Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Rapamycin induces chromosome malsegregation in mammalian cell lines and yeast. Previous studies indicate that the function impaired in ataxia-telangiectasia (A-T) patients is necessary for both the growth inhibition and the chromosome malsegregation induced by rapamycin, and that treating the non-tumorigenic Chinese hamster cell line CHEF/18 with rapamycin results in supernumerary centrosomes and multipolar spindles. In this paper we report that lymphoblastoid cell lines established from A-T patients as well as hamster A-T-like cells are more resistant to rapamycin than the respective normal cell lines. Two cell lines derived from Nijmegen Breakage Syndrome (NBS) patients, who have clinical symptoms similar to those of A-T but a different molecular defect, were not resistant to rapamycin. Both A-T lymphoblastoid cells and A-T-like fibroblasts had giant centrosomes formed by more than two areas of gamma-tubulin-reacting material. Such giant centrosomes were also observed in CHEF/18 cells after prolonged treatment with rapamycin. Formation of giant centrosomes, possibly due to the coalescence of supernumerary centrosomes, was associated with increased aneuploidy in treated cells. Expression analysis of cell-cycle regulatory genes in rapamycin-treated human lymphoblastoid cells indicated that rapamycin decreased the expression of the tumor suppressor gene GADD45. The levels of RB, p21 and p53 mRNA were also decreased, although to a lesser extent. As rapamycin is often used as an immunosuppressant in pediatric transplant patients, these data indicate that caution should be taken, especially when the drug is given for prolonged periods of time.
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PMID:Altered centrosomes in ataxia-telangiectasia cells and rapamycin-treated Chinese hamster cells. 1592 Jul 52

N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.
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PMID:mTOR inhibitors (rapamycin and its derivatives) and nitrogen containing bisphosphonates: bi-functional compounds for the treatment of bone tumours. 1758 50

We examined the effects of rapamycin on activation, proliferation, and expression of cytotoxic effector molecules in Molt-4 human T lymphocytes. We investigated the effects of rapamycin on cell viability, caspase family protein activities. Western blots of Bcl-2, Bak, p53, p21, p27, Rb, CDK2, and cyclin B1, as well as measurement of reactive oxygen species (ROS) generation and mitochondrial membrane potential transition. Cells were cultured in the presence or absence of rapamycin. Flow cytometric analysis was performed using propidium iodide stain. Viability of Molt-4 cells was decreased by the addition of rapamycin in dose- and time-dependent manners. Rapamycin induced no nuclear fragmentation in Molt-4 cells. Generation of H2O2 in rapamycin-treated Molt-4 cells increased in a time-dependent manner. There were no changes among catalytic activities of caspase proteases. And there was no evidence of expression of Bcl-2, p53, p21, p27, or Rb proteins. G2/M phase cell cycle arrest was identified by flow cytometry. We noted decreased expressions of CDK2 and cyclin B1. We also noted increased Bak protein expression and change in mitochondrial membrane potential transition. In conclusion, rapamycin-induced cytotoxicity was characterized by generation of ROS, which modulated Bak protein expression and mitochondrial dysfunction. G2/M phase cell cycle arrest was achieved by decreased expressions of CDK2 and cyclin B1.
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PMID:Rapamycin-induced cytotoxic signal transduction pathway. 1892 49

