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)

This study tested the hypothesis that inhibitor of differentiation-2 (Id2), p53, and heat shock proteins (HSP) are responsive to suspension-induced muscle atrophy. Fourteen days of hindlimb suspension were used to unload the hindlimbs and induce atrophy in gastrocnemius muscles of young adult and aged rats. Following suspension, medial gastrocnemius muscle wet weight was reduced by approximately 30%, and the muscle wet weight normalized to the animal body weight decreased by 11 and 15% in young adult and aged animals, respectively. mRNA abundances of Id2, p53, HSP70-2, and HSP27 did not change with suspension, whereas HSP70-1 mRNA content was lower in the suspended muscle compared with the control muscle in both young adult and aged animals. Our immunoblot analyses indicated that protein expressions of HSP70 and HSP60 were not different between suspended and control muscles in both ages, whereas HSP27 protein content was increased in suspended muscle relative to control muscle only in young adult animals. Id2 and p53 protein contents were elevated in the cytosolic fraction of suspended muscle compared with the control muscle in both young and aged animals, but these changes were not found in the nuclear protein fraction. Furthermore, compared with young adult, aged muscles had a lower HSP70-1 mRNA content but higher HSP70-2 mRNA content and protein contents of Id2, p53, HSP70, and HSP27. These findings are consistent with the hypothesis that Id2 and p53 are responsive to unloading-induced muscle atrophy. Moreover, our data indicate that aging is accompanied with altered abundances of HSP70-1 and HSP70-2 mRNA, in addition to Id2, p53, HSP70, and HSP27 protein in rat gastrocnemius muscle.
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PMID:Hindlimb unloading increases muscle content of cytosolic but not nuclear Id2 and p53 proteins in young adult and aged rats. 1628 27

The change and the role of MAPK cascade pathway and P53 pathway after liver transplantation were explored. Thirty-four punctured donor liver specimens and 10 normal liver specimens were classified as group A (no rejection, n = 10), group B (mild/moderate acute rejection, n = 10), group C (serious acute rejection, n = 8), group D (chronic rejection/fibrosis, n = 6) and group E (control, n = 10). By using immunohistochemistry, the expression levels of mitogen activated protein kinase (MAPK), Ras and P53 proteins, and by in situ hybridization, MAPK and ras mRNA expression levels were detected. The results showed that the expression levels of MAPK and Ras proteins were increased by turns in groups A, B and C, and decreased by turns in groups D and E. The protein expression of P53 was higher in the treated groups. The expression of Ras, HSP70 mRNA was identical as that of protein. It is suggested that the MAPK cascade pathway and P53 pathway can protect the hepatocytes by different mechanisms after liver transplantation. MAPKs cascade pathway repairs hepatocyte injury or accelerates hepatocytes into proliferation or differentiation. P53 pathway blocks cell cycle within G1 phase to make hepatocyte repair or apoptosis to reduce disorder differentiation.
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PMID:Impact of MAPK cascade pathway and P53 pathway upon liver transplant. 1646 73

Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1alpha expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1alpha expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1alpha levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1alpha by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1alpha with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.
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PMID:Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. 1650 82

The proteasome inhibitor bortezomib is an efficacious apoptotic agent in many tumor cells. This paper shows that bortezomib induced apoptosis in human hepatoma HepG2 cells associated with many modifications in the expression of survival or death factors. Although bortezomib increased the level of the protective factors HSP70 and HSP27, the effects of the drug that favour cell death were predominant. These events include accumulation of c-Jun, phospho-c-Jun and p53; increase in FasL level with activation of caspase-8; changes related to members of Bcl-2 family with increase in the level of pro-apoptotic members and decrease in that of anti-apoptotic ones; dissipation of mitochondrial potential with cytochrome c release and activation of caspase-3. In contrast, Chang liver cells exhibited a very low susceptibility to bortezomib-induced apoptosis, which was accompanied by modest modifications in the expression of apoptotic factors. In HepG2 cells bortezomib markedly increased AP-1 activity and the expression of its transcriptional targets such as c-Jun, FasL, BimEL, which are involved in apoptosis. Moreover, AP-1 induced its own production by increasing c-Jun content in the composition of the same AP-1 complex. In addition, bortezomib caused activation of JNK1, which in turn increased the level of phospho-c-Jun as well as stimulated the activation of caspase-3 and t-Bid, two fundamental apoptotic factors. Interestingly, siRNA silencing of c-Jun or JNK1 reduced HepG2 cell susceptibility to apoptosis and prevented the increase in AP-1 activity. Both JNK-1 and AP-1 thus exerted a crucial role in bortezomib-induced apoptosis. Differently, in Chang liver cells the different composition of AP-1 complex as well as the failure of JNK activation seemed to be responsible for the low susceptibility to apoptosis. Given the high susceptibility of hepatoma cells to bortezomib, our results suggest the potential application of this compound in clinical trials for liver cancers.
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PMID:JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways. 1652 74

