undertaken to address the transcriptional activity of the DeltaNp63 variant. Here, we showed that all NH2-terminally deleted p63 isoforms retain a potential in transactivation and growth suppression. Interestingly, DeltaNp63beta possesses a remarkable ability to suppress cell proliferation and transactivate target genes, which is consistently higher than that seen with DeltaNp63alpha. In contrast, DeltaNp63gamma has a weak or undetectable activity dependent upon the cell lines used. We also demonstrate that an intact DNA-binding domain is required for DeltaNp63 function. In addition, we found that the novel activation domain for the DeltaNp63 variant is composed of the 14 unique DeltaN residues along with the adjacent region, including a PXXP motif. Finally, we demonstrated that a PPXY motif shared by DeltaNp63alpha and DeltaNp63beta is required for optimal transactivation of target gene promoters, suggesting that the PPXY motif is requisite for DeltaNp63 function.
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PMID:The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63. 1631 57

1. Colostrinin (CLN) induces maturation and differentiation of murine thymocytes, promotes proliferation of peripheral blood leukocytes, induces immunomodulator cytokines, and ameliorates oxidative stress-mediated activation of c-Jun NH2-terminal kinases. 2. Here we report that upon treatment with CLN, medullary pheochromocytoma (PC12) cells ceased to proliferate and extend neurites. 3. The arrest of CLN-treated PC12 cells in the G1 phase of the cell cycle was due to an increase in the phosphorylation of p53 at serine(15) (p53ser15) and expression of p21WAF1. PC12 cells treated with inhibitory oligonucleotides to p53 lacked p53ser15 and p21WAF1 expression, and did not show morphological changes after CLN exposure. Transfection with inhibitory oligonucleotides to p21WAF1 had no effect on p53 activation; however, cells failed to arrest or extend neurites. An oligonucleotide inhibiting luciferase expression had no effect on CLN-mediated p53 activation, p21WAF1 expression, growth arrest, or neurite outgrowth. 4. We conclude that CLN induces delicate cassettes of signaling pathways common to cell proliferation and differentiation, and mediates activities that are similar to those of hormones and neurotrophins, leading to neurite outgrowth.
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PMID:Colostrinin-driven neurite outgrowth requires p53 activation in PC12 cells. 1639 41

trans-[PtCl(2)NH(3)(4-Hydroxymethylpyridine)] (trans-PtHMP) is an analogue of clinically ineffective transplatin, which is cytotoxic in the human leukemia cancer cell line. As DNA is a major pharmacological target of antitumor platinum compounds, modifications of DNA by trans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. Our results demonstrate that the replacement of the NH(3) group in transplatin by the 4-hydroxymethylpyridine ligand affects the character of DNA adducts of parent transplatin. The binding of trans-PtHMP is slower, although equally sequence-specific. This platinum complex also forms on double-stranded DNA stable intrastrand and interstrand cross-links, which distort DNA conformation in a unique way. The most pronounced conformational alterations are associated with a local DNA unwinding, which was considerably higher than those produced by other bifunctional platinum compounds. DNA adducts of trans-PtHMP also reduce the affinity of the p53 protein to its consensus DNA sequence. Thus, downstream effects modulated by recognition and binding of p53 protein to DNA distorted by trans-PtHMP and transplatin are not likely to be the same. It has been suggested that these different effects may contribute to different antitumor effects of these two transplatinum compounds.
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PMID:Recognition of DNA modified by trans-[PtClNH(4-hydroxymethylpyridine)] by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex. 1640 18

13-Deoxytedanolide is a structurally unique macrolide with strong antitumor activity isolated from a marine sponge. Recently, we showed that 13-deoxytedanolide bound to the large subunit of the yeast ribosome and inhibited polypeptide elongation in vitro, but the mechanism by which it exerts antitumor activity is still unknown. Here we show that 13-deoxytedanolide strongly induces plasminogen activator inhibitor 1 (PAI-1) promoter-derived gene expression. 13-Deoxytedanolide, unlike TGF-beta, did not cause apparent nuclear translocation of Smad2/3, but it relocalized the temperature-sensitive mutant of mouse p53 (p53Val153) from the cytoplasm to the nucleus at a nonpermissive temperature, suggesting that 13-deoxytedanolide inhibits protein synthesis. Indeed, the drug inhibited in vivo protein synthesis at low nanomolar concentrations and strongly activated stress-activated protein kinases such as p38 mitogen-activated protein kinase and Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that activates both p38 and JNK, also activated PAI-1 gene expression, while other protein synthesis inhibitors that do not activate the kinases failed to do so. PAI-1 gene expression by 13-deoxytedanolide and anisomycin was blocked by SB202190, a specific inhibitor of p38, and SP600125, an inhibitor of both p38 and JNK. 13-Deoxytedanolide and anisomycin caused activation of apoptosis signal-regulating kinase 1, MKK3/MKK6, and SEK1/MKK4, the regulatory kinases upstream of p38 and JNK. These results suggest that 13-deoxytedanolide, like anisomycin, triggers a ribotoxic stress response that activates stress-activated protein kinase cascades, thereby inducing PAI-1 gene expression and apoptosis.
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PMID:Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. 1642 34

The tumor suppressor p53 is negatively regulated by the ubiquitin ligase MDM2. The MDM2 recognition site is at the NH2-terminal region of p53, but the positions of the actual ubiquitination acceptor sites are less well defined. Lysine residues at the COOH-terminal region of p53 are implicated as sites for ubiquitination and other post-translational modifications. Unexpectedly, we found that substitution of the COOH-terminal lysine residues did not diminish MDM2-mediated ubiquitination. Ubiquitination was not abolished even after the entire COOH-terminal regulatory region was removed. Using a method involving in vitro proteolytic cleavage at specific sites after ubiquitination, we found that p53 was ubiquitinated at the NH2-terminal portion of the protein. The lysine residue within the transactivation domain is probably not essential for ubiquitination, as substitution with an arginine did not affect MDM2 binding or ubiquitination. In contrast, several conserved lysine residues in the DNA-binding domain are critical for p53 ubiquitination. Removal of the DNA-binding domain reduced ubiquitination and increased the stability of p53. These data provide evidence that in addition to the COOH-terminal residues, p53 may also be ubiquitinated at sites in the DNA-binding domain.
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PMID:Ubiquitination of p53 at multiple sites in the DNA-binding domain. 1644 3

This study first investigates the anticancer effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. Plumbagin treatment also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity by dominant-negative p53 transfection partially decreased plumbagin-induced apoptosis and G2/M arrest, suggesting it might be operated by p53-dependent and independent pathway. Plumbagin treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that c-Jun NH2-terminal kinase (JNK) is a critical mediator in plumbagin-induced cell growth inhibition. Activation of JNK by plumbagin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and MDM2 interaction. SP600125 (anthra [1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone), a specific inhibitor of JNK, significantly decreased apoptosis by inhibiting the phosphorylation of p53 (serine 15) and subsequently increased the interaction of p53 and MDM2. SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin. Further investigation revealed that plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in plumbagin-induced G2/M arrest and apoptosis of human nonsmall cell lung cancer cells.
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PMID:Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo. 1663 41


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