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)

We compared the DNA-binding activity of transcription factors and gene expression patterns in BJ human diploid fibroblasts (HDFs) expressing or not telomerase (hTERT) in stress-induced premature senescence (SIPS). Senescent BJ cells were also studied. Hydrogen peroxide (H2O2)-induced SIPS modulated gene expression in both BJ and hTERT-BJ1 cells. Increased p21(WAF-1) mRNA level was amongst the common gene expression changes in BJ and hTERT-BJ1 cells induced by SIPS. Telomerase expression markedly changed gene expression in non-stressful conditions. Expression patterns of senescent BJ cells partially overlapped those of BJ and hTERT-BJ1 cells in SIPS. The basal levels of DNA-binding activity of NF-kappaB and phosphorylated ATF-2 were different in BJ and hTERT-BJ1 cells. Both cell lines displayed a higher DNA-binding activity of p53 and HIF-1 72 h after H2O2 exposure. Our results indicate that similar mechanisms involving p21(WAF-1) and probably p53 are at work in BJ and hTERT-BJ1 HDFs under H2O2-induced SIPS, suggesting that generalized DNA damage rather than telomere length/telomerase plays a crucial role in H2O2induced SIPS. We propose that H2O2-induced SIPS involves a rearrangement of proliferative and apoptotic pathways. The marked changes in gene expression induced by telomerase suggest that apart from immortalization of HDFs, telomerase also alters the normal cellular functions but does not protect against SIPS.
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PMID:Gene expression and regulation in H2O2-induced premature senescence of human foreskin fibroblasts expressing or not telomerase. 1548 61

Apigenin is a nontoxic dietary flavonoid that has been shown to possess anti-tumor properties and therefore poses special interest for the development of a novel chemopreventive and/or chemotherapeutic agent for cancer. Ovarian cancer is one of the most common causes of cancer death among women. Here we demonstrate that apigenin inhibits expression of vascular endothelial growth factor (VEGF) in human ovarian cancer cells. VEGF plays an important role in tumor angiogenesis and growth. We found that apigenin inhibited VEGF expression at the transcriptional level through expression of hypoxia-inducible factor 1alpha (HIF-1alpha). Apigenin inhibited expression of HIF-1alpha and VEGF via the PI3K/AKT/p70S6K1 and HDM2/p53 pathways. Apigenin inhibited tube formation in vitro by endothelial cells. These findings reveal a novel role of apigenin in inhibiting HIF-1 and VEGF expression that is important for tumor angiogenesis and growth, identifying new signaling molecules that mediate this regulation.
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PMID:Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. 1574 77

The interaction between HIF-1alpha, Mdm2, and p53 proteins during hypoxia has received recent attention. Here, we investigated the consequences of interaction between HIF-1alpha and Mdm2 under hypoxic conditions. Endogenous HIF-1alpha and Mdm2 proteins were co-immunoprecipitated from lysates of hypoxic HCT116 p53WT and p53(-/-) cells, suggesting that association of these two proteins is a p53-independent event. The cellular Mdm2 protein content was not significantly altered in hypoxic tumor cells. Overexpression of Mdm2 resulted in an increase in HIF-1alpha protein content in hypoxic cells and increased hypoxia-induced vascular endothelial growth factor (VEGF) transcriptional activation. These results point toward a novel and p53-independent function of Mdm2 to promote tumor cell adaptations to hypoxia by interacting with and promoting HIF-1 activation.
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PMID:Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia. 1588 Jun 52

In the presence of oxygen and iron, hypoxia-inducible factor (HIF-1alpha) is rapidly degraded via the prolyl hydroxylases (PHD)/VHL pathways. Given striking similarities between p53 and HIF-1alpha regulation, we previously suggested that HIF-1 transcriptionally initiates its own degradation and therefore inhibitors of transcription must induce HIF-1alpha. Under normoxia, while inducing p53, inhibitors of transcription did not induce HIF-1alpha. Under hypoxia or low iron (DFX), inhibitors of transcription dramatically super-induced HIF-1alpha. Removal of inhibitors resulted in outburst of the HIF-1-dependent transcription followed by depletion of HIF-1alpha. Although hypoxia/DFX induced PHD3, we excluded the PHD/VHL pathway in the regulation of HIF-1alpha under hypoxia/DFX. The transcription-dependent degradation of HIF-1alpha under hypoxia occurs via the proteasome and is accelerated by protein acetylation. Thus, HIF-1alpha is regulated by two distinct mechanisms. Under normoxia, HIF-1alpha is degraded via the classic PHD/VHL pathway, is expressed at low levels and therefore does not activate the feedback loop. But under hypoxia, HIF-1alpha accumulates and transcriptionally activates its own degradation that is independent from the PHD/VHL pathway.
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PMID:Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion. 1589 3

We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-1 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.
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PMID:Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. 1609 61