In the Western world cancer is the second leading cause of mortality, and prostate carcinoma represents in men the second most important type of cancer-causing death. We have already shown that resveratrol (200 microM) triggers in DU145, an androgen-resistant prostate cancer cell line, a necrotic-like cell death, while propolis ethanolic extract (100 microg/ml) causes an apoptotic-like cell demise. The present research is aimed to better elucidate the molecular mechanisms activated by the two micronutrients. Vinorelbine bitartrate, a drug widely used in prostate cancer therapy, was utilized as a reference drug, because it is known to induce apoptosis. The combined treatments between the micronutrients and vinorelbine have been studied to test a possible vinorelbine dose reduction, avoiding its side effects without altering its cytotoxic action. In this investigation SEM and TEM analyses were performed to examine the morphological modifications induced; our observations confirmed necrotic cell features after treatment with resveratrol, and apoptotic modifications after propolis. We also measured cell cycle progression to study a correlation with p21 and p53, two well-known cell cycle checkpoints. The levels of HSP27 and HSP70, two chaperones also exerting antioxidant/antiapoptotic functions, were been also analyzed. Our data indicate that the two micronutrients modulate cell cycle distribution, increasing p53 levels, without the induced HSPs being able to rescue DU145 from death. The results presented suggest chemotherapy based on resveratrol and propolis, alone or in combination with vinorelbine, as a potential useful tool for prostate cancer therapy; the increase in cell cycle control and the modulation of HSPs expression reinforce this suggestion.
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PMID:Resveratrol and propolis extract: an insight into the morphological and molecular changes induced in DU145 cells. 1655 47

The role of cyclooxygenase-2 (COX-2) and the mechanism by which it influences the development and behavior of prostate cancer is unclear. Selective COX-2 inhibitors may be effective against prostate cancer via COX-2-independent mechanisms. But administration of high doses of COX-2 inhibitors over longer period of time may not be devoid of side effects. There is increasing interest in using COX-2 inhibitors in combination with other chemopreventive agents to overcome the issue of toxicity. However, the molecular mechanisms underlying their combined actions are not well understood. Therefore, the present study was designed to determine the effects of low doses of docosahexaenoic acid (DHA) in combination with celecoxib on the molecular targets at the proteins level in rat prostate cancer cells. Two-dimensional gel electrophoresis, in combination with mass spectrometry analysis, was used for protein identification. Western blot analysis confirmed the proteins identified. Paraffin-embedded tissue sections from the rat prostate tumor were used to detect base level expression of heat shock protein 70 (HSP70) and p53. The rate of cancer cell growth was inhibited more effectively (p < 0.01) by DHA in combination with celecoxib at lower doses (2.5 microM each). A total number of twelve proteins were differentially expressed by the combined action of DHA and celecoxib at low doses. It was interesting to note that these agents activated both HSP70 and p53 proteins. Activation of HSP70 by the combined actions of DHA and celecoxib in the presence of wild-type p53 reveals a unique COX-2 independent mode of action against prostate cancer.
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PMID:Docosahexaenoic acid in combination with celecoxib modulates HSP70 and p53 proteins in prostate cancer cells. 2685 34

