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)

Resveratrol and other polyphenols have anti-carcinogenic and anti-tumorigenic activities in various carcinomas. However, such studies are limited in endometrial cancer. We hypothesize that resveratrol suppresses cancer growth through modulation of cell cycle and cell growth regulatory genes. To test this hypothesis, we treated endometrial cancer cells (Ishikawa cell line) with resveratrol (1, 10, 50 and 100 micro M) for 1, 3, 5 and 7 days, and analyzed for growth signal genes (EGF and VEGF), cell cycle regulatory genes (p53 and p21), and apoptosis-related genes (bcl-2 and bax). Results of these experiments demonstrate that after resveratrol treatment, the growth of Ishikawa cells was inhibited in a dose dependent manner. The gene and protein expression data suggest that resveratrol treatment significantly decreased EGF, whereas VEGF was up-regulated in Ishiwaka cell lines. Interestingly, protein expressions of p21 and Bax were decreased, even though their mRNA expressions did not show significant changes. The present study suggests that resveratrol can suppress proliferation of Ishikawa cells through down-regulation of EGF.
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PMID:Resveratrol suppresses growth of Ishikawa cells through down-regulation of EGF. 1296

In the present study we investigated the prognostic relevance of molecular and immunological changes in pancreatic carcinoma. 82 tissue specimens of adenocarcinoma of the pancreas were stained immunohistochemically with following factors: p53, p21WAF1, Cyklin D, EGF, EGF-R, cERB-B2, CD95, BCL-2 and Cathepsin D. We further determined the serum levels of sCD44, sCD44v6, neopterin and IL-2R. Except Cyclin D none of the immunohistochemically determined factors had prognostic significance. Interestingly all of the immunological serum parameters were of high prognostic significance. These data demonstrate the prognostic relevance of immunological parameters in human adenocarcinoma of the pancreas and could raise the possibility of an early immunological intervention in pancreatic cancer.
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PMID:[Prognostic value of molecular biologogy and immunologic parameters in human pancreatic carcinoma]. 1451 15

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
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PMID:Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. 1456 7

Nested variant of urothelial carcinoma is characterized by confluent small nests and abortive tubules of mildly atypical neoplastic cells infiltrating the lamina propria and/or muscularis propria of the bladder. Despite its deceptively bland histomorphologic appearance, the lesion is reported to have an aggressive behavior. The collective immunohistochemical expression of suppressor genes, growth factor, and proliferation activity marker has not been previously studied in this disease. Formalin-fixed, paraffin-embedded archival tissues from 12 cases of nested variant of urothelial carcinoma were stained with monoclonal antibodies to p21, p27, p53, EGF-R, and bcl-2, as well as the proliferation marker MIB-1. The area of predominant immunoreactivity was also evaluated. The pattern of immunostaining was compared with the clinical parameters. p21 was positive in 10 of 12 cases and located at the deepest portion of the tumor in 5 of 10 positive cases. Immunoreactivity for p27 was seen in 11 of 12 cases and limited to the superficial portion of the tumor in 9 of 11 positive cases. Only 3 and 2 of 12 cases were positive for p53 and bcl-2, respectively. MIB-1 immunoreactivity ranged from 2 to 35% of the neoplastic cells, with most tumors showing a proliferation index of >15%. Follow-up ranged from 3 to 30 months (mean, 17.6 mo). All patients except one were alive, although three patients developed metastases. Nested variant of urothelial carcinoma is a deceptively benign-appearing neoplasm with potential of deep invasion and metastases. Immunohistochemically, nested variant of urothelial carcinoma shares some features with high-risk conventional urothelial carcinomas, such as loss of p27 expression and high proliferation index. Nevertheless, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen.
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PMID:Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases. 1468 30

Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a bioactive green tea polyphenol, on EGFR signaling in cervical cells. EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity. The EGCG-dependent reduction in ERK and AKT activity is associated with reduced phosphorylation of downstream substrates, including p90RSK, FKHR, and BAD. These changes are associated with increased p53, p21(WAF-1), and p27(KIP-1) levels, reduced cyclin E level, and reduced CDK2 kinase activity. Consistent with these findings, flow cytometry and TUNEL (terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling) staining revealed EGCG-dependent G(1) arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. In addition to inhibiting EGFR, cell-free studies demonstrated that EGCG directly inhibits ERK1/2 and AKT, suggesting that EGCG acts simultaneously at multiple levels to inhibit EGF-dependent signaling. Importantly, the EGCG inhibition is selective, as EGCG does not effect the EGFR-dependent activation of JNK. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.
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PMID:Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. 1470 54

Increased endothelial apoptosis and decreased apoptosis of vascular smooth muscle cells (VSMC) are central to initiation of myo-intimal thickening. We hypothesized that apoptosis of endothelial cells (EC) induces the release of anti-apoptotic mediator(s) active on VSMC. We found that serum-free medium conditioned by apoptotic EC decreases apoptosis of VSMC compared with fresh serum-free medium. Inhibition of endothelial apoptosis during conditioning with a pan-caspase inhibitor ZVAD-FMK blocked the release of the anti-apoptotic factor(s) active on VSMC. VSMC exposed to serum-free medium conditioned by apoptotic EC showed increased ERK 1/2 phosphorylation, enhanced Bcl-xl expression, and inhibition of p53 expression. Fractionation of the conditioned medium followed by mass spectral analysis identified one bioactive component as a C-terminal fragment of the domain V of perlecan. Serum-free medium supplemented with either a synthetic peptide containing the EGF motif of the domain V of perlecan or chondroitin 4-sulfate, a glycosaminoglycan anchored on the domain V of perlecan, increased ERK 1/2 phosphorylation and Bcl-xl protein levels while inhibiting apoptosis of VSMC. These results suggest that a proteolytic activity developing downstream of activated caspases in apoptotic EC initiates degradation of pericellular proteoglycans and liberation of bioactive fragments with a robust impact on inhibition of VSMC apoptosis.
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PMID:Apoptosis of endothelial cells triggers a caspase-dependent anti-apoptotic paracrine loop active on VSMC. 1497 81