In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)-1alpha in breast cancer, especially the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1alpha and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochemistry was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1alpha, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated positively with HIF-1alpha expression (P = .04), p53 accumulation (P = .001), and overexpression of glucose transporter 1 (GLUT-1) (P < .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly associated with p300 in HIF-1alpha positive patients (P = .02). p53 accumulation significantly positively correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1alpha-positive patients (P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly associated with GLUT-1 overexpression (P = .01) and coexpression of CAIX/GLUT-1 (P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly associated with p53 accumulation and HIF-1alpha levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1alpha-overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1-regulated response toward hypoxia.
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PMID:p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer. 1686 72

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor involved in the adaptation of cells to hypoxia. In addition to regulation of HIF-1alpha protein level, HIF-1 activity is also enhanced by several pathways involving asparagine hydroxylation and phosphorylation. Here, we investigated the relationship between casein kinase 2 (CK2), p53 and HIF-1. An increase in p53 protein level and transcriptional activity was observed when CK2 was inhibited by different inhibitors under normoxia and hypoxia. This increase was in parallel with a decrease in HIF-1 activity without changes in HIF-1alpha protein level, indicating a regulation of its transcriptional activity. Similar results were obtained using CK2alpha siRNA. Ectopic overexpression of p53 also led to an inhibition of HIF-1 activity. Conversely, CK2 inhibition had no effect in p53-null cells indicating that the inhibitory effect of CK2 inhibitors requires the presence of p53. p53 activity was not required because overexpression of a p53 mutated in its DNA-binding domain exerted the same effect as wild-type p53 and because the effect of CK2 inhibitors was still observed when p53 activity was inhibited by pifithrin-alpha. Since CK2 activity is increased in hypoxic conditions, this process provides one more mechanism to ensure enhanced HIF-1 activity under such conditions.
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PMID:Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level. 1688 92

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-alpha), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67-74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1alpha expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1alpha during hypoxia, the tandem " HIF-ROS " induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF-alpha, and inhibition of neuronal protection mechanisms with repression of IGF-1.
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PMID:Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea. 1714 99

A few highly aggressive and malignant tumor cells could acquire identities by turning on genes expressed by endothelial cells and recruit blood vessels to sustain tumor growth. Hypoxia was reported recently to play an essential role in these events. These 'plastic' tumor-cell phenotypes and the exact mechanism driving transendothelial differentiation by hypoxia-inducible factor (HIF)-1alpha is unclear. In this study, epithelial ovarian carcinoma cells were exposed to hypoxia and the tumor cells were transformed into endothelial cells-like (ECs-like). Typical endothelial features such as cell markers and uptaking of acetylated low density lipoprotein were identified constantly. Small interference RNA was used to block the expression of HIF-1alpha. Analysis revealed that hypoxia promotes transendothelial differentiation through stimulating HIF-1-dependent transcriptional expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 (Flk-1) and P53, and through decreasing HIF-1-independent transcriptional expression of Cyclin D1. These results demonstrate that ECs-like derived from epithelial ovarian cancer cells are similar to endothelial progenitor cells rather than endothelial cells. HIF-1alpha is crucial but not unique in alternation of tumor cells towards ECs-like.
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PMID:Characteristics and differentiated mechanism of vascular endothelial cells-like derived from epithelial ovarian cancer cells induced by hypoxia. 1739 8

There is growing evidence to suggest that altered patterns of STC1 gene expression relate to the process of human cancer development. Our previous study has demonstrated the involvement of HIF-1 in the regulation of STC1 expression in human cancer cells. Recently, STC1 has been implicated as a putative pro-apoptotic factor in regulating the cell-death mechanism. Thus it would be of interest to know if STC1 is regulated by a tumor suppressor protein, p53. In this study, we provide evidence to demonstrate that the induction of STC1 expression in apoptotic human nasopharyngeal cancer cells (CNE2) is mediated by the activation of p53. Our study indicated that the activation of STC1 and heat-shock protein (hsp70) accompanied iodoacetamide (IDAM)-induced apoptosis in CNE-2. In addition, cellular events such as GSH depletion, mitochondrial membrane depolarization, reduction of pAkt and procaspase-3, and the induction of total p53 protein, acetylated p53, and annexin V positive cells were observed. The activation of STC1 was found to be at the transcriptional level and was independent of prior protein synthesis. Co-treatment of IDAM exposed cells with N-acetyl cysteine (NAC) prevented cell death by restoring mitochondrial membrane potential and cellular levels of GSH. NAC co-treatment also suppressed STC1 expression but had no effect on IDAM-induced hsp70 expression. RNA interference studies demonstrated that endogenous p53 was involved in activating STC1 gene expression. Collectively, the present findings provide the first evidence of p53 regulation of STC1 expression in human cancer cells.
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PMID:Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53. 1739 53


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