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)

In LNCaP prostate cancer cells CG-1521, a new inhibitor of histone deacetylases, alters the acetylation of p53 in a site-specific manner. While p53 is constitutively acetylated at Lys320 in LNCaP cells, treatment with CG-1521, stabilizes the acetylation of p53 at Lys373, elevating p21 (and inducing cell cycle arrest). Treatment with CG-1521 also promotes Bax translocation to the mitochondria and cleavage, and apoptosis. TSA stabilizes the acetylation of p53 at Lys382, elevating p21 levels and inducing cell cycle arrest, but does not induce Bax translocation or apoptosis. In LNCaP cells CG-1521, but not TSA, promotes the rapid degradation of HDAC2. These data suggest that the acetylation of p53 at Lys373 is required for the p53-mediated induction of cell cycle arrest and apoptosis, while acetylation of p53 at Lys382 induces only cell cycle arrest. In p53(-/-) PC3 cells both compounds induce p21 and cell cycle arrest, but not Bax translocation or apoptosis, suggesting that both compounds can also induce p21 through a p53-independent mechanism.
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PMID:Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. 1574 40

Most attacks of acute pancreatitis display a self-limiting course. This suggests that pancreatic acinar cells may be able to protect themselves against cellular injury thus preventing further progression of the disease. In this review we describe several genes overexpressed in acute experimental pancreatitis which take part in the pancreatic stress response. We discuss the possible function of the pancreatitis-associated protein 1, the small nuclear protein p8, the glycoprotein clusterin, different heat shock proteins, the p53-dependent stress proteins TP53INP1alpha and TP53INP1beta, the vacuole membrane protein-1, as well as the interferon-inducible protein-15, the antiproliferative p53-dependent protein PC3/TIS21/BTG2, and the pancreatitis-induced protein-49. The implications of these proteins in pathophysiological processes like apoptosis regulation, regeneration, cell cycle and growth control, regulation of inflammation, and vacuole formation are discussed. Study of the function of stress proteins expressed in response to pancreatitis could widen our understanding of the pathophysiology of the disease and enable us to develop new rational therapeutic strategies.
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PMID:The stress response of the exocrine pancreas. 1575 6

Treatment with epigallocatechin-3-gallate (EGCG), a polyphenolic compound of green tea, results in activation of p53 and induction of apoptosis in prostate cancer LnCaP cells. However, no direct evidence has delineated the role of p53 and p53-dependent pathways in EGCG-mediated apoptosis. To understand the mechanism of negative growth regulation of prostate cancer cells by EGCG we undertook a genetic approach and generated an isogenic pair of prostate carcinoma cells PC3 (p53-/-) by stably introducing a cDNA encoding wild-type p53. Treatment of the resultant cells, PC3-p53, with EGCG led to, as reported earlier in LnCaP cells, an increase in p53 protein, which exacerbated both G1 arrest and apoptosis. This response was accompanied by an increase in the levels of p21 and Bax. The cells lacking p53 continued to cycle and did not undergo apoptosis upon treatment with similar concentrations of EGCG, thus establishing the action of EGCG in a p53-dependent manner. This observation was revalidated in another prostate cancer LNCaP cells harboring wild-type p53. Inactivation of p53 using small interfering RNA (siRNA) rendered these cells resistant to EGCG-mediated apoptosis. Because p53 activation led to increase in p21 and Bax, we investigated whether these two proteins are important in this process. Ablation of p21 protein by siRNA prevented G1 arrest and apoptosis in PC3-p53 cells. The p53-dependent increase in Bax expression altered the Bax/Bcl-2 ratio and paralleled the activation of caspase 9 and 3 and cleavage of PARP. Transfection of cells with Bax siRNA abolished these effects and inhibited apoptosis but did not affect the accumulation of the cells in G1. In summary, using isogenic cell lines and siRNA, we have clearly demonstrated that EGCG activates growth arrest and apoptosis primarily via p53-dependent pathway that involves the function of both p21 and Bax such that down-regulation of either molecule confers a growth advantage to the cells.
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PMID:Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. 1576 47