A large number of data derived from molecular analyses support the hypothesis that human cancer is a genetic disease and a distinct subset of genes have been found to be genetically changed in most tumors. Molecular alterations in pancreatic cancer include: (1) oncogenes such as K-ras, c-myc, c-fos, and c-erbB-2; (2) tumor suppressor genes such as p53, p16, DPC4/SMAD4, and DCC; and (3) growth factors such as EGF, FGF, HGF, PDGF, VEGF, TGF-beta. Genetic alterations of K-ras and p53 are common in human pancreatic cancer, but the occurrence of pancreatic cancer is a multi-step phenomenon in which the accumulation of genetic changes is extremely important.
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PMID:[Recent advances in gene change of pancreatic cancer]. 1505 82

Substaging using molecular markers has been proposed to try to identify prognostic factors allowing to define groups of patients with lung cancer for whom specific therapy might be of benefit. The pre-operative assessment of these markers seems to be important specially in case of neoadjuvant chemotherapy. The aim of our study was to compare the expression of two potential prognostic factors (p53 and Ki-67) and two potential therapeutic targets (EGF-R and c-erbB-2) assessed on biopsy samples (B) of non-small cell lung cancer (NSCLC) with that of the corresponding resected tumor (RT). The expression of these biological markers was evaluated by immunohistochemistry on B and on the paired RT in 28 patients. The mean percentage of p53 positive cells was 28% in RT and 38% in B with 81% CR between B and RT and 19% FP on B. Considering RT results as standard, the positive (PPV) and negative predictive value (NPV) of the B were, respectively, 74 and 100%. The mean percentage of EGF-R positive cells was 11% in RT and 28% in B. With a cut-off of 1%, we found 85% concordant results (CR) between B and RT, 4% false negative (FN) and 11% false positive (FP) on B. The PPV and NPV values of the B were, respectively, 80 and 92%. The 8% B and 19% RT were considered as positive for c-erbB-2. We found 15% FN and 4% FP on B with 81% CR between B and RT for c-erbB-2. The NPV of the B was 83%. The mean percentage of Ki-67 positive cells was 32% in RT and 14% in B. We found 82% CR between B and RT, 14% FN and 4% FP on B. The PPV of the B was 96%. In conclusion, biopsies may provide reliable information about p53, EGF-R, c-erbB-2 and Ki-67 in lung carcinoma and could help to elaborate a therapeutic strategy.
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PMID:Correlation of different markers (p53, EGF-R, c-erbB-2, Ki-67) expression in the diagnostic biopsies and the corresponding resected tumors in non-small cell lung cancer. 1514 May 42

We have developed a murine mammary tumor cell line, MC4-L4, and after 15 passages, a spindle-shaped population became evident. The cuboidal cells, MC4-L4E, cloned by limit dilution, proved to be epithelial tumor cells. When inoculated in syngeneic mice, they gave rise to invasive metastatic carcinomas expressing estrogen and progesterone receptors. These tumors regressed after anti-progestin treatment and stopped growing after 17-beta-estradiol administration. In vitro, they were insensitive to medroxyprogesterone acetate (MPA), 17-beta-estradiol, and EGF and were inhibited by TGFbeta1. They expressed mutated p53 and estrogen receptors alpha; progesterone receptors were undetectable. Cells were polyploid and shared the same four common marker chromosomes present in the parental tumor in addition to an exclusive marker. Spindle-shaped cells, MC4-L4F, were selected by differential attachment and detachment and proved to be non-epithelial non-tumorigenic cells. They were cytokeratin negative, showed mesenchymal features by electron microscopy, differentiated to adipocytes when treated with an adipogenic cocktail, were stimulated by TGFbeta1 and EGF, showed a wild-type p53, and did not exhibit the marker chromosomes of the parental tumor. Although they expressed estrogen receptors alpha, they were insensitive to 17-beta-estradiol in proliferation assays. Co-cultures of both cell types had a synergic effect on progesterone receptors expression and on cell proliferation, being the epithelial cells, the most responsive ones, and 17-beta-estradiol increased cell proliferation only in co-cultures. Cytogenetic studies and data on p53 mutations rule out the possibility of an epithelial mesenchymal transition. Their unique characteristics make them an excellent model to be used in studies of epithelial-stromal interactions in the context of hormone responsiveness in hormone related tumors.
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PMID:Isolation of a stromal cell line from an early passage of a mouse mammary tumor line: a model for stromal parenchymal interactions. 1538 83

Gliomas result from specific genetic alterations--such as activation of specific oncogenes and/or inactivation of specific tumor suppressor genes. These alterations affect specific pathways involved in either signal transduction or cell cycle control, leading to phenotypic changes such as uncontrolled proliferation, inhibition of apoptosis, genetic instability, invasive properties. Tumoral progression includes multiple molecular pathways of clinical relevance: early alterations (p53 mutations for astrocytomas, 1p and 19q loss for oligodendrogliomas) and late alterations (EGF-R amplification, PTEN and P16/CDKN2A inactivation). Genetic profile is not only of diagnostic--but also prognostic relevance, as shown by 1p associated to 19q loss in oligodendrogliomas which is predictive of better prognosis and higher response rate.
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PMID:[The genetics of glioma: molecular classification]. 1561 8


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