UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF-1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1alpha-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including DNA double-strand break repair enzymes.
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PMID:The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. 1276 91

The tumour suppressor activity of p53 in vivo can be subject to pressure from the physiological stress of hypoxia and we report on the development of a cell system to define the p53-dependent stages in the adaptation of cells to hypoxia. p53(+/+) cells exposed to hypoxia exhibited a transient arrest in G2/M, but escaped from this checkpoint and entered a long-term G(0)/G(1) arrest. By contrast, isogenic p53-null cells exposed to hypoxic conditions exhibited a 6-10-fold higher level of apoptosis, suggesting that p53 acts as a survival factor under limiting oxygen concentrations. Surprisingly, hypoxia-dependent growth arrest in p53(+/+) cells did not result in either p21(WAF1) or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser(392)-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser(392)-site phosphorylation as well as stabilization of both p53 and HIF-1 proteins. In contrast to hypoxia, 5-flourouracil (5-FU)-induced p53-dependent cell death correlated with enhanced Ser(392) phosphorylation of p53 and elevated p21(WAF1) protein levels. Hypoxia inhibited 5-FU-induced p53-dependent cell death and attenuated p53 phosphorylation at the ATM and CK2/FACT phosphorylation sites. Although anoxia activates the p53 response, hypoxia silences the p53 transactivation pathway and identifies a physiological signalling model to study mechanisms of p53 inactivation under hypoxic conditions.
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PMID:Hypoxia attenuates the p53 response to cellular damage. 1277 95

Human apurinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative or alkylating compounds as well as in the regulation of stress inducible transcription factors such as AP-1, NF-kappaB, HIF-1 and p53. With respect to transcriptional regulation, both redox dependent and independent mechanisms have been described. APE/Ref-1 also acts as a transcriptional repressor. Recent data indicate that APE/Ref-1 negatively regulates the activity of the Ras-related GTPase Rac1. How these different physiological activities of APE/Ref-1 are coordinated is poorly understood. So far, convincing evidence is available that the expression of the APE/Ref-1 gene is inducible by oxidative stress and that overexpressed APE/Ref-1 protein protects cells against the genotoxic and cell killing effects of reactive oxygen species (ROS), whereas down-regulation sensitizes cells. Therefore, APE/Ref-1 can be considered to be part of an adaptive cellular response mechanism to oxidative genotoxic stress. The physiological relevance of increase of either the repair or redox activity of APE/Ref-1 for this adaptive response is unclear. Data will be shown that transfection of the truncated protein exhibiting either one of the activities provoked increase of resistance. Since APE/Ref-1 expression level and intracellular localization is variable in different types of tumors and frequently found to be different in non-malignant compared to the corresponding malignant human tissue, the protein is thought to be a diagnostic and prognostic tumor marker. Because of its involvement in DNA repair and apoptosis-related signaling mechanisms, APE/Ref-1 is also being discussed as a novel target for tumor-therapeutic approaches.
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PMID:APE/Ref-1 and the mammalian response to genotoxic stress. 1459 68

Deregulated expression of c-Myc can sensitize cells to a variety of death stimuli, including loss of growth factors and oxygen. In this study, we examined whether rodent fibroblasts that conditionally express c-Myc undergo a similar mechanism of cell death in response to serum or oxygen deprivation. Our results demonstrate that murine embryonic fibroblasts from bax-/-bak-/- mice that conditionally express c-Myc did not die in response to either oxygen or serum deprivation. Fibroblasts from p53-/- mice that conditionally express c-Myc died in response to oxygen (but not serum) deprivation. The inability of p53 to regulate oxygen deprivation-induced cell death was due to the lack of induction of p53 target genes Puma, Noxa, and Pten. In contrast, serum deprivation transcriptionally induced Puma and Pten in cells that conditionally express c-Myc. The failure of p53 to regulate oxygen deprivation-induced cell death led us to hypothesize whether hypoxia-inducible factor (HIF) might be a critical regulator of cell death during oxygen deprivation. Fibroblasts from HIF-1beta-/- cells that conditionally express c-Myc were not able to transcriptionally activate HIF during oxygen deprivation. These cells died in response to oxygen deprivation. Thus, oxygen deprivation-induced cell death in fibroblasts with deregulated expression of c-Myc is independent of p53 or HIF-1 status, but is dependent on the Bcl-2 family member Bax or Bak to initiate mitochondrial dependent cell death.
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PMID:c-Myc sensitization to oxygen deprivation-induced cell death is dependent on Bax/Bak, but is independent of p53 and hypoxia-inducible factor-1. 1462 95

