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)

We have analysed the importance of proper substrate methylation by S-adenosylmethionine-dependent methyltransferases for cell survival and cell cycle progression. We show that treatment of cells with the methyltransferase inhibitor adenosine dialdehyde (AdOx) causes cell cycle arrest and death in different cell types. The phenotypical outcome and form of cell death was strikingly dependent on the AdOx concentration. Lower AdOx concentrations led to a G2 arrest and predominantly caused apoptosis, as judged by biochemical and morphological criteria. Apoptotic cell death was largely dependent on the presence of the tumour suppressor p53, but did not require the Bcl-2 family member Bax. Interestingly, higher concentrations of AdOx led to a novel and so far undescribed form of cell death, which was characterized by distinct, caspase-independent alterations of the cell shape including a marked protuberation of the nucleus, cytoplasmic extensions, actin aggregation, and incomplete chromatin condensation. Although this latter form of cell death was clearly distinguishable from apoptosis, early apoptotic features such as Bax activation were detected, indicating a commitment but incomplete execution of apoptosis. Altogether, these data show that methylation reactions play a distinct role in cell survival, which might influence the decision between different phenotypic forms of cell death.
 ...
PMID:Methyltransferase inhibition induces p53-dependent apoptosis and a novel form of cell death. 1600 40

Tamoxifen treatment for breast cancer increases proliferation of the endometrium, resulting in an enhanced prevalence of endometrial pathologies, including endometrial cancer. An exploratory study was performed to begin to understand the molecular mechanism of tamoxifen action in the endometrium. Gene-expression profiles were generated of endometrial samples of tamoxifen users and compared with matched controls. The pathological classification of samples from both groups included atrophic/inactive endometrium and endometrial polyps. Unsupervised clustering revealed that samples of tamoxifen users were, irrespective of pathological classification, fairly similar and consequently form a subgroup distinct from the matched controls. Using SAM analysis (a statistical method to select genes differentially expressed between groups), 256 differentially expressed genes were selected between the tamoxifen and control groups. Upon comparing these genes with oestrogen-regulated genes, identified under similar circumstances, 95% of the differentially expressed genes turned out to be tamoxifen-specific. Finally, construction of a gene-expression network of the differentially expressed genes revealed that 69 genes centred around five well-known genes: TP53, RELA, MYC, epidermal growth factor receptor and beta-catenin. This could indicate that these well-known genes, and the pathways in which they function, are important for tamoxifen-controlled proliferation of the endometrium.
 ...
PMID:Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study. 1632 41

The p63alpha isoforms of the p53 family have been demonstrated to play a crucial role in the development and differentiation of the skin. We show that expression of the TAp63alpha isoform leads to an upregulation of the cutaneous papillomavirus HPV 20 promoter, which is increased at least three-fold when c-Jun is co-expressed, in contrast to a minimal increase in activity in the presence of c-Jun alone. Co-expression of TAp63alpha with JunB or JunD, respectively, and in combination, leads to a reduction in the viral promoter activation measured by the expression of TAp63alpha alone. JunB and JunD also inhibits the additive effect exerted on the TAp63alpha activation by c-Jun. Co-immunoprecipitation assays demonstrate a complex formation of c-Jun, JunB and JunD with TAp63alpha through the SAM domain mediating protein-protein interactions, which is characteristic for p63alpha. Co-expression of p53 mutant R248W not only downregulates the differential modulation of the viral promoter by TAp63alpha alone and in the presence of the Jun family members, but leads to a reduction in the protein levels of the overexpressed c-Jun, JunB, JunD, as well as TAp63alpha. This model system provides insight into yet unknown pathways through which TAp63alpha and Jun may cooperate in the pathogenesis of HPV associated cutaneous lesions.
 ...
PMID:TAp63alpha indirectly regulates a cutaneous HPV promoter through complex formation with Jun family members. 1647 46

p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis. Even though p63 activity is regulated mainly at the posttranslational level, the control of p63 protein stability is far from being fully understood. Here, we show that the Hect (homologous to the E6-associated protein C terminus)-containing Nedd4-like ubiquitin protein ligase Itch binds, ubiquitylates, and promotes the degradation of p63. The physical interaction occurs at the border between the PY and the SAM (sterile alpha motif) domains; a single Y504F mutation significantly affects p63 degradation. Itch and p63 are coexpressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes. These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions.
 ...
PMID:The E3 ubiquitin ligase Itch controls the protein stability of p63. 1690 49

