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)

To investigate the radioprotective potential of eckol, a component of the seaweed Ecklonia cava, against radiation in vivo, we evaluated the effect of eckol on cyto- and histo-protective capability of the lymphocytes and intestine against damage induced by a single whole body irradiation (WBI) in vivo. Here, we ascertained that eckol protected the lymphocytes' viability and rescued intestinal cells from radiation-induced apoptosis by decreasing the amount of pro-apoptotic p53 and Bax and increasing that of anti-apoptotic Bcl-2. These findings indicate that the overexpression of anti-apoptotic protein, which may lead to resistance to DNA damage, is involved deeply in protection of gastrointestinal cells after irradiation. Thus, eckol that can protect cells and tissues against ionizing radiation may have considerable potential as adjuncts to successful radiotherapy.
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PMID:Modulation of apoptosis of eckol against ionizing radiation in mice. 1852 2

Scotin is a pro-apoptotic mammalian gene, which is induced upon DNA damage or cellular stress in a p53-dependent manner. In this report, we have used Drosophila as a model system to obtain a preliminary insight into the molecular mechanism of Scotin function, which was further validated using the mammalian system. Targeted expression of Scotin in developing Drosophila induced apoptosis and developmental defects in wings and eyes. Co-expression of Scotin with the anti-apoptotic protein p35, while inhibited the apoptosis in both dividing and non-dividing cells, rescued adult wing or eye phenotypes only when Scotin was expressed in non-dividing cells. This suggests that mechanisms of Scotin-induced apoptosis in dividing and non-dividing cells may vary. Suppressor-enhancer screen using cell cycle regulators suggested that Scotin may mediate cell cycle arrest at both G(1)/S and G(2)/M phases. Overexpression of Scotin in mammalian cells resulted in mitotic arrest and subsequently apoptosis. Furthermore, a larger proportion of cells overexpressing Scotin showed sequestration of Cyclin B1 in the cytoplasm. These results suggest that one of the ways by which Scotin induces apoptosis is by causing cell cycle arrest.
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PMID:Cell cycle regulation by the pro-apoptotic gene Scotin. 1867 3

Nuclear protein 1 (NUPR1/com1/p8) has been shown to interact with transcriptional regulators such as p300, PTIP, estrogen receptor-beta, and SMAD. NUPR1 also has been implicated in the regulation of cell cycle and apoptosis. An increase in NUPR1 expression has been seen with serum starvation and in response to compounds such as cycloheximide, ceramide, and staurosporine. There are several overtly conflicting reports about the exact role of NUPR1 in tumor biology. This work investigates the nature of the relationship between NUPR1 and the cdk-inhibitor p21 (Waf1/Cip1) expression. We show that the expression of resident and doxorubicin-induced p21 paralleled that of endogenous NUPR1 levels. NUPR1 formed a complex with p53 and p300 and bound the p21 promoter and transcriptionally upregulated p21 expression. Moreover, NUPR1 allowed cells to progress through cell cycle in presence of doxorubicin. Since NUPR1 upregulated p21, concomitant with phosphorylation of Rb and upregulation of the anti-apoptotic protein, Bcl-x(L) we propose that NUPR1 expression imparts a cell growth and survival advantage. Importantly, we also report that NUPR1 conferred resistance to two chemotherapeutic drugs, Taxol and doxorubicin.
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PMID:NUPR1 interacts with p53, transcriptionally regulates p21 and rescues breast epithelial cells from doxorubicin-induced genotoxic stress. 1869 Aug 48

Non-small cell lung Cancer (NSCLC) is extremely resistant to chemotherapeutic agents, such as cisplatin. High expression of the inflammatory enzyme cyclooxygenase-2 (COX-2) has been shown to inhibit chemotherapy-induced apoptosis, but little is known about COX-2 regulation upon drug treatment. Recent data indicate the tumor suppressor protein p53 as an important regulator of COX-2. Therefore, TP53 status could change tumor sensitivity to chemotherapy through induction of the anti-apoptotic protein COX-2. The main objective of this work was to analyze the effect of chemotherapy on the expression of COX-2, according to TP53 status. We report herein that lung cancer cell lines expressing wild-type p53, when exposed to cisplatin treatment, induced COX-2 (mRNA and protein), with concurrent synthesis of prostaglandins (PGE(2)). In contrast, COX-2 expression was not changed after cisplatin treatment of cells containing an inactive form of p53. Further, after silencing of wild-type p53 expressed in A549 cells by RNA interference, cisplatin was no longer able to induce COX-2 expression. Therefore, we suggest that induction of COX-2 by cisplatin in NSCLC cell lines is dependent on p53. For paclitaxel treatment, an increase in COX-2 mRNA expression was observed in H460 and A549 (wild-type p53 cell lines). Moreover, paclitaxel treatment increased COX-2 expression in ACC-LC-319 cell lines (p53 null), showing a p53-independent effect. These data may have therapeutic implications in the selection of patients and strategy for future COX-2 inhibition trials.
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PMID:Role of p53 in the induction of cyclooxygenase-2 by cisplatin or paclitaxel in non-small cell lung cancer cell lines. 1921 9