p53 is frequently mutated in patients with prostate cancer, especially in those with advanced disease. Therefore, the selective elimination of p53 mutant cells will likely have an impact in the treatment of prostate cancer. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53-defective cells to chemotherapy while sparing normal cells. To test this idea, we knocked down ataxia telangiectasia mutated (ATM) gene by RNA interference in prostate cancer cell lines and in normal human diploid fibroblasts IMR90. ATM knockdown in p53-defective PC3 prostate cancer cells accelerated their cell cycle transition, increased both E2F activity and proliferating cell nuclear antigen expression, and compromised cell cycle checkpoints, which are normally induced by DNA damage. Consequently, PC3 cells were sensitized to the killing effects of the DNA-damaging drug doxorubicin. Combining ATM knockdown with the Chk1 inhibitor UCN-01 further increased doxorubicin sensitivity in these cells. In contrast, the same strategy did not sensitize either IMR90 or LNCaP prostate cancer cells, both of which have normal p53. However, IMR90 and LNCaP cells became more sensitive to doxorubicin or doxorubicin plus UCN-01 when both p53 and ATM functions were suppressed. In addition, knockdown of the G(2) checkpoint regulators ATR and Chk1 also sensitized PC3 cells to doxorubicin and increased the expression of the E2F target gene PCNA. Together, our data support the concept of selective elimination of p53 mutant cells by combining DNA damage with checkpoint inhibitors and suggest a novel mechanistic insight into how such treatment may selectively kill tumor cells.
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PMID:RNA silencing of checkpoint regulators sensitizes p53-defective prostate cancer cells to chemotherapy while sparing normal cells. 1580 89

Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.
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PMID:EphB4 expression and biological significance in prostate cancer. 1593 Feb 80

We discovered a series of salicylhydrazide class of compounds with remarkable anticancer activity against a panel of hormone receptor-positive and -negative cell lines. In the present study, we evaluated the in vitro activity of SC21 and SC23 against a range of human tumor cell types and the in vivo efficacy of compound SC21 in a PC3 human prostate cancer xenograft model in mice. We also determined the effects of SC21 on cell cycle regulation and apoptosis. Our in vitro results show that salicylhydrazides are highly potent compounds effective in both hormone receptor-positive and -negative cancer cells. SC21 induced apoptosis and blocked the cell cycle in G(0)/G(1) or S phase, depending on the cell lines used and irrespective of p53, p21, pRb, and p16 status. SC21 effectively reduced the tumor growth in mice without apparent toxicity. Although the mechanism of action of SC21 is not completely elucidated, the effect on cell cycle, the induction of apoptosis and the activity against a panel of tumor cell lines of different origins prompted us to carry out an in-depth preclinical evaluation of SC21.
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PMID:Discovery and preclinical evaluation of a novel class of small-molecule compounds in hormone-dependent and -independent cancer cell lines. 1602 Jun 68

Toward the goal of developing effective treatments for prostate cancers, we examined the effects of cyclin-dependent kinase inhibitors on the survival of prostate cancer cells. We show that roscovitine, R-roscovitine, and CGP74514A (collectively referred to as CKIs) induce the apoptosis of LNCaP and LNCaP-Rf cells, both of which express wild-type p53. Apoptosis required caspase-9 and caspase-3 activity, and cytochrome c accumulated in the cytosol of CKI-treated cells. Amounts of p53 increased substantially in CKI-treated cells, whereas amounts of the endogenous caspase inhibitor XIAP decreased. CKIs did not appreciably induce the apoptosis of LNCaP cells treated with pifithrin-alpha, which prevents p53 accumulation, or of prostate cancer cells that lack p53 function (PC3 and DU145). Ectopic expression of p53 in PC3 cells for 44 hours did not reduce XIAP abundance or induce apoptosis. However, p53-expressing PC3 cells readily apoptosed when exposed to CKIs or when depleted of XIAP by RNA interference. These findings show that CKIs induce the mitochondria-mediated apoptosis of prostate cancer cells by a dual mechanism: p53 accumulation and XIAP depletion. They suggest that these events in combination may prove useful in the treatment of advanced prostate cancers.
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PMID:Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells. 1614 Sep 39

Although genistein has chemopreventive effects in several human malignancies, including cancers of the breast, colon, and prostate, the mechanisms of action are not fully understood. Herein we report novel mechanisms whereby genistein down-regulates the MDM2 oncogene, perhaps explaining some of its anticancer activities. In a dose- and time-dependent manner, genistein reduced MDM2 protein and mRNA levels in human cell lines of breast, colon, and prostate cancer; primary fibroblasts; and breast epithelial cells. The inhibitory effects were found at both transcriptional and posttranslational levels and were independent of tyrosine kinase pathways. We found that the NFAT transcription site in the region between -132 and +33 in the MDM2 P2 promoter was responsive to genistein. At the posttranslational level, genistein induced ubiquitination of MDM2, which led to its degradation. Additionally, genistein induced apoptosis and G2 arrest and inhibited proliferation in a variety of human cancer cell lines, regardless of p53 status. We further showed that MDM2 overexpression abrogated genistein-induced apoptosis in vitro and that genistein inhibited MDM2 expression and tumor growth in PC3 xenografts. In conclusion, genistein directly down-regulates the MDM2 oncogene, representing a novel mechanism of its action that may have implications for its chemopreventive and chemotherapeutic effects.
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PMID:Genistein, a dietary isoflavone, down-regulates the MDM2 oncogene at both transcriptional and posttranslational levels. 1616 95