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.
 ...
PMID:Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. 1705 95

Adenosine has been shown to initiate apoptosis through different mechanisms: (i) activation of adenosine receptors, (ii) intracellular conversion to AMP and stimulation of AMP-activated kinase, (iii) conversion to S-adenosylhomocysteine (AdoHcy), which is an inhibitor of S-adenosylmethionine (AdoMet)-dependent methyltransferases. Since the pathways involved are still not completely understood, we further investigated the role of AdoHcy hydrolase in adenosine-induced apoptosis. In HepG2 cells, adenosine induced caspase-like activity and DNA fragmentation, a marker of apoptosis. These effects were potentiated by co-incubation with homocysteine or adenosine deaminase inhibitor, pentostatin, and were mimicked by inhibition of AdoHcy hydrolase by adenosine-2',3'-dialdehyde (Adox). Adenosine-induced effects were significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, whereas inhibitors of adenosine kinase did not affect adenosine-induced changes. Various adenosine receptor agonists and AICAR, an activator of AMP-activated kinase, did not mimic the effect of adenosine. Thus, adenosine-induced apoptosis is likely due to intracellular action of AdoHcy and independent of AMP-activated kinase and adenosine receptors. Because elevated AdoHcy levels are associated with reduced mRNA methylation, we studied mRNA expression in Adox-treated cells by microarray analysis. Since several p53-target genes and other apoptosis-related genes were up-regulated by Adox, we conclude that AdoHcy is involved in adenosine-induced apoptosis by altering gene expression.
 ...
PMID:Role of S-adenosylhomocysteine hydrolase in adenosine-induced apoptosis in HepG2 cells. 1709 37

Down-regulation of GADD45beta, which is known to influence cell growth control, apoptosis, and cellular response to DNA damage, has been verified to be specific in hepatocellular carcinoma and consistent with the degree of malignancy. Here, we identified promoter elements for several transcriptional factors in the proximal promoter of GADD45beta using the luciferase assay. As a methyl donor for biological transmethylation reactions, S-adenosylmethionine (SAMe) could restore GADD45beta expression in HepG2 in Northern blot analyses and quantitative real-time polymerase chain reaction. Activity and binding capacity of nuclear factor (NF)-kappaB were confirmed to be specifically induced by SAMe, as evidenced by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and a decrease of IkappaBalpha in Western blot analyses. The most upstream NF-kappaB-binding site was crucial for transcriptional activation. In contrast to NF-kappaB, although there is an E2F-1-binding site adjacent to the NF-kappaB sites, treatment with SAMe could not induce E2F-1-binding activity. Despite showing a similar GADD45beta promoter regulatory pattern as HepG2 (p53 wild type), Hep3B (p53-null) did not exhibit GADD45beta induction by SAMe, and the induction could be partially recovered on reconstituting p53 in Hep3B. Thus, our results suggest that GADD45beta induction by SAMe via NF-kappaB may represent a novel mechanism of SAMe-mediated hepatoprotection, with p53 playing an important role.
 ...
PMID:The induction of growth arrest DNA damage-inducible gene 45 beta in human hepatoma cell lines by S-adenosylmethionine. 1759 73

The p53 tumor suppressor plays the leading role in malignancy and in maintaining the genome's integrity and stability. p53 belongs to a gene family that in vertebrates includes two additional members, p63 and p73. Although similar in sequence, gene structure, and expression potential, the three p53 members differ in domain organization (in addition to the transactivation, DNA-binding, and tetramerization domains, p63 and p73 encode a sterile alpha motif, SAM, domain) and functional roles (with p63 and p73 assuming additional key roles in development). It is interesting to note that outside vertebrates, p53-like sequences have only been found as single genes, of either the p53 or the p63/p73 type (i.e., without or with a SAM domain, respectively). In this paper, we report that the diversification of this family is not restricted to the vertebrate lineage, as both a p53- and a p63/p73-type sequence are present in the unicellular choanoflagellate, Monosiga brevicollis. Furthermore, multiple independent duplication events involving p53-type sequences took place in several other animal lineages (cnidarians, flat worms, insects). These findings argue that selective factors other than those associated with the evolution of vertebrates are also relevant to the diversification of this family. Understanding the selective pressures associated with the multiple independent duplication events that took place in the p53 family and the roles of p53-like proteins outside vertebrates will provide further insight into the evolution of this very important family. In addition, the presence of both a p53 and a p63/73 copy in the unicellular M. brevicollis argues for its suitability as a model system for elucidating the functions of the p53 members and the mechanisms associated with their functional diversification.
 ...
PMID:Early diversification and complex evolutionary history of the p53 tumor suppressor gene family. 1792 39

Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia. The HTLV-1-encoded protein Tax transactivates the viral long terminal repeat and plays a critical role in virus replication and transformation. Previous work from our laboratory demonstrated that coactivator-associated arginine methytransferase 1, a protein arginine methytransferase, was important for Tax-mediated transactivation. To further investigate the role of methyltransferases in viral transcription, we utilized adenosine-2,3-dialdehyde (AdOx), an adenosine analog and S-adenosylmethionine-dependent methyltransferase inhibitor. The addition of AdOx decreased Tax transactivation in C81, Hut102, and MT-2 cells. Unexpectedly, we found that AdOx potently inhibited the growth of HTLV-1-transformed cells. Further investigation revealed that AdOx inhibited the Tax-activated NF-kappaB pathway, resulting in reactivation of p53 and induction of p53 target genes. Analysis of the NF-kappaB pathway demonstrated that AdOx treatment resulted in degradation of the IkappaB kinase complex and inhibition of NF-kappaB through stabilization of the NF-kappaB inhibitor IkappaBalpha. Our data further demonstrated that AdOx induced G(2)/M cell cycle arrest and cell death in HTLV-1-transformed but not control lymphocytes. These studies demonstrate that protein methylation plays an important role in NF-kappaB activation and survival of HTLV-1-transformed cells.
 ...
PMID:Inhibition of methyltransferases results in induction of g2/m checkpoint and programmed cell death in human T-lymphotropic virus type 1-transformed cells. 1794 56

The catalysis by SET7/9 histone lysine methyltransferase of AdoMet N-methylation of the transcriptional factor p53-Lys4-NH 2 has been investigated with particular attention paid to the means of product specificity. After formation of the SET7/9.p53-Lys4-NH 3 (+).AdoMet complex, the following events occur: (i) the appearance of a water channel, (ii) a depronation of p53-Lys4-NH 3 (+) via this water channel into the aqueous solvent, and (iii) AdoMet methylation of p53-Lys4-NH 2 to form p53-Lys4-N(Me)H 2 (+). The formation of a water channel does not occur on formation of the SET7/9.p53-Lys4-NH 3 (+), SET7/9.p53-Lys4-N(Me)H 2 (+).AdoHcy, or SET7/9.p53-Lys4-N(Me)H 2 (+).AdoMet complex. Without a water channel, the substrate p53-Lys4-N(Me)H is not available because the proton dissociation p53-Lys4-N(Me)H 2 (+) --> p53-Lys4-N(Me)H + H (+) does not occur. The lack of formation of a water channel is due to the positioning of the methyl substituent of the SET7/9.p53-Lys4-N(Me)H 2 (+).AdoMet complex. By quantum mechanics/molecular mechanics, the computed free energy barrier of the methyl transfer reaction [p53-Lys4-NH 2 + AdoMet --> p53-Lys4-N(Me)H 2 (+) + AdoHcy] in the SET7/9 complex is Delta G (++) = 20.1 +/- 2.9 kcal/mol. This Delta G (++) is in agreement with the value of 20.9 kcal/mol calculated from the experimental rate constant (1.2 +/- 0.1 min (-1)). Our bond-order computations establish that the methyl transfer reaction in protein lysine methyltransferases occurs via a linear S N2 associative reaction with bond making of approximately 50%.
 ...
PMID:Mechanism of product specificity of AdoMet methylation catalyzed by lysine methyltransferases: transcriptional factor p53 methylation by histone lysine methyltransferase SET7/9. 1826 Jun 47


<< Previous 1 2 3 4 5 6 7 Next >>