Proteins containing extended polyglutamine repeats cause at least nine neurodegenerative disorders, but the mechanisms of disease-related neuronal death remain uncertain. We show that sympathetic neurons containing cytoplasmic inclusions formed by 97 glutamines expressed within human huntingtin exon1-enhanced green fluorescent protein (Q97) undergo a protracted form of nonapoptotic death that is insensitive to Bax deletion or caspase inhibition but is characterized by mitochondrial dysfunction. By treating the neurons with combined cytosine arabinoside and NGF withdrawal, we demonstrate that Q97 confers a powerful resistance to apoptosis at multiple levels: despite normal proapoptotic signaling (elevation of P-ser15-p53 and BimEL), there is no increase of Puma mRNA or Bax activation, both necessary for apoptosis. Even restoration of Bax translocation with overexpressed Puma does not activate apoptosis. We demonstrate that this robust inhibition of apoptosis is caused by Q97-mediated accumulation of Hsp70, which occurs through inhibition of proteasomal activity. Thus, apoptosis is reinstated by short hairpin RNA-mediated knockdown of Hsp70. These findings explain the rarity of apoptotic death in Q97-expressing neurons. Given the proteasomal blockade, we test whether enhancing lysosomal-mediated degradation with rapamycin reduces Q97 accumulation. Rapamycin reduces the amount of nonpathological Q25 by 70% over 3 d, but Q97 accumulation is unaffected. Interestingly, Q47 inclusions form more slowly as a result of constitutive lysosomal degradation, but faster-forming Q97 inclusions escape lysosomal control. Thus, cytoplasmic Q97 inclusions are refractory to clearance by proteasomal and lysosomal systems, leading to a toxicity that dominates over neuroprotective Hsp70. Our findings may explain the rarity of apoptosis but the inevitable cell death associated with polyQ inclusion diseases.
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PMID:Cytoplasmic inclusions of Htt exon1 containing an expanded polyglutamine tract suppress execution of apoptosis in sympathetic neurons. 1911 73

Mammalian target of rapamycin (mTOR) is a regulator of cell growth and proliferation and its activity is altered in many human cancers. The main objective of this study was to evaluate in vitro and in vivo targeting of mTOR by photodynamic therapy (PDT), a treatment modality for cancer. The amphiphilic endolysosomal localizing photosensitizer AlPcS(2a) and the p53 mutated rapamycin-resistant colon adenocarcinoma cell line WiDr were used as models. AlPcS(2a)-PDT downregulated the levels of Ser(2448) phosphorylated mTOR (p-mTOR), total mTOR and phosphorylation of ribosomal S6 (p-S6) immediately after light exposure in a dose-dependent manner, indicating a direct targeting of the mTOR signaling network. Low-dose PDT attenuated the level of p-mTOR in a transient manner; approximately 35% reduction of p-mTOR was obtained 5 min after a LD(35) PDT dose, but returned to the basal level 24 h later. Treatment with the mTOR inhibitor rapamycin reduced the p-mTOR level by 25% after 4-24 h of incubation. Combination treatment of rapamycin and PDT in vitro resulted in synergistic cytotoxic effects when rapamycin was administered after PDT. However, antagonistic effects were obtained when rapamycin was incubated both before and after PDT. In vivo, activated mTOR in the WiDr-xenografts was downregulated by 35 and 75% 5 min and 24 h post PDT respectively as measured by immunoblotting. In contrast to untreated tumors where p-mTOR expression was found throughout the tumors, immunohistochemical staining revealed only expression of p-mTOR in the rim of the tumor at 24 and 48 h post PDT. In conclusion, AlPcS(2a)-PDT is a novel mTOR-targeted cancer therapy. Rapamycin synergistically enhances the cytotoxicity of PDT only when administered post light exposure.
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PMID:Photodynamic therapy targets the mTOR signaling network in vitro and in vivo. 1912 12