Pluripotent human embryonic stem (hES) cells require mechanisms to maintain genomic integrity in response to DNA damage that could compromise competency for lineage-commitment, development, and tissue-renewal. The mechanisms that protect the genome in rapidly proliferating hES cells are minimally understood. Human ES cells have an abbreviated cell cycle with a very brief G1 period suggesting that mechanisms mediating responsiveness to DNA damage may deviate from those in somatic cells. Here, we investigated how hES cells react to DNA damage induced by ionizing radiation (IR) and whether genomic insult evokes DNA repair pathways and/or cell death. We find that hES cells respond to DNA damage by rapidly inducing Caspase-3 and -8, phospho-H2AX foci, phosphorylation of p53 on Ser15 and p21 mRNA levels, as well as concomitant cell cycle arrest in G2 based on Ki67 staining and FACS analysis. Unlike normal somatic cells, hES cells and cancer cells robustly express the anti-apoptotic protein Survivin, consistent with the immortal growth phenotype. SiRNA depletion of Survivin diminishes hES survival post-irradiation. Thus, our findings provide insight into pathways and processes that are activated in human embryonic stem cells upon DNA insult to support development and tissue regeneration.
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PMID:Survival responses of human embryonic stem cells to DNA damage. 1937 64

The Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer. Treatment with microtubule-targeting agents, including taxanes and Vinca alkaloids, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl2 expression remains poorly understood. We report here that p53 contributes to vinorelbine-induced Bcl-2 down-regulation. Indeed, the decrease in Bcl-2 protein levels observed during vinorelbine-induced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We identified, by chromatin immunoprecipitation, a novel p53 binding site in the Bcl-2 promoter, within a region upstream P(1) promoter. We showed that vinorelbine treatment increased this interaction in A549 cells. This work strengthens the links between p53 and Bcl-2 at a transcriptional level, upon microtubule-targeting agent treatment. Our study also provides answers that will be useful to assess microtubule-targeting agents' mechanism of action and that may help to better understand and increase their effectiveness.
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PMID:Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter. 1955 69

It has been suggested that the downregulation of AR expression should be considered the principal strategy for the treatment of hormone-refractory prostate cancer. We have previously shown that inhibition of AR induced PI3K-independent activation of Akt that was mediated by CaMKII. In this study, we found that the CaMKII inhibitor KN-93 has a broader effect on apoptosis than just inhibition of CaMKII: first, KN-93 inhibits AR activity and induces cell death in PCa cells after androgen deprivation when many other drugs fail to kill prostate cancer cells; second, KN-93 inhibits expression of the anti-apoptotic protein Mcl-1 and induces expression of the pro-apoptotic protein PUMA; third, KN-93-mediated cell death is p53-independent; and fourth, KN-93 induces the generation of ROS. The ROS induction allows KN-93 to circumvent the activation of Akt, which occurs in prostate cancer cells under androgen deprivation, since Akt could not inhibit ROS-mediated apoptosis. KN-93 also synergistically induces cell death in combination with low doses of doxorubicin and converts the phenotype of prostate cancer cells from TRAIL-resistant to -sensitive. These data suggest that KN-93 could be used for novel therapeutic approaches when hormonal therapy has failed.
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PMID:KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer. 2002 17

