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 this article, we introduce our rapid-production model for pancreatic duct adenocarcinomas and describe the mechanisms of pancreatic duct carcinogenesis so far elucidated in Syrian golden hamsters. It is evident that a series of histogenetic steps are involved, leading from hyperplasia through atypical hyperplasia to intraductal carcinoma and invasive carcinoma. As DNA alters, K-ras mutation appears to be an early event, whereas p53 mutations generally occur in the tumor-progression phase. The induced cancer cells may show autocrine growth, secreting TGF-alpha and vascular endothelial growth factor (VEGF), and are immortalized with a shortened TRF length and increased telomerase activity. The rapid-production model of pancreatic duct adenocarcinomas has not only provided a major stimulus to understanding induction mechanisms but should also serve as a bioassay to facilitate the identification of dietary risk factors and the search for appropriate chemopreventive or chemotherapeutic agents or both to help control this deadly disease.
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PMID:Mechanistic analysis of pancreatic ductal carcinogenesis in hamsters. 954 70

Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PEdelta53L/TGF-alpha/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PEdelta53L/TGF-alpha/KDEL decreases the apoptotic threshold through protein synthesis inhibition and simultaneous production of ceramide in tumor cells that lack functional p53 protein. In contrast, no increase in local or systemic toxicity was observed with the chimeric toxin and radiation. We conclude that biochemical targeting of the chimeric toxin and physical targeting of ionizing radiation may increase the therapeutic ratio in the treatment of human cancers with alterations of p53 expression. This strategy offers a high therapeutic potential for Pseudomonas exotoxin A chimeric proteins and irradiation.
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PMID:Modulation of apoptotic response of a radiation-resistant human carcinoma by Pseudomonas exotoxin-chimeric protein. 969 44

The relationship between transforming growth factor-beta1 (TGF-beta1) induced growth arrest and apoptosis in rat liver derived epithelial (RLE) cells was analyzed. TGF-beta1 treatment of RLE cells induced both cell cycle arrest and apoptosis. However, pretreatment of the cells with either dexamethasone or cyclohexamide suppressed TGF-beta1 induced apoptosis, without preventing the cell cycle arrest. Both p53 and Bax were subsequently shown to be overexpressed during the TGF-beta1 induced apoptosis. Furthermore, it was revealed that cycloheximide suppressed expression of both p53 and Bax. In contrast, dexamethasone treatment prevented Bax expression alone. Treatment of RLE cells with several growth factors either alone or in combination was ineffective in counteracting TGF-beta1 induced apoptosis. In additon, we show that TGF-alpha also induced both p53 and Bax expressions and augmented TGF-beta-induced apoptosis. Thus, p53 and Bax are likely to be key factors in TGF-beta1 induced apoptosis in RLE cells.
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PMID:Induction of p53 and Bax during TGF-beta 1 initiated apoptosis in rat liver epithelial cells. 979 Sep 6

Adenocarcinoma of the pancreas carries a grave prognosis for affected patients. Certain oncogenes (K-ras and HER-2/neu) are mutated in a large proportion of these aggressive tumors. Adenocarcinoma of the pancreas has also been associated with loss of tumor suppressor genes (p53, DPC4, p16/MTS), either by deletion or by mutation and loss of function. Growth factors (EGF, TGF-alpha, HGF) and growth factor receptors (EGF-R, c-met, CCK) are expressed at levels not found in the normal pancreas. Finally, factors important for angiogenesis (FGF, integrins, selectins) are likely to play an important role in the growth and metastasis of clinically relevant tumors. This review attempts to summarize and assimilate current research into the molecular and cellular biology of pancreatic cancer.
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PMID:The molecular and cellular biology of pancreatic cancer. 980 1

