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)

To clarify the relative role of hepatitis C virus (HCV) and hepatitis B virus (HBV) in hepatocarcinogenesis in hepatitis B surface antigen (HBsAg)-negative hepatocellular carcinoma (HCC) in Taiwan, polymerase chain reaction (PCR) was used to detect the HCV-RNA and HBV-DNA sequences in the serum and liver tissues from 31 HBsAg-negative HCC patients. Twenty-one were positive for antibody to HCV (group 1) and 10 were negative (group 2). Hepatitis C virus-RNA was detected by PCR in the serum of 16 group 1 patients and in the liver tissue of 17; while HBV-DNA was found in the liver tissue of only four, and no HBV-DNA was found in the serum. Hepatitis C virus RNA was detected in the serum of one group 2 patient and in the liver tissue of another. In contrast, HBV viral DNA was found in the serum of four group 2 patients and in the liver tissues of five patients. This indicates that HCV plays an important role in hepatocarcinogenesis in HBsAg-negative patients in Taiwan, especially in those with antibody to HCV. In those without antibody to HCV, HBV might still be associated with the development of HCC in a significant proportion of such patients. In order to study the role of the p53 mutation in hepatocarcinogenesis, we investigated the status of the p53 mutation in 61 HCC samples from Taiwan. The exon 5 to 8 of the p53 gene in the tumour tissue of 61 HCC were amplified and sequenced. A total of 20 cases (32.8%) were found to have mutations: 36.6% (15/41) from the HBsAg-positive group and 25.0% (5/20) from the HBsAg-negative group. The corresponding normal liver showed no mutation. The mutation is widely distributed throughout the exon 5 to 8. Only four cases (6.6%), all positive for HBsAg, had a specific hotspot mutation at codon 249 with G to T transversion. These results show that scattered point mutations in p53 are not uncommon in HCC samples from Taiwan and may be important in the development of this cancer. However, the aflatoxin-related specific mutation seems much less related to the genesis of HCC in Taiwan. To study the role of telomerase activity in hepatocarcinogenesis, a total of 39 HCC tissues and the corresponding non-tumour liver tissues were analysed. The results showed that telomerase activity was detected in all the 39 tumour tissues, while it could be detected in six of the 39 non-tumour liver tissues. The high positive rate of telomerase activity in HCC samples suggests that telomerase activity is closely related to the development or progression of HCC. To determine whether exon 1 and exon 2 of the p16 gene are altered in HCC, thirty-four tumours from 30 HCC patients were examined by DNA sequencing analysis of PCR-amplified genomic DNA. Homozygous deletions of MTS1/p16/CDKN2 exon 1 were identified in 1/34 primary tumours (3%), no mutations or rearrangements were found in these specimens. These data suggest that alterations of MTS1/p16/CDKN2 gene are rarely found in HCC, and might play little role in the development of this cancer. To study the clonality of HCC, 18 patients with multiple HCC, most of them small in size, were analysed by DNA fingerprinting. In patients positive for hepatitis B surface antigen, the integration pattern of hepatitis B viral DNA in liver tissue was also analysed. The results by both methods showed that 8/9 hepatitis B surface antigen-positive patients were different in clonality. In the remaining nine patients negative for hepatitis B surface antigen, four had different band patterns in their tumours by DNA fingerprinting. This study indicated that polyclonality of multiple HCC was rather frequent and it highlighted the importance of eliminating the underlying cause of liver injury to improve the survival of these patients. Microsatellite markers were used to study the genetic changes of HCC. Thirty cases of HCC, most of them small in size, were studied. A total of 242 microsatellite markers mapping to 1-22 and X chromosomes was used. The results showed that the range of loss of het
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PMID:Molecular mechanism of hepatocarcinogenesis. 940 51

Based on studies of the cell cycle in tissue cultures of cancer cell lines and cells from normal tissue interference in the regulatory network of pRB/cdk4/cyclin D1/p16 in combination with the tumour suppressor gene p53 was investigated. It was shown that overexpression of p53 and p16, but not p53 on its own, induced apoptotic cell death only in tumour cells. Gene transfer of the same two genes to tumours transplanted subcutaneously in mice also caused fast regression of some of the tumours.
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PMID:[p16 and p53 genes transferred with the help of adenovirus to induce apoptic tumor cell death]. 941 96

