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)

In Ewing's sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer.
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PMID:Microarray analysis of Ewing's sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy. 1829 40

Our previous studies indicated that oridonin, a diterpenoid isolated from Rabdosia rubescens, induced human melanoma A375-S2 cell apoptosis. In this study, we investigated whether the proapoptotic effect of oridonin on A375-S2 cells would depend on an interference with function of the insulin-like growth factor 1 (IGF-1) receptor, a plasma membrane receptor critical for the survival or antiapoptotic ability in melanoma cells. We found that IGF-1 receptor (IGF-1R) signaling was a potential survival pathway against a low concentration of 20 micromol/L oridonin-induced apoptosis in A375-S2 cells. The activation of Ras or its downstream effector p38 mitogen-activated protein kinase (p38 MAPK) was shown to be necessary for IGF-1-mediated protection, but the activation of phosphatidylinositol-3-OH kinase (PI3 kinase) or extracellular signal-regulated kinase (ERK) did not correlate with the regulation of survival. However, in the presence of 40 micromol/L (IC50 at 24 h) oridonin, A375-S2 cells could not be protected by IGF-1 from apoptosis, accompanied by a severe impairment of IGF-1R expression. Therefore, we concluded that the proapoptotic activity of oridonin was partially attributed to its repression of IGF-1R signaling. In addition, p53 was supposed to be a pivotal transducer of proapoptotic and survival signaling pathway in this system.
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PMID:Oridonin induces human melanoma A375-S2 cell death partially through inhibiting insulin-like growth factor 1 receptor signaling. 1869 33

PTEN regulates cell homeostasis by inhibiting growth signals transduced through PI3-kinases. The gene is mutated in several cancer types, but so far, only a limited number of mutations have been reported in colorectal cancer. In the present study, direct sequencing was used to analyze the whole coding region and exon-intron boundaries of PTEN in a series of microsatellite stable (n=34) and microsatellite unstable (n=30) colorectal carcinomas with known TP53 mutation status. We detected 21 PTEN mutations in altogether 13 tumors (20%), including 19 mutations in the coding sequence and two in the exon-intron boundaries. Sixteen of these alterations have not been previously reported in colorectal cancer. Furthermore, seven out of the 13 altered tumors harbored more than one mutation, potentially leading to loss of gene function. Finally, all PTEN mutations found were in tumors harboring wild-type TP53. In conclusion, PTEN is mutated in a significant subgroup of colorectal carcinomas, and our findings further extend the previously small spectrum of reported PTEN changes. Additionally, it seems that mutations in PTEN and TP53 are mutually exclusive for this cancer type.
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PMID:Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instability- and TP53 mutation- status. 1878 14

The radiosensitizing effect of wortmannin (WM) treatment during and after irradiation was studied in radioresistant bladder tumor cell lines with normal (MGH-U1 cells) or defective p53 activity (RT112 cells). WM modulated G(2)/M cell cycle arrest induced by higher X-ray doses (10 Gy) in both cell lines, although the alteration was significant only in RT112 cells. The observation suggests that WM activity is independent of p53. Constitutive expression of DNA-PKcs was found to be higher in RT112 cells than in MGH-U1. Treatment with WM enhanced radiation-induced apoptosis significantly in RT112 cells while it had no effect on MGH-U1 cells. Although a variety of PI3-kinases and PI3-K like kinases (including ATM) could be inhibited by WM, our observation of increased early lethality by WM treatment in RT112 is in agreement with previous results. They suggest that the WM-dependent radiosensitization of RT112 is a direct consequence of the inhibition of DNA-PK, resulting in the inhibition of DSB repair in the fast component. This early effect in the p53 deficient cell line could also indicate that processes other than apoptosis may contribute to the increased radiosensitization. In our opinion, the expression level of DNA-PKcs in human tumor cells may be a good predictor for the success of DNA-PKcs inhibitors when used as radiosensitizers.
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PMID:Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin. 1878 32

Defects in insulin signalling and glucose metabolism are associated with the development of diabetes. Insulin signalling is initiated by the binding of insulin to its receptor and triggering cascades of events including activation of PI3kinase/Akt signalling pathway. Calreticulin (CRT) is a calcium binding chaperone molecule located in the endoplasmic reticulum. Targeted deletion of CRT in mice is embryonic lethal as a result of developmental and metabolic abnormalities. Rescued CRT null mice develop severe hypoglycemia the reason for which is not known. In addition, ventricular cardiomyocytes isolated from CRT null (crt-/-) mice have increased glycogen deposits. Therefore, the aim of this study was to investigate the changes in the glucose uptake and insulin signalling pathway (mainly PI3 kinase/Akt) in the absence of CRT. Here we show a significant increase in the glucose uptake by the crt-/- cells. This increase was accompanied by a significant increase in both insulin receptor beta expression, Insulin receptor substrate-1 phosphorylation, GLUT-1 expression and in insulin stimulated Akt phosphorylation and kinase activity in the crt-/- cells. Intriguingly, the increased expression of insulin receptor beta in the crt-/- was due to decreased levels of p53 protein. The current study is the first evidence for the up-regulation of insulin receptor density and activity in the absence of CRT function.
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PMID:Calreticulin regulates insulin receptor expression and its downstream PI3 Kinase/Akt signalling pathway. 1884 Apr 78

Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein that is overexpressed in many advanced cancers. However, the functional mechanisms by which OPN contributes to the development of ovarian cancer are poorly understood. Here, we reveal that acquired expression of OPN by HO-8910 ovarian cancer cells greatly promoted the progression of ovarian cancer. OPN expression dramatically increased the colony formation of ovarian cancer cells in vitro and tumor growth in vivo. Under the stress induced by serum depletion or curcumin treatment, OPN expression promoted the survival of ovarian cells through preventing stress-induced apoptosis. At the molecular level, both endogenous and exogenous OPN expression activated the PI3-K/Akt survival pathway and dramatically decreased p53 expression under serum depletion. In addition, HIF-1alpha was induced in OPN-producing cells under normoxia. Furthermore, we also found that inhibition of the PI3-K/Akt pathway attenuated OPN-mediated HIF-1alpha up-regulation in ovarian cancer cells. Taken together, these results indicate that OPN can increase the survival of ovarian cancer cells under stress conditions in vitro and promote the late progression of ovarian cancer in vivo, and the survival-promoting functions of OPN are mediated through Akt activation and the induction of HIF-1alpha expression.
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PMID:Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1alpha expression through the PI3-K/Akt pathway. 1901 48

The evaluation of tumour molecular markers may be beneficial in prognosis and predictive in therapy. We develop a stopping rule approach to assist in the efficient utilisation of resources and samples involved in such evaluations. This approach has application in determining whether a specific molecular marker has sufficient variability to yield meaningful results after the evaluation of molecular markers in the first n patients in a study of sample size N (n</=N). We evaluated colorectal tumours for mutations (microsatellite instability, K-ras, B-raf, PI3 kinase, and TGFbetaR-II) by PCR and protein markers (Bcl2, cyclin D1, E-cadherin, hMLH1, ki67, MDM2, and P53) by immunohistochemistry. Using this method, we identified and abandoned potentially uninformative molecular markers in favour of more promising candidates. This approach conserves tissue resources, time, and money, and may be applicable to other studies.
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PMID:Statistical strategies to improve the efficiency of molecular studies of colorectal cancer prognosis. 1901 65

The PTEN tumour suppressor gene is induced by the early growth response 1 (EGR1) transcription factor, which also transactivates p53, p73, and p300/CBP as well as other proapoptotic and anti-cancer genes. Here, we describe a novel Akt-EGR1-alternate reading frame (ARF)-PTEN axis, in which PTEN activation in vivo requires p14ARF-mediated sumoylation of EGR1. This modification is dependent on the phosphorylation of EGR1 at S350 and T309 by Akt, which promotes interaction of EGR1 with ARF at K272 in its repressor domain by the ARF/Ubc9/SUMO system. EGR1 sumoylation is decreased by ARF reduction, and no EGR1 sumoylation is detected in ARF(-/-) mice, which also exhibit reduced amounts of PTEN. Our model predicts that perturbation of any of the clinically important tumour suppressors, PTEN, EGR1, and ARF, will cause some degree of dysfunction of the others. These results also explain the known negative feedback regulation by PTEN on its own synthesis through PI3 kinase inhibition.
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PMID:PTEN regulation by Akt-EGR1-ARF-PTEN axis. 1905 11

The tumor suppressor p53 is central to many cellular stress responses. Although numerous protein factors that control p53 have been identified, the role of microRNAs (miRNAs) in regulating p53 remains unexplored. In a screen for miRNAs that modulate p53 activity, we find that miR-29 family members (miR-29a, miR-29b and miR-29c) upregulate p53 levels and induce apoptosis in a p53-dependent manner. We further find that miR-29 family members directly suppress p85 alpha (the regulatory subunit of PI3 kinase) and CDC42 (a Rho family GTPase), both of which negatively regulate p53. Our findings provide new insights into the role of miRNAs in the p53 pathway.
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PMID:miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. 1907 65

Thyroid carcinoma is the most common endocrine neoplasm and the seventh most frequent human malignancy. It can be distinguished into differentiated and undifferentiated. Differentiated tumors include those arising from thyrocytes, i.e. papillary and follicular carcinoma, while medullary carcinoma originates from parafollicular or C cells. Anaplastic carcinoma comprises undifferentiated tumors. The factors inducing thyroid carcinoma development are not fully understood despite some well-established associations, such as the one between ionizing radiation and papillary carcinoma and that between iodine deficiency and follicular carcinoma. Genetic investigations of differentiated thyroid tumors have documented mutation of genes involved in the regulation of MAP kinase pathway activation in papillary carcinoma, and of genes involved in the regulation of the PI3 kinase pathway in follicular carcinoma. Analysis of their clinical course and of positivity for mutations has demonstrated that prognosis is greatly affected by the type of mutated gene. Genetic investigations therefore have the potential to direct diagnosis, but especially to tailor therapy and follow-up to the individual patient and even the individual gene. Anaplastic carcinoma, a highly aggressive, undifferentiated form, can arise as such or else be the de-differentiated progression of a papillary or a follicular carcinoma. It displays a mutated tumor suppressor gene (p53), which is crucial in the regulation of cell apoptosis, in addition to the mutations found in papillary and follicular forms. Medullary carcinoma is a malignant neoplasm with an intermediate clinical course between differentiated and undifferentiated forms. It manifests more frequently as a sporadic neoplasm or as a familial MEN. The latter is a high-penetrance, autosomal dominant hereditary disorder. Identification of the gene responsible for medullary carcinoma has radically changed the diagnostic approach to the familial forms, enabling early neonatal diagnosis of mutation carriers and of the disease, and early surgical approach by prophylactic thyroidectomy. Genetic studies have significantly affected the endocrinologist's diagnostic approach, as in the case of medullary carcinoma; over the next few years they are expected to provide further information to tackle papillary and follicular thyroid carcinoma. This review addresses the main genetic mutations responsible for neoplastic transformation in thyroid disorders.
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PMID:Genetic mutations in thyroid carcinoma. 1920 25


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