Experimental data suggest that dysregulation of growth factors and the cognate receptors may play an important role in hepatocarcinogenesis. The objective of the present study was to characterize the expression of two hepatotrophic growth factor/receptor systems [transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) and hepatocyte growth factor/c-met receptor (HGF/c-met)], both of which are implicated in the development of human liver tumors. In addition, we have analyzed the expression of transforming growth factor-beta receptor type II (TGF-beta-RII) and p53, genes associated with growth inhibition and tumor suppression, respectively. Surgical biopsy specimens from 86 human hepatocellular carcinomas were analyzed. TGF-alpha was overexpressed in 17%, equally expressed in 21%, and down-regulated in 62% of the hepatocellular carcinomas when compared to the surrounding hepatic tissue. No major changes were found with EGFR expression. HGF was over-expressed in 33% and down-regulated in 21% of the tumors. The c-met receptor was overexpressed in 20%, equally expressed in 48%, and down-regulated in 32% of the neoplasms. In contrast, TGF-beta-RII was overexpressed in only 8%, equal in 42%, and down-regulated in 50% of tumors. Nuclear staining of p53, indicative of a mutation(s), was observed in the great majority of the tumors (80%), whereas no nuclear p53 was detected in peritumoral tissues. Interestingly, simultaneous down-regulation of c-met and TGF-beta-RII was observed in 23% of the hepatocellular carcinomas, 85% of which also showed nuclear p53 staining. Taken together, our data suggest that down-regulation of c-met and TGF-beta-RII may, together with p53 mutations, play a significant role in human liver carcinogenesis.
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PMID:Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. 981 84

Skin cancer is the most common tumor type in Caucasians, with an incidence that approaches the lifetime risk for all other cancer subtypes combined. The most common predisposing factor is exposure to ultraviolet (UV) radiation present in sunlight. The purpose of this investigation was to evaluate the effects of UVC on the proliferation of a p53-/- human keratinocyte cell line, HaCaT, and how UVC alters the response of these cells to transforming growth factors (TGF)-alpha and TGF-beta1. UVC treatment during G0/G1 phase resulted in decreased incorporation of [3H]thymidine, an effect that was enhanced by pretreatment with TGF-beta1. However, irradiation of HaCaT cells in S or G2/M phase had no effect on the incorporation of [3H]thymidine, suggesting that these cells failed to undergo G2/M arrest in response to UV-mediated DNA damage. UVC had no effect on TGF-beta1-mediated growth inhibition, but decreased the mitogenic response of HaCaT cells to TGF-alpha. Seven days after irradiation, there were no differences between the number of cells that were exposed to UVC and those that were not, suggesting that the effects of UVC on proliferation of HaCaT cells was transient. These results suggested that UVC did not stimulate proliferation of p53-/- HaCaT cells, or cause cell cycle arrest in G2/M, which would allow transmission of chromosomal damage to daughter cells during M phase. Failure of the G2/M cell cycle checkpoint may be one of the mechanisms by which p53 results in genomic instability.
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PMID:Effects of ultraviolet C radiation on cellular proliferation in p53-/- keratinocytes. 995 33

An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)- retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-alpha tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given.
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PMID:Evaluation of biomarker modulation by fenretinide in prostate cancer patients. 1032 1

Patients with Barrett's columnar-lined esophagus are at increased risk of developing esophageal adenocarcinoma, the incidence of which has increased rapidly especially in the USA. Although the number of patients with Barrett's adenocarcinoma is fewer in Japan than in the USA, all gastroenterologist should know its multistep carcinogenic process. Tumor suppressor genes (p53, p16), oncogenes (c-erbB-2, H-ras, K-ras, cyclin D1, src), and growth factor/receptor (TGF-alpha, EGFR) seem to cause the malignant transformation of Barrett's esophagus. Because detection of these molecular alterations is feasible, more accurate diagnosis of Barrett's esophageal biopsy specimens should be made by adding the molecular examination to the conventional pathologic examination.
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PMID:[Molecular alterations in Barrett's esophagus and adenocarcinoma]. 1037 32