A decade of advances in understanding of the molecular basis of sporadic and familial cancers has combined with developments in mammalian gene transfer technology to stimulate intensive research into the potential applications of somatic gene therapy for cancer. Somatic gene immunotherapy is already in progress to stimulate and direct the natural targeting capabilities of the immune system against the threat of disseminated residual disease. The association of a plethora of mutated tumor suppressor genes (p53, p16 BRCA1, BRCA2) with diverse cancers has also highlighted the potential of somatic gene therapy with wild-type versions of suppressor genes as an anti-cancer therapeutic modality either in its own right or in synergistic association with traditional anti-cancer therapies. The methodologies for gene transfer technology range from direct intravenous injection of naked modified DNAs to intravenous injection of liposome-encapsulated DNAs or microsphere-bound DNAs. Recombinant retroviral and adenoviral vectors have natural transfection capabilities and display tropism for particular tissues that are of selective advantage against particular cancers. Liposomes display very high efficiencies of gene transfer with the advantages of successful transfer to a wide range of tissue types but their widespread systemic distribution offers problems in relation to selective targeting of tumor cells. The challenges to current gene transfer processes are much the same as that of other anti-cancer therapies: achieving selective targeting of cancer cells whilst optimizing dosages and minimizing the risk of collateral damage to healthy tissues.
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PMID:The basis for somatic gene therapy of cancer. 941 90

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28

We have previously described the development of radiation transformed human fetal prostate epithelial cells, 267B1. Using this in vitro model system, we investigated the molecular mechanisms of prostate carcinogenic progression by comparing nontumorigenic (267B1/B) and tumorigenic (267B1/D) cells. We examined the G1- to S-phase transition in synchronized cells to determine if the progression of 267B1 cells from nontumorigenic to tumorigenic was the consequence of a perturbation in the G1- to S-phase transition involving p53, pRb, p21, or p16. Nontumorigenic 267B1/B cells showed a time-dependent increase in the expression of p53 and a corresponding increase in p21 following exposure to ionizing radiation (6 Gy). The levels of pRb and p16 protein were virtually unchanged. In contrast, tumorigenic 267B1/D cells exhibited a p53-independent induction of p21 protein with a parallel increase in p16 protein in response to ionizing radiation, but no change in pRb was observed. These results suggest that the progression of 267B1 cells from nontumorigenic to tumorigenic involves p53-independent processes.
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PMID:p53-Independent tumorigenic progression of human prostate cells. 943 43

Alterations in the expression of genes affecting cell cycle progression occur in all human cancers. These may occur either by overexpression of genes such as cyclin D1, mutation of regulatory genes such as p16, or abrogation of checkpoints following DNA damage as in the cases of mutation or deletion of the p53 gene. Perturbation of the normal functions of these genes has a profound effect on cellular proliferation, differentiation and apoptosis. There is increasing evidence that such alterations may modulate the cellular response to treatment with chemotherapeutic agents. In many cases genetic alterations may induce resistance to drug treatment as in the case of mutations of the p53 gene. However, the deregulated expression of cell cycle genes may also increase sensitivity to treatment by directly altering the expression of the target for chemotherapeutic drugs as in the case of deletion of the retinoblastoma gene. It is crucial to understand the interactions between drug mechanisms of action and the genetic alterations in cancer to exploit potential areas in which the alterations found in tumors may constitute potential vulnerability.
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PMID:Modulation of chemosensitivity through altered expression of cell cycle regulatory genes in cancer. 943 33

Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.
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PMID:Overcoming cellular senescence in human cancer pathogenesis. 943 77

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

Cancer of the pancreas is a genetic disease. Sporadic cancers of the pancreas are frequently associated with the activation of an oncogene, K-ras, and the inactivation of multiple tumor suppressor genes, including p53, DPC4, p16, and BRCA2. An improved understanding of the genetics of pancreas cancer should lead to new tests to screen for this disease and novel rational gene-based therapies.
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PMID:Genetics of pancreatic cancer. From genes to families. 944 84

The development of neoplasia frequently involves inactivation of the p53 and retinoblastoma (Rb) tumor suppressor pathways and disruption of cell cycle checkpoints that monitor the integrity of replication and cell division. The human papillomavirus type 16 (HPV-16) oncoproteins, E6 and E7, have been shown to bind p53 and Rb, respectively. To further delineate the mechanisms by which E6 and E7 affect cell cycle control, we examined various aspects of the cell cycle machinery. The low-risk HPV-6 E6 and E7 proteins did not cause any significant change in the levels of cell cycle proteins analyzed. HPV-16 E6 resulted in very low levels of p53 and p21 and globally elevated cyclin-dependent kinase (CDK) activity. In contrast, HPV-16 E7 had a profound effect on several aspects of the cell cycle machinery. A number of cyclins and CDKs were elevated, and despite the elevation of the levels of at least two CDK inhibitors, p21 and p16, CDK activity was globally increased. Most strikingly, cyclin E expression was deregulated both transcriptionally and posttranscriptionally and persisted at high levels in S and G2/M. Transit through G1 was shortened by the premature activation of cyclin E-associated kinase activity. Elevation of cyclin E levels required both the CR1 and CR2 domains of E7. These data suggest that cyclin E may be a critical target of HPV-16 E7 in the disruption of G1/S cell cycle progression and that the ability of E7 to regulate cyclin E involves activities in addition to the release of E2F.
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PMID:Disruption of the G1/S transition in human papillomavirus type 16 E7-expressing human cells is associated with altered regulation of cyclin E. 944 90


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