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)

Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS) are scarce. We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region. In addition, using quantitative RT-PCR we studied the expression of MDM2, CDK4, DDIT3 (CHOP/GADD153), DYRK2, HMGA2, TSPAN31 and YEATS4 (GAS41) in 11 cases. We showed that CDK4 (12q14.1) belonged to a distinct amplicon than MDM2 (12q15). There was no continuity in the amplified sequences between MDM2 and CDK4. Moreover, while MDM2 was amplified and overexpressed in all cases, CDK4 was not amplified or overexpressed in 13% of cases. The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3, a gene known for being involved in myxoid liposarcoma translocations. DDIT3 was amplified in 3 cases and overexpressed in 9 cases. The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status. This suggested that the CDK4 amplicon, as well as the overexpression of DDIT3, might be generated by the disruption of a fragile region in 5' DDIT3. HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS. HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7. We also found a frequent amplification and overexpression of YEATS4, an oncogene that inactivates P53, suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis.
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PMID:HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. 1821 54

Molecular paleopathology has become an emerging field that helps to characterize molecular markers of past disease. Especially highly sensitive genetic techniques such as PCR are an important means of unraveling changes in ancient DNA extracted from bone tissue, teeth and mummified soft tissue. In the present study, excavated bone material from the skeleton of a Scythian sovereign, morphologically and immunohistochemically suspicious of a metastatic prostate carcinoma, was analyzed by PCR for amplifiable human gene sequences. Short sequences of the human GADD153 DNA repair gene and p53 tumor suppressor gene were detectable which revealed the absence of mutations according to the data of automatic sequencing. Using bisulfite-treated DNA from the bone, methylation-specific PCR detected hypermethylated promoter sequences of the p14ARF tumor suppressor gene. In summary, these data show that it is possible: a) to amply short human DNA stretches from 2,500-year-old bone material, b) to detect tumorigenetically important genes within this DNA, c) to detect epigenetically modified DNA in ancient bone material. The finding of hypermethylated p14ARF sequences merits attention because this may indicate an intraosseal neoplastic process and may corroborate the hypothesis of prostate cancer.
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PMID:Detection and analysis of cancer genes amplified from bone material of a Scythian royal burial in Arzhan near Tuva, Siberia. 1822 81

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
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PMID:ATF3 protects against renal ischemia-reperfusion injury. 1823 2

Glioblastomas (GBMs) are resistant to apoptosis but less so to autophagy; a fact that may at least partly explain the therapeutic benefits of the pro-autophagic drug temozolomide in the treatment of GBM patients. Galectin-1 (Gal1) whose expression is stimulated by hypoxia is a potent modulator of GBM cell migration and a pro-angiogenic molecule. Hypoxia is also known to confer cancer cells with resistance to chemotherapy and radiotherapy and to modulate the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. The present study investigates whether decreasing Gal1 expression (by means of a siRNA approach) in human Hs683 GBM cells increases their sensitivity to pro-autophagic or pro-apoptotic drugs. The data reveal that temozolomide, the standard treatment for glioma patients, increases Gal1 expression in Hs683 cells both in vitro and in vivo. However, reducing Gal1 expression in these cells by siRNA increases the anti-tumor effects of various chemotherapeutic agents, in particular temozolomide both in vitro and in vivo. This decrease in Gal1 expression in Hs683 cells does not induce apoptotic or autophagic features, but is found to modulate p53 transcriptional activity and decrease p53-targeted gene expression including DDIT3/GADD153/CHOP, DUSP5 ATF3 and GADD45A. The decrease in Gal1 expression also impairs the expression levels of seven other genes implicated in chemoresistance: ORP150, HERP, GRP78/Bip, TRA1, BNIP3L, GADD45B and CYR61, some of which are located in the ER and whose expression is also known to be modified by hypoxia. This novel facet of Gal1 involvement in glioblastoma biology may be amenable to therapeutic manipulation.
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PMID:Evidence of galectin-1 involvement in glioma chemoresistance. 1831 12

Selenium at low concentrations has a chemopreventive role against cancer, while at high concentrations, selenite exerts a direct antitumor effect. However, the mechanisms behind these effects remain elusive. In this study, we found that different concentrations of selenite triggered different signal pathways in human leukemia NB4 cells. Low concentrations of selenite elicited mild endoplasmic reticulum (ER) stress and mediated cell survival by activating unfolded protein response signaling, whereas high concentrations of selenite induced severe ER stress and caused cell death by activation of the pro-apoptotic transcription factors GADD153. In addition, selenite at low concentrations activated other anti-apoptotic pathways, such as AKT and ERK, whereas high concentrations of selenite induced activation of p53 and oxidative stress, which mediated the antitumor activity of selenite by causing mitochondrial dysfunction and caspase activation. These findings uncover the molecular mechanisms of the chemopreventive and antitumor effects of different concentrations of selenite.
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PMID:Exposure of human leukemia NB4 cells to increasing concentrations of selenite switches the signaling from pro-survival to pro-apoptosis. 1915 35