Mitochondria fulfill a wide array of functions dedicated to the energetic metabolism as well as the control of cell death. These functions imply that mitochondria can be activated by a variety of signals and can integrate them to trigger a process called mitochondrial membrane permeabilization (MMP), which induces the ultimate events of apoptosis. MMP consists in a sudden increase in the permeability of mitochondrial membrane that results in the release of critical proapoptotic intermembrane space effectors into the cytosol such as cytochrome c, apoptosis-inducing factor (AIF), Smac/Diablo, Endo G, and pro-caspases. In many models of apoptosis, mitochondrial translocation of proteins and/or lipids concomitantly with alterations of the intracellular milieu has been shown to activate MMP. This applies to tumor suppressors of the Bax/Bcl-2 family (Bax, Bad, Bid, Bim), several protein kinases (Akt, ASK1, hexokinase), p53, NF-kappaB, and nuclear orphan receptors such as TR3/Nur77. After mitochondrial membrane association, these proteins target constitutive mitochondrial proteins including the permeability transition pore complex (PTPC), Bcl-X(L), HSP70, and/or the lipid interphase. Subsequently, they switch their vital function into a lethal function to promote membrane permeabilization and protein release. In this review, we will describe some general rules of inter-organelle cross-talk activating MMP and will review selected examples of pro-apoptotic protein translocation. Finally, we will propose new pharmacological strategies to modulate this process in a therapeutic perspective.
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PMID:The modulation of inter-organelle cross-talk to control apoptosis. 1678 50

We previously demonstrated that after traumatic brain injury (TBI), acute progesterone withdrawal (AW) causes an increase in anxiety behaviors and cerebro-cellular inflammation compared to tapered progesterone withdrawal (TW). Our current study investigates the behavioral and cellular effects of AW two weeks after termination of treatments to determine the longer-term influence of withdrawal after injury. Adult, male Sprague-Dawley rats received either bilateral frontal cortex contusion (L) or sham (S) surgery. Rats were injected at 1 and 6 h post-injury, then every 24 h for six days. Vehicle (V)-treated rats were given 9 injections of 22.5% cyclodextrin, whereas AW rats received 9 injections of 16 mg/kg progesterone and TW rats received 7 injections of P at 16 mg/kg, followed by one at 8 mg/kg and one at 4 mg/kg. On day 8, sensory neglect and locomotor activity tests were initiated. Animals were killed 22 days post-TBI and the brains prepared for either molecular or histological analysis. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and heat shock protein 70 (HSP70) in TW vs. AW animals. P53 was increased in VL animals, whereas all progesterone-treated groups were equivalent to shams. TW animals had markedly decreased sensory neglect compared to AW animals and increased center time in locomotor activity assays. In addition, lesion reconstruction revealed a decreased lesion size for TWL over AWL over VL animals. Glial fibrillary acidic protein (GFAP) immunofluorescent staining followed this pattern as well. In conclusion, after TBI, AW affects select behaviors and molecular markers in the chronic recovery period.
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PMID:Tapered progesterone withdrawal promotes long-term recovery following brain trauma. 1679 38

Resistance of glioblastoma multiforme to radiotherapy poses a major clinical challenge. Farnesyltransferase inhibitors (FTI), such as R115777, have potential to increase radiotherapeutic benefit in this disease, although their mechanism of action is unclear. In our study with eight glioblastoma multiforme cell lines, the most sensitive ones underwent cell cycle arrest in response to FTI treatment. Radiosensitization by FTIs, however, seemed to involve other pathways. If R115777 treatment was initiated < 6 hours before irradiation, all eight glioblastoma multiforme lines were radiosensitized. However, if the time between drug and radiation was extended to 24 hours, cells harboring wild type but not mutated p53 were able to counteract drug-induced radiosensitization. The involvement of the p53/p21 pathway in the development of resistance was confirmed by showing that U87 cells transfected with human papillomavirus E6 to block p53 or interfering RNA to inhibit p21 stayed radiosensitive for 24 hours after drug treatment. The time dependency of R115777-induced radiosensitization suggested that the initial FTI target for early radiosensitization was short-lived, and that a p21-directed pathway restored resistance. Consideration of prenylated molecules that could potentially be involved led us to consider HDJ-2, a co-chaperone of heat shock protein 70. This hypothesis was strengthened by finding that cellular radiosensitivity was increased by genetic inhibition of HDJ-2, whereas overexpression conferred radioresistance. Importantly, irradiation of cells caused HDJ-2 to migrate from the cytoplasm to the nucleus, and this migration was inhibited by prior FTI treatment. These results have clinical relevance in that they help explain the variability in responses to FTIs that occurs following radiotherapy and elucidate some of the reasons for the complexity underlying FTI-induced radiosensitization.
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PMID:HDJ-2 as a target for radiosensitization of glioblastoma multiforme cells by the farnesyltransferase inhibitor R115777 and the role of the p53/p21 pathway. 1681 51

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP.
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PMID:Neuregulin 1-Beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol. 1682 72


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