A review is presented on the role of conventional and molecular tumour markers (TM) in diagnosis and monitoring of patients with biliopancreatic malignancies. For biliopancreatic malignancy, following CEA as more historical and basic TM of gastrointestinal diseases, the mainstay marker is CA 19-9 as monosialo-ganglioside/glycolipid and sialyl derivative of lacto-N-fucopentaose II (sialyl-Lewis(a), hapten of human Lewis(a) bloodgroup determinant). It is detected in serum of healthy individuals at low concentration < 40 U/ml, with lower and often transitional elevation in benign hepatobiliary diseases and with highest levels in excretory ductal pancreatic adenocarcinoma (s = 70%-95%, sp = 72%-90%), biliary (s = 55%-79%), hepatocellular and cholangiocellular cancer (s = 22%-51%) besides gastric, colorectal and ovarian cancer and occasionally in lung, breast and uterine cancer. Physiologically elevated concentrations in healthy individuals have to be considered in all sorts of secretions (e.g. sputum, saliva, bronchial/gastric secretions, bile juice) of individuals with Lewis(a)-positive secretor status in contrast with low or lacking serum levels of CA 19-9 in patients with Lewis(a-/b-) status (7%-10% of population). In biliopancreatic malignancies, especially pancreatic cancer, CA 19-9 correlates well with clinical course of disease following surgical, chemo- or radiotherapy by a quick normalisation within 2-4 weeks after complete surgery, a transient decrease with successful palliative therapy and an often anticipated increase (lead time up to 6 months) before clinical detection in case of relapse or progressive disease. From CA 19-9 related TM tests some are detecting in addition to sialyl-Lewis(a) (sialyllacto-N-fucopentaose II) also the non-fucosylated precursor sialyl-Lewis(c) (sialyllacto-N-tetraose: CA 50, CA 242, Span-1) solely detected by the DUPAN-2 test and independent of the Lewis(a) secretor status. Some other markers comprise in addition to sialyl-Lewis(a) partially the non-sialylated Lewis(a) antigen (CA 195, CAM 43, CA 494) or are less related (CAM 17.1). The initial phase of screening and early detection is hoped to be better assessed by using molecular markers detecting gene mutations (p53, K-ras), growth factors (EGF, TGF-alpha, TGF-beta, HB-EGF, a/bFGFs, KGF) and growth factor receptor alterations (EGFr, c-erbB2/3/4). From these, K-ras mutations detected in blood, stool and bile juice of patients at risk for pancreatic cancer seem to be more promising than p53 alterations as a more later step in carcinogenesis, although they are neither yet well established nor standardised by reliable assays. In contrast growth factor and growth factor receptor alterations mainly concerning signal transducing systems seem to reflect increased tumour aggressiveness, thus shorter survival and poorer prognosis thereby contributing in the selection of patients for more aggressive therapy.
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PMID:Role of tumour markers, cytogenetics. 1043 9

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The proto-oncogene c-myc has been shown to be important in apoptosis regulation and to be amplified and overexpressed in human and rodent liver neoplasia. The objectives of the study reported here were to determine whether apoptosis regulation is altered in transgenic hepatocytes that overexpress c-myc and whether growth factors or nongenotoxic carcinogens alter apoptosis regulation in c-myc versus wild-type hepatocytes. Hepatocytes isolated from c-myc transgenic mice had four fold more c-myc RNA and protein (at 12-48 h) in addition to increased apoptosis levels compared with wild-type hepatocytes. The increased apoptosis in c-myc hepatocytes was accompanied by increased p53, bax, and bak and decreased bcl-2 protein levels. Hepatocytes overexpressing c-myc were more sensitive to apoptosis induced by bleomycin but less sensitive to apoptosis induced by transforming growth factor (TGF)-beta. Phenobarbital, a potent liver tumor promoter, inhibited apoptosis in c-myc hepatocytes but not in wild-type hepatocytes, decreased p53 and bax, and increased bcl-2 protein levels. Nafenopin inhibited apoptosis in both c-myc and wild-type hepatocytes, whereas 2,3,7,8-tetrachlorodibenzo-pdioxin did not inhibit apoptosis in either wild-type or c-myc hepatocytes. TGF-alpha inhibited apoptosis and increased bcl-X(L) and decreased bak protein levels in c-myc hepatocytes but not in wild-type hepatocytes. Insulin-like growth factor-II did not affect apoptosis in c-myc or wild-type hepatocytes. In this study, overexpression of c-myc altered the response to apoptotic stimuli in transgenic hepatocytes. Furthermore, phenobarbital and TGF-alpha inhibited c-myc-induced apoptosis, which may have resulted in a selective growth advantage for an initiated cell population and which may be a mechanism for tumor promotion.
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PMID:Dysregulation of apoptosis by c-myc in transgenic hepatocytes and effects of growth factors and nongenotoxic carcinogens. 1044 34


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