E1B55K adenovirus codes the protein that inactivates the p53 protein of host cells and facilitates its own cell proliferation. We prepared E1B55K-deleted adenovirus and investigated its cytopathic effects in primary lung cancer cells to evaluate the possibility of its application in gene therapy. A p53 wild-type small cell lung cancer cell line (SBC3) and three p53 mutant cell lines (SBC5, small cell lung cancer; PC3, adenocarcinoma; and EBC1, squamous cell carcinoma) were infected with AxE1AdB, in which the E1B55K gene was deleted, to assess the cytotoxicity and induction of apoptosis. Moreover, the mRNA expression in virus-infected cells was studied with cDNA array analysis to investigate the response of cancer cells to the virus infection. As a result, AxE1AdB had no detectable cytopathic effect on SBC3 cells, and SBC3 cells continued to replicate. In contrast, AxE1AdB killed SBC5, PC3, and EBC1 cells with great efficiency. In SBC3, apoptosis of the host cells was observed in the early infection stage; in the p53-mutant cell lines, apoptosis of the cells was restricted. An analysis of gene expression in the host cells indicated a significant increase of Bax mRNA in SBC3 and its deficiency in SBC5. Overall, our results suggest that AxE1AdB replicated selectively in the p53-mutant lung cancer cells and showed strong cytotoxicity against them. In the p53-intact cells, p53 induced apoptosis through Bax expression and prevented virus replication and escalation of the infection.
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PMID:E1B-deleted adenovirus replicates in p53-deficient lung cancer cells due to the absence of apoptosis. 1621 Dec 79

TIS21(/BTG2/PC3), orthologs of mouse, human and rat, respectively, is initially identified as one of the early growth response genes and induced by various stimulations. TIS21 belongs to antiproliferative (APRO) gene family containing the BTG-Box A (Y(50)-N(71)) and BTG-Box B (L(97)-E(115)), which are highly conserved among various species. On the other hand, it has lately been found that the expression of TIS21 is constitutive and high in thymus, lung alveolar epithelium, proximal tubule of kidney and basal cell layer of prostate acini. Potential roles of TIS21 have been suggested as transcriptional co-regulator, differentiation and antiapoptotic factor in neurogenesis, key mediator of the stage-specific expansion of thymocyte and negative regulator of hematopoietic progenitor expansion, and tumor suppressor gene in both mouse and human. In addition, as pan-cell cycle regulator TIS21 induces G1/S arrest by pRB dependently and pRB independently and G2/M arrest and cell death in the p53 null tumor cells, and regulates the development of vertebrate patterning in mouse, paraxial mesoderm development in zebrafish, and notochord development in Xenopus. It has been known that the expression of TIS21 depends on the induction of wt p53 when cells are damaged, however, it can also be upregulated p53 independently by the activation of PKC-delta pathway in tumor cells. The characteristic roles of TIS21 are discussed in the present review: (1) TIS21 inhibits early phase of carcinogenesis in its high expressers such as kidney, prostate, breast and thymus: Loss of constitutive and high expression of TIS21 was observed in the precancerous lesions as well as tumor tissues. As an endogenous cell death molecule, TIS21 may be involved in translocation of Pin-1 to cytoplasm. Pin-1 subsequently interacts with Serine(147) residue in TIS21 protein, resulting in mitochondrial depolarization. (2) TIS21 regulates transition of cell cycle at G1/S and G2/M phases in cancer cells with inactive pRB and/or p53, as well as in normal cells by regulating pRB/p16(INK4a) pathway. The latter has already been well elucidated; TIS21 inhibits the expression of cyclin D1, thus resulting in the arrest of cells at G1/S phase by pRB and p53 dependent manner. On the other hand, TIS21 inhibits degradations of cyclin A and cyclin B1 at G2/M phase, and directly binds to Cdc2, resulting in the failure of mitotic exit and then increasing the tumor cell death, when stimulated by high concentration of EGF. Therefore, TIS21 can be suggested as a pan-cell cycle modulator. (3) TIS21 regulates embryo development by activating BMP signal through interaction with Smad 1 and Smad 8, thereby regulating vertebral patterning in mice. It is also involved in notochord development in Xenopus and paraxial mesoderm development in zebrafish. Based on the previous report that the expression of TIS21 is involved in the induction of senescence after chemotherapy of cancer cells, which can be a mechanism to resist carcinogenesis, TIS21(/BTG2/PC3), the endogenous cell death molecule and pan-cell cycle regulator, might be a link between cellular senescence and carcinogenesis.
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PMID:TIS21 (/BTG2/PC3) as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. 1645 75


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