Capsaicin, a pungent ingredient of red pepper, has been reported to possess antitumor activities. In this study, the effects of capsaicin on human HepG2 cells were investigated. Capsaicin reduced viability by PI incorporation in HepG2 cells in a dose and time dependent manner. Capsaicin promoted intracellular Ca2+ production and reactive oxygen species (ROS). The alpha psi(m) significantly decreased after capsaicin treatment for 24 h. Co-treatment of HepG2 cells with capsaicin and BAPTA (an intracellular Ca2+ chelator) significantly reduced intracellular Ca2+ levels, prevented alpha psi(m) disruption and inhibited apoptosis induction. The protein levels of Bcl-2 decreased and Bax increased in the mitochondrial fraction while the Bax protein decreased, and p53 and cytochrome c protein levels increased in the cytosolic fraction in HepG2 cells after capsaicin treatment for 24 h by Western blot. Immunostaining and confocal microscopic analysis also showed that capsaicin promoted cytoplasmic GADD153 expression and GRP78 nuclear translocation. The caspase-3 activity significantly increased after capsaicin treatment for 24 h. Our results indicated that the capsaicin-induced apoptosis in HepG2 cells may result from the elevation of intracellular Ca2+ production, ROS, disruption of alpha psi(m), regulation of Bcl-2 family protein expression and caspase-3 activity.
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PMID:Capsaicin-induced apoptosis in human hepatoma HepG2 cells. 1933 Nov 47

Although rhein has been shown to induce apoptosis in several cancer cell lines, the mechanism of action of rhein-induced cell cycle arrest and apoptosis at the molecular level is not well known. In this study, the mechanism of rhein action on A-549 human lung cancer cells was investigated. Rhein induced G0/G1 arrest through inhibition of cyclin D3, Cdk4 and Cdk6. The efficacious induction of apoptosis was observed at 50 microM for 12 h and up to 72 h as examined by a flow cytometric method. Flow cytometric analysis demonstrated that rhein increased the levels of GADD153 and GRP78, both hallmarks of endoplasmic reticulum stress, promoted ROS and Ca2+ production, induced the loss of mitochondrial membrane potential (delta psi(m)), promoted cytochrome c release from mitochondria, promoted capase-3 activation and led to apoptosis. Rhein also increased the levels of p53, p21 and Bax but reduced the level of Bcl-2. The Ca2+ chelator BAPTA was added to the cells before rhein treatment, thus blocking the Ca2+ production and inhibiting rhein-induced apoptosis in A-549 cells. Our data demonstrate that rhein induces apoptosis in A-549 cells via a Ca2+ -dependent mitochondrial pathway.
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PMID:The roles of endoplasmic reticulum stress and Ca2+ on rhein-induced apoptosis in A-549 human lung cancer cells. 1933 Nov 67

1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor kappaB (NF-kappaB) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappaB activity. A confocal microscope showed that emodin induced NF-kappaB translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER- and mitochondria-induced apoptosis of C6 cells.
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PMID:Emodin has cytotoxic and protective effects in rat C6 glioma cells: roles of Mdr1a and nuclear factor kappaB in cell survival. 1954 30

Capsaicin, a pungent compound found in hot chili peppers, induces apoptotic cell death in various cell lines, however, the precise apoptosis signaling pathway is unknown. Here, we investigated capsaicin-induced apoptotic signaling in the human breast cell line MCF10A and found that it involves both endoplasmic reticulum (ER) stress and calpain activation. Capsaicin inhibited growth in a dose-dependent manner and induced apoptotic nuclear changes in MCF10A cells. Capsaicin also induced degradation of tumor suppressor p53; this effect was enhanced by the ER stressor tunicamycin. The proteasome inhibitor MG132 completely blocked capsaicin-induced p53 degradation and enhanced apoptotic cell death. Capsaicin treatment triggered ER stress by increasing levels of IRE1, GADD153/Chop, GRP78/Bip, and activated caspase-4. It led to an increase in cytosolic Ca(2+), calpain activation, loss of the mitochondrial transmembrane potential, release of mitochondrial cytochrome c, and caspase-9 and -7 activation. Furthermore, capsaicin-induced the mitochondrial apoptotic pathway through calpain-mediated Bid translocation to the mitochondria and nuclear translocation of apoptosis-inducing factor (AIF). Capsaicin-induced caspase-9, Bid cleavage, and AIF translocation were blocked by calpeptin, and BAPTA and calpeptin attenuated calpain activation and Bid cleavage. Thus, both ER stress- and mitochondria-mediated death pathways are involved in capsaicin-induced apoptosis.
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PMID:Capsaicin-induced apoptosis is regulated by endoplasmic reticulum stress- and calpain-mediated mitochondrial cell death pathways. 1969 54

Receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) bind to cancer cell surface GRP78, which functions as a signaling receptor promoting proliferation and survival. Patients with prostate, ovary, and skin cancer may develop auto-antibodies to the alpha(2)M* binding site which are receptor agonists whose presence indicates a poor prognosis. By contrast, antibodies directed against the COOH-terminal domain of GPR78 (anti-CTD antibody), are antagonists which down regulate pro-proliferative signaling and upregulate p53. Unfolded protein response (UPR) signaling plays an important role in cell survival and proliferation as well as apoptosis. We, therefore, studied the effect of anti-CTD antibody on UPR signaling in 1-LN and DU-145 prostate cancer cells. Treatment of these cells, which express GRP78 on their cell surface, with this antibody significantly downregulated IRE1-alpha, PERK, and ATF6alpha-dependent UPR signaling. By contrast, the pro-apoptotic protein GADD153 was elevated. Anti-CTD antibody treatment also elevated apoptotic components, cleaved PARP-1, and Erdj5. In general, a two to threefold effect was observed for the parameters which were studied. These studies suggest that anti-CTD antibody induces growth inhibitory and pro-apoptotic effects by modulating UPR signaling in human prostate cancer cells.
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PMID:Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78. 2009 Dec 33


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