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

New insights into the genetic basis of carcinogenesis have been obtained by modern molecular biological techniques. Several susceptibility genes are known. The hereditary breast and ovarian cancer syndrome (germline mutations in BRCA1 and BRCA2) and endometrial cancer in the context of the hereditary non-polyposis colorectal cancer syndrome (HNPCC), germline mutations in mismatch-repair genes, are the most frequent hereditary cancer syndromes in gynaecology. Mutations in TP53 (Li-Fraumeni syndrome) and PTEN (Cowden's disease), associated with increased risk of breast cancer, are responsible for a smaller portion of familial breast cancer. The risk of inheritance and disease can be identified and defined by investigating family history, risk calculation programs, and genetic testing. Afterwards, options of primary, secondary, and tertiary prevention can be formulated. Presently, prophylactic surgery is the only option proven by clinical trials that can reduce the mortality of hereditary breast and ovarian cancer.
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PMID:[Prophylactic surgery of mammary and ovarian carcinoma]. 1623 64

The phosphatase and tensin homolog tumor suppressor (PTEN) belongs to a class of "gatekeeper" tumor suppressors together with p53, retinoblastoma and adenomatous polyposis. It is considered one of the most important tumor suppressors in the post p53 era. Previously to identify the molecules involved in the signaling network regulated by PTEN using proteomic tools, we reported global proteome profiles at different time points using the PTEN inducible NIH3T3 cells (Kim, S.-y., Kim, Y. S., Bahk, Y. Y., Mol. Cells 2003, 15, 396-405). However, the system had a critical limitation that NIH3T3 cell has endogenous wild-type PTEN and, thus to be exact, the induced PTEN could not give the answer about the real physiological roles of this tumor suppressor. Here, to find out PTEN-related protein network we have established various PTEN (wild-type, an activity inert C124G, and a lipid phosphatase deficient G129E)-expressing cell clones in U-87 MG human glioblastoma cells lacking detectable PTEN as a result of genetic lesions. In this biological context, we compared their morphological and expression patterns, and proteome images of each PTEN-expressing cell clone by 2-DE followed by identification with MALDI-TOF MS. We obtained some pieces of evidence that morphological change by PTEN expression is mediated by its protein phosphatase activity and their growth rate by the lipid phosphatase activity. The proteomic approaches showed that 30 proteins possibly correlated with PTEN's protein phosphatase activity (13 down-regulated and 17 up-regulated) and 20 with the lipid phosphatase activity (14 down-regulated and 6 up-regulated) were identified. Taken together, we conclude that the comparative analysis of proteome from various PTEN-expressing cells has yielded interpretable data to elucidate the protein network directly and/or indirectly caused by individual phosphatase activities of PTEN in vivo.
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PMID:Proteome profile changes that are differentially regulated by lipid and protein phosphatase activities of tumor suppressor PTEN in PTEN-expressing U-87 MG human glioblastoma cells. 1629 7

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1(+/-) and p53 null mice to generate Lkb1(+/-)/p53(+/-) and Lkb1(+/-)/p53(-/-) mice. Similar to the Lkb1(+/-) mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1(+/-)/p53(+/-) mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1(+/-)/p53(-/-) mice is approximately 2 months earlier than Lkb1(+/-)/p53(+/-) and Lkb1(+/-) mice, whereas the latter two show a similar time to onset which is at approximately 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.
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PMID:Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. 1635 36

Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.
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PMID:Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. 1662 53

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estradiol (E2) have been reported to downregulate the expression of E2 receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E2 replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. These data strongly suggest the protective roles of E2 and ER against colorectal cancer. However, the mechanisms remain unexplored. LoVo cells were transient transfected to overexpress ER-beta, DNA fragmentation and caspase activity assay were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the TNF-alpha promoter activity. Our data clearly demonstrated that E2 and ER-beta alone could upregulate p21 and p27 proteins, which further activate caspase-8 and caspase-9 to induce apoptosis in LoVo cell, and the ER-beta. effects were enhanced by E2. However, overexpressed ER-beta did not influence the expression and promoter activity of TNF-alpha. In addition, E2 and overexpressed ER-beta downregulated the beta-catenin proteins which cause the downregulation of its target genes, cyclin D1 and Rb, to inhibit the cell cycle and cell proliferation. The results indicate that overexpressed ER-beta may induce LoVo cell apoptosis and anti-proliferation by increasing p53 signaling in a ligand-dependent manner, and without hTNF-alpha involvement. Efforts aiming at enhancing ER-beta expression and/or activity may prove to be an attractive alternative therapy against colorectal cancer.
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PMID:Apoptotic effects of over-expressed estrogen receptor-beta on LoVo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner. 1683 Jul 93

Mutations in genes of the DNA mismatch repair system (MMR) are strongly linked to the development of hereditary non-polyposis colorectal cancer and play a significant role in sporadic cancer too. Besides the repair of chromosomal mismatches produced during replication, the MMR is the linkage of DNA mismatches to cell cycle control. Proteins of the MMR are necessary for the induction of apoptosis in response to non-tolerable amounts of DNA damage. We correlated the immunoreactivity of the MMR proteins hMSH2, hMLH1 and PMS2 to the immunoreaction of p53, the proliferation marker Ki67 and clinical prognosis factors such as tumor grading and staging, steroid receptor expression and hemangiosis carcinomatosa or lymphangiosis carcinomatosa in 200 samples from patients with diagnosed breast cancer. No correlation could be detected among the expression of the three MMR-proteins hMSH2, hMLH1 and PMS2. The expression of hMSH2 correlated positively with the expression of p53, with the appearance of distant metastases, low differentiation and the appearance of hemangiosis carcinomatosa and lymphangiosis carcinomatosa, while it negatively correlated with the expression of the estrogen receptor. No correlation was detected between hMLH1 or PMS2 and any of the investigated factors. The expression of hMSH2 seems to be related with predictors of an unfavorable course of disease in breast cancer.
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PMID:Immunohistochemistry of proteins for DNA mismatch repair in correlation to prognostic factors of mammarian cancer. 1739 69