Thyroid cancer is the most common endocrine malignancy and exhibits the full range of malignant behaviors from the relatively indolent occult differentiated thyroid cancer to uniformly aggressive and lethal anaplastic thyroid cancer. Iodine is a well known key element in thyroid normal function maintenance and thyroid cancer development. However, the effects induced by iodine and the molecular mechanisms involved remain poorly understood in thyroid cancer. We investigated the apoptotic effect of iodine on three different subtypes of thyroid cancer cells. We observed that apoptosis induced by iodine was mitochondrial-mediated. Iodine treatment decreased the level of mutant p53 including the R273H mutant that possesses anti-apoptotic features, but increased the p21 level. Surprisingly, high doses of iodine promoted instead of suppressed the expression of anti-apoptotic protein Bcl-xL expression. Moreover, iodine transiently activated the subfamily members of mitogen activated protein kinases (MAPKs) (ERK1/2, p38 and JNK1/2) which contribute to modulate p53, p21 and Bcl-xL expression. The further results showed the three subfamily members of MAPKs all worked as anti-apoptotic factors. Collectively, iodine-induced apoptotic pathway is involved in the activation of MAPKs-related p21, Bcl-xL and mutant p53 regulation. The findings provide solid molecular evidence to explain the potential pathway for iodine to influence thyroid cancer development. It may also reveal some novel molecular targets for the treatment of thyroid cancer.
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PMID:Iodine induces apoptosis via regulating MAPKs-related p53, p21, and Bcl-xL in thyroid cancer cells. 2013 58

The antiproliferative effect of tandem somatostatin receptor (SSTR) activation, epidermal growth factor receptor (EGFR) inhibition, and induction of DNA damage was analyzed using octreotide (OCT), a SSTR agonist, the clinical DNA methylating agent temozolomide (TMZ), Iressa, an EGFR inhibitor, and dual EGFR-DNA targeting agents termed "combi-molecules". Using SSTR-expressing glioma cells harbouring low levels of EGFR (U87MG) or transfected to overexpress EGFR (U87/EGFR) or a variant (U87/EGFRvIII), we showed that Iressa, alone or in combination with the DNA damaging agent TMZ, and combi-molecules RA2 and RA5 inhibited EGF-induced phosphorylation of EGFR in U87MG and more moderately in U87/EGFR and U87/EGFRvIII transfected cells. This translated into equivalent levels of Erk 1/2 inhibition. Activation of SSTRs with OCT did not modulate the effects of the various treatments on Erk 1/2 phosphorylation. Likewise, SSTR activation did not alter TMZ- or DNA-damaging combi-molecules, RA2 and RA5, induced p53 activation nor upregulation. However, SSTR activation significantly shifted TMZ-, RA2- and RA5-induced cell-cycle arrest to earlier phases (i.e., G2/M to late S, late S to S, S to G1). Further analysis showed that apoptosis was not induced. This was in agreement with the fact that p53 activation did not induce Bax upregulation nor did EGFR inhibition promote Bad dephosphorylation. Moreover, enhancement of survivin, an anti-apoptotic protein, expression was observed. The results in toto suggest that the combination of SSTR activation with EGFR inhibition and DNA damage affects cell-cycle progression but a disconnection between the targeted signalling pathways in these brain tumour cells precludes synergistic cell-killing by the triple growth inhibitory events.
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PMID:Receptor activation and inhibition in cellular response to chemotherapeutic combinational mimicries: the concept of divergent targeting. 2046 86

Antioxidant property and hematopoietic repair capacity are important characteristics of radioprotective agents. Some studies have demonstrated that 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a molecule isolated from the waterlily, has antioxidant, hematopoietic repair, and anti-inflammatory activities. In this study, we try to determine whether PGG extracted from a lily, Nymphaea tetragona var. angusta, has radioprotective effects on splenocytes in vitro against (60)Co gamma-ray irradiation with absorption doses of 2 Gy and 4 Gy. Results show that PGG treatment dramatically enhances the proliferation of splenocytes compared with irradiated but untreated controls. In addition, PGG treatment before irradiation protects the splenocytes from lethal effects of irradiation and decreases DNA damages as identified by the alkaline comet assay. PGG-treated cells also show less radiation-induced apoptosis. These cells have lower concentrations of the pro-apoptotic protein p53 and more of the anti-apoptotic protein Bcl-2. The results presented in this study suggest that PGG has a cytoprotective effect on immune cells exposed to normally damaging amount of radiation. Thus, PGG could be an effective, non-toxic radioprotective agent.
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PMID:1,2,3,4,6-penta-O-galloyl-beta-D-glucose protects splenocytes against radiation-induced apoptosis in murine splenocytes. 2060


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