Low NO concentrations synthesized by constitutively expressed NO synthases act on several signaling pathways activating transcription factors (TF), such as NF-kappaB or AP-1, and thereby influence gene expression. In contrast, during inflammatory reactions the inducible NO synthase produces NO for prolonged periods of time. The resulting nitrosative stress directly affects redox-sensitive TF like NF-kappaB, AP-1, Oct-1, c-Myb, or zinc finger-containing TF, but also additional mechanisms have been identified. Nitrosative stress in some cases induces expression of TF (AP-1, p53), indirectly modulates activity or stability of TF (HIF-1, p53) or their inhibitors (NF-kappaB), or modulates accessibility of promoters via increased DNA methylation or histone deacetylation. Depending on the promoter the result is induced, increased, decreased or even totally inhibited expression of various target genes. In unstimulated cells nitrosative stress increases NF-kappaB- or AP-1-dependent transcription, while in activated cells nitrosative stress rather abolishes NF-kappaB- or AP-1-dependent transcription. Sometimes the oxygen concentration also is of prime importance, since under normoxic conditions nitrosative stress activates HIF-1-dependent transcription, while under hypoxic conditions nitrosative stress leads to inhibition of HIF-1-dependent transcription. This review summarizes what is known about effects of physiological NO levels as well as of nitrosative stress on transcription.
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PMID:Nitrosative stress and transcription. 1466 80

An understanding of underlying mechanisms involved in the activation of HIF-1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF-1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, resulting in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF-1alpha, a key component of HIF-1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF-1alpha. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF-1alpha to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies.
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PMID:Hypoxia-inducible factor-1 and oncogenic signalling. 1498 27

HIF-1 (hypoxia-inducible factor-1), a heterodimeric transcription factor comprising HIF-1alpha and HIF-1beta subunits, serves as a key regulator of metabolic adaptation to hypoxia. HIF-1 activity largely increases during hypoxia by attenuating pVHL (von Hippel-Lindau protein)-dependent ubiquitination and subsequent 26 S-proteasomal degradation of HIF-1alpha. Besides HIF-1, the transcription factor and tumour suppressor p53 accumulates and is activated under conditions of prolonged/severe hypoxia. Recently, the interaction between p53 and HIF-1alpha was reported to evoke HIF-1alpha degradation. Destruction of HIF-1alpha by p53 was corroborated in the present study by using pVHL-deficient RCC4 (renal carcinoma) cells, supporting the notion of a pVHL-independent degradation process. In addition, low p53 expression repressed HIF-1 transactivation without affecting HIF-1alpha protein amount. Establishing that p53-evoked inhibition of HIF-1 reporter activity was relieved upon co-transfection of p300 suggested competition between p53 and HIF-1 for limiting amounts of the shared co-activator p300. This assumption was confirmed by showing competitive binding of in vitro transcription/translation-generated p53 and HIF-1alpha to the CH1 domain of p300 in vitro. We conclude that low p53 expression attenuates HIF-1 transactivation by competing for p300, whereas high p53 expression destroys the HIF-1alpha protein and thereby eliminates HIF-1 reporter activity. Thus once p53 becomes activated under conditions of severe hypoxia/anoxia, it contributes to terminating HIF-1 responses.
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PMID:p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). 1499 92

Nitric oxide (NO) is a mobile, highly reactive signal molecule, and changes the expression of specific genes in effector cells. Under physiological conditions, NO reacts with molecular oxygen and with reactive oxygen species (ROS) to produce intermediates known as reactive nitrogen species (RNS). The production of NO and RNS in the cell is controlled by hormones, neurotransmitters, cytokines, and growth factors. Hence NO and its derivatives act as secondary paracrinous factors and transmit the signal from NO-producing to neighboring cells. Intracellular reception of NO and RNS is due to Src-related tyrosine protein kinases, G-protein Ras, cytochrome oxidase, and guanylate cyclase. Receptor proteins mostly contain heme, active thiol, or iron-sulfur groups, and are both on the plasma membrane and in internal cell compartments. Many of the NO receptors are the key components of cell regulatory systems controlling the transcription factors AP-1, HIF-1, NF-kappa B, and p53 and the expression of their target genes. A distinguishing feature of NO signaling is that changes in redox potential of the cell switch the NO receptor and, consequently, modify the NO effect. Depending on the ROS level, NO activates different signal transduction pathways to induce (or suppress) different gene sets. The data considered indicate that antioxidants may be used to directionally change the transcriptional response of the cell to NO.
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PMID:[Redox-dependent regulation of gene expression induced by nitric oxide]. 1504 36

Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle- and apoptosis-control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF-1-dependent. Our aim was to evaluate the expression of the HIF-1alpha, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF-1alpha expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF-1alpha-negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF-1alpha, p53 and p21 and proliferation and apoptosis. HIF-1alpha overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF-1alpha, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF-1alpha) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.
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PMID:Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. 1517 Jun 65

Hypoxia-inducible factor (HIF)-1 alpha is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions. Under different circumstances, HIF-1 alpha may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF-1 alpha as a prognostic factor. This study evaluated HIF-1 alpha expression in 172 consecutive patients with stage I-IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF-1 alpha nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point. Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive cut-point was used, HIF-1 alpha was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1 alpha. The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1 alpha. The prognostic data may reflect a change in the behavior of HIF-1 alpha in increasingly hypoxic environments.
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PMID:Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. 1518 41

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