The aim of this article is to present updated guidelines for the use of serum, tissue and faecal markers in colorectal cancer (CRC). Lack of specificity and sensitivity preclude the use of all existing serum markers for the early detection of CRC. For patients with stage II or stage III CRC who may be candidates for either liver resection or systemic treatment should recurrence develop, CEA should be measured every 2-3 months for at least 3 years after diagnosis. Insufficient evidence exists to recommend routine use of tissue factors such as thymidylate synthase, microsatellite instability (MSI), p53, K-ras and deleted in colon cancer (DCC) for either determining prognosis or predicting response to therapy in patients with CRC. Microsatellite instability, however, may be used as a pre-screen for patients with suspected hereditary non-polyposis colorectal cancer. Faecal occult blood testing but not faecal DNA markers may be used to screen asymptomatic subjects 50 years or older for early CRC.
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PMID:Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. 1751 20

Only few clinical factors predict the prognosis of patients with Ewing tumors. Unfavorable outcome is associated with primary metastatic disease, age > 15 years, tumor volume above 200 ml, and the histological response to chemotherapy. The aim of this study was to elucidate the prevalence and clinical impact of microsatellite instability (MSI) together with the relation between MSI and mismatch repair protein expression in Ewing tumors. DNA from 61 primary Ewing tumors and 11 Ewing tumor cell lines was extracted and microsatellite analysis for the detection of instability or loss of heterozygosity was performed for the five markers of the Bethesda panel BAT25, BAT26, D5S346, D2S123, and D17S250, which represents the established marker panel for the analysis of hereditary non-polyposis colorectal carcinoma (HNPCC) patients. In addition, single nucleotide repeat regions of the two tumor genes BAX and transforming growth factor receptor II (TGFBR2) were also included. All of the 61 samples were suitable for LOH analysis and 55 for the determination of MSI-status. LOH of these microsatellite markers was detected in 9 of the 61 patients (14.8%). Over all, genetic instability, i.e. MSI and/or LOH, was detected in 17 tumors (27.9%). One out of the 11 tumor cell lines (STA ET1) was characterized by instability of all the five Bethesda markers, while from primary tumor samples, only one showed MSI in more than one microsatellite marker (D5S346 and D17S250, MSI-high). Eight of the fifty-five patients (14.5%) showed instability of one microsatellite locus (MSI-low). No instability was detected in BAT26, D2S123, BAX and TGFBR2. There was no significant correlation between MSI and loss of expression of mismatch repair proteins MLH1, MSH2, or MSH6. The impairment of the p53 signaling pathway (expression of TP53 and/or MDM2 by immunohistochemistry) was significantly associated with reduced overall survival (15 of 49 patients (30.6%), P = 0.0410, log-rank test). We conclude that MSI is not prevalent in Ewing tumor and that the nature of instability differs from the form observed in colorectal carcinoma, the model tumor of MSI. This is documented by the different pattern of MSI (no BAT26 instability) in Ewing tumors and the lack of a strict correlation between MSI-high and loss of expression of MSH2, MSH6 and MLH1.
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PMID:Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression. 1753 Feb 87

Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21-/-p53-/- colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G1 cell cycle arrest independent of p21(WAF/CIP1) and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties.
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PMID:LKB1 catalytically deficient mutants enhance cyclin D1 expression. 1757 27

DNA mismatch repair (MMR) is a highly conserved system that repairs DNA adducts acquired during replication, as well as some forms of exogenous/endogenous DNA damage. Additionally, MMR proteins bind to DNA adducts that are not removed by MMR and influence damage-response mechanisms other than repair. Hereditary non-polyposis colorectal cancer, as well as mouse models for MMR deficiency, illustrate that MMR proteins are required for maintenance of genetic stability and tumor suppression. In both humans and mice, the phenotype associated with Msh6-associated tumorigenesis is distinct from that of Msh2. In this study, we hypothesized that Msh6-/-;p53+/- mice would display earlier tumor onset than their Msh6-/- or p53+/- counterparts, indicating that concomitant loss of these two tumor suppressors contributes to tumorigenesis via mechanisms that are only partially interrelated. We generated a Msh6-/-;p53+/- mouse model which succumbed to malignant disease at an accelerated rate and with a tumor spectrum distinct from both Msh6-/- and p53+/- models. Alteration of tumor phenotype in the Msh6-/-;p53+/- mice included a marked increase in microsatellite instability that was associated with loss of heterozygosity of the remaining p53 allele. Also, genetic instability was inversely correlated with survival. This manuscript marks the first in vivo investigation into the association between Msh6 and p53, and their combined role in the suppression of spontaneous tumorigenesis, cell survival and genomic stability. Our results support the hypothesis that p53 and Msh6 are functionally interrelated and that, with concomitant mutation, these tumor suppressors act together to accelerate tumorigenesis.
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PMID:The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis. 1761 58


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