Betel-quid use is associated with liver cancer whereas its constituent arecoline is cytotoxic, genotoxic, and induces p53-dependent p21(WAF1) protein expression in Clone-9 cells (rat hepatocytes). The ataxia telangiectasia mutated (ATM)/rad3-related (ATR)-p53-p21(WAF1) and the phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways are involved in the DNA damage response and the pathogenesis of cancers. Thus, we studied the role of ATM/ATR and PI3K in arecoline-induced p53 and p21(WAF1) protein expression in Clone-9 cells. We found that arecoline (0.5 mM) activated the ATM/ATR kinase at 30 min. The arecoline-activated ATM/ATR substrate contained p-p53Ser15. Moreover, arecoline only increased the levels of the p-p53Ser6, p-p53Ser15, and p-p53Ser392 phosphorylated p53 isoforms among the known isoforms. ATM shRNA attenuated arecoline-induced p-p53Ser15 and p21(WAF1) at 24 h. Arecoline (0.5 mM) increased phosphorylation levels of p-AktSer473 and p-mTORSer2448 at 30-60 min. Dominant-negative PI3K plasmids attenuated arecoline-induced p21(WAF1), but not p-p53Ser15, at 24 h. Rapamycin attenuated arecoline-induced phosphrylated p-p53Ser15, but not p21(WAF1), at 24 h. ATM shRNA, but not dominant-negative PI3K plasmids, attenuated arecoline-induced p21(WAF1) gene transcription. We conclude that arecoline activates the ATM/ATR-p53-p21(WAF1) and the PI3K/Akt-mTOR-p53 pathways in Clone-9 cells. Arecoline-induced phosphorylated p-p53Ser15 expression is dependent on ATM whereas arecoline-induced p21(WAF1) protein expression is dependent on ATM and PI3K. Moreover, p21(WAF1) gene is transcriptionally induced by arecoline-activated ATM.
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PMID:Arecoline-induced phosphorylated p53 and p21(WAF1) protein expression is dependent on ATM/ATR and phosphatidylinositol-3-kinase in clone-9 cells. 1934 84

Rapamycin, a potential anti-cancer agent, modulates activity of various factors functioning in translation, including eIF4E, an initiation factor selectively regulating expression of a subset of cellular transcripts. We show here that rapamycin suppresses levels of the p53-regulator MDM2 by translational inhibition without affecting mdm2 mRNA expression or protein stability. Rapamycin inhibits translation of mdm2 mRNA from the constitutive P1 promoter, which contains two upstream ORFs (uORFs) in the 5'UTR. Suppression is accompanied by increased hypo-phosphorylation of 4EBP-1, an inhibitory eIF4E binding protein. Ectopic expression of eIF4E abrogates rapamycin-mediated MDM2 inhibition, suggesting that eIF4E is crucial in modulating MDM2 expression in rapamycin-treated cells. Rapamycin administration also results in elevated PUMA expression and PARP cleavage, which is reproduced by siRNA knockdown of eIF4E or MDM2, suggesting that MDM2 suppression by rapamycin stimulates p53-mediated apoptosis. Together, our results define translational regulation of MDM2 expression by eIF4E and provide a molecular mechanism underlying rapamycin-induced p53-dependent apoptosis.
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PMID:Rapamycin increases the p53/MDM2 protein ratio and p53-dependent apoptosis by translational inhibition of mdm2 in cancer cells. 1956 Feb 64

[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate.
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PMID:Gateways to clinical trials. 1996 3

Akt and mTOR are therapeutic targets for the treatment of cancer. The effects of inhibiting mTOR, with rapamycin, and Akt, with A-443654, concurrently, on cell morphology, cell proliferation, the cell cycle, and apoptosis were examined using the benign MCF10A and malignant MCF10CA1a human breast epithelial cells. Rapamycin and A-443654 in combination produced the greatest morphological changes and inhibited cell proliferation by G2/M arrest. Rapamycin and A-443654 in combination induced apoptosis at earlier times and at lower A-443654 concentrations in MCF10CA1a tumor cells than in the benign MCF10A cells. Rapamycin and A-443654 increased p53 and p15(INK4B) protein levels, decreased anti-apoptotic Bcl-2 levels, and increased Bad levels in the MCF10CA1a tumor cells by approximately 5-fold. These results suggest that the combined inhibition of Akt and mTOR may have beneficial therapeutic and safety margin effects.
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PMID:Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells. 2041 28

Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the mTOR inhibitor rapamycin converted nutlin-3a-induced senescence into quiescence. We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells.
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PMID:The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. 2060 26


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