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)

Tumor suppressor genes such as p53 contribute to the oncogenic process via loss-of-function mechanisms such as genetic mutation or complex formation with other cellular or viral proteins. p53 is mutated in approximately 50% of human tumors and has an important role in the genesis or progression of both colorectal and hepatocellular cancers. Colorectal cancer is leading cause of cancer mortality in the United States, whereas hepatocellular cancer is the leading worldwide cause of cancer death; the liver is a primary site of morbidity in both diseases. Because systemic tumor suppressor gene therapy is currently not feasible, we have chosen to develop a regional form of such therapy directed at primary or metastatic liver neoplasms. Gene replacement therapy with p53 is a promising new strategy to treat advanced human cancers.
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PMID:p53 gene therapy in vivo of herpatocellular and liver metastatic colorectal cancer. 860 33

Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancers. We have proposed a sequential multistage scheme involving tubular cell damage, regenerative cell proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene alteration, and amplification as essential steps for estrogen carcinogenesis in this model. A systematic study was undertaken to assess the expression of nuclear proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by Northern blot analysis to further support this scheme. Hamster kidney RNA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated castrated male hamsters and corresponding age-matched untreated controls was used in these studies, as well as primary estrogen-induced renal tumor RNA, for reference. Although no significant changes in the expression of these proto-oncogenes were detected in the first 4 months of estrogen treatment relative to age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar estrogen-exposed hamsters. Although no significant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal tumor. In contrast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in WT-1 expression was observed in the primary renal tumor. It is evident that two WT-1 transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney. In summary, the estrogen-induced inappropriate gene expression, including p53, reported herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain proximal tubular interstitial cells necessary for estrogen-driven tumor formation in the hamster.
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PMID:Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis. 865 6

Tumor suppressor genes such as Rb and p53 usually kill tumor cells when overexpressed ectopically. This is a consequence of their normal cell cycle regulatory functions. By contrast, the E1a gene of adenovirus, a common cold virus, converts tumor cells into viable normal cells. This has advantages for investigation and control of cancer. In particular, E1a is a master programmer of the epithelial phenotype. This provides a new tool for understanding the molecular basis of the epithelial-mesenchymal transition, and how it goes awry in cancer cells. Furthermore, epithelial cells are sensitive to a form of apoptosis - 'anoikis' - that is induced by detachment from extracellular matrix. This property confers strict anchorage-dependence. Transcriptional programming, by E1a or the formation of cell-cell junctional complexes, programs epithelial cells to be sensitive to anoikis.
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PMID:Reversal of malignancy by the adenovirus E1a gene. 865 90

Types of growth include embryonic, fetal, neonatal, juvenile and mature. Until full differentiation is achieved, cells grow through proliferation from progenitor cells. At maturity, the cellular genome is fixed with committed patterns of cell cycle duration and adaptation, ranging from static to renewing type 3. The static cell type cannot proliferate and adapts through hypertrophy. The renewing type continuously proliferates even without stimulus. In all cell types the processes of differentiation and proliferation are mutually exclusive. Cellular kinetics involve (a) the duration of the cell cycle, (b) the birth rate of cells, and (c) the growth rate fractions. The duration of the cell cycle is 2-4 days. All growth factors (GF) exert their influence during G1 phase. Release a GF by one cell type can influence the proliferation of another (= paracrine stimulation). At the end of G1 is the point of highest sensitivity to toxicity. Tumor suppressor genes act here through tyrosine phosphorylation. During S, the cell replicates its chromosomes. During G2 the immune surveillance and DNA damage repair mechanisms operate. Injured cells stay here longer enabling repair of their damaged DNA. Cell division involves both nuclear (mitosis) and cytoplasmic (cytokinesis) phases giving rise to 2 new cells. The cell cycle has 2 checkpoints. The first involves the G1-S transition and the second the G2-M transition. The types of cell cycle inhibition include (a) cycle- and phase-specific inhibition; (b) cycle-and nonphase-specific inhibition; (c) noncycle-and nonphase-specific inhibition, and finally (d) noncycle, nonphase-, and nonorgan-specific inhibition. Proliferation is a circadian process and it is stimulated by a variety of stimuli which include (1) interference with hormonal feedback pathways; (2) inhibition of the tissue trophic activity; (3) sustained presence of antigenic substances; (4) tissue ischemia; (5) changes of conditions luminally or on surfaces of tissues; (6) sustained cytotoxicity; (7) cell death; and (8) surgical resection. Proliferation can be arrested through senescence, apoptosis, injury or even during the development of immune cells. In the past, tissue/cell kinetics have been studied by tritiated thymidine histoautoradiography. Recently, monoclonal antibodies to proliferation-associated antigens, have been successfully employed. These antigens are cycle-associated proteins and include (1) PCNA; (2) p53; (3) Ki67; (4) AGNOR; (5) Statin; and (6) BrdU. Practical examples are given comparing PCNA and BrdU markers from 3 tissues, i.e. liver, glandular stomach, and uterus, across 2 or 3 strains of rats. Mean values of labeling indices are cited. Within the PCNA marker, 2 different clones are compared from the glandular stomach of SD rats of 2 different ages. Gender and across species comparisons are also made. All these comparisons denote that in every study where markers are used (a) there is a need for a concurrent study control group of the same age; (b) there is a need for in-house control data for this particular organ by species, strain, gender and age; (c) there is ancillary assessment of the trophic status of the target tissue; (d) there is a need for at least 2 different time points during assessment; (e) there is a need for such proliferation data prior to commencing the 2 year rodent bioassay; and (f) that PCNA is the most reliable and versatile of all markers used, capable of rendering good results even from archival specimens.
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PMID:Proliferation markers. 867 72

Endometriosis is a very common gynecological condition in which tissue similar to endometrium proliferates at sites outside the uterine cavity, most commonly the ovary. Although it generally remains a benign condition, malignant transformation has been documented. and it is commonly found in association with endometrioid subtype ovarian cancer. Tumor suppressor genes are commonly altered in ovarian cancers, and the development of endometriosis may involve mutations in the same class of genes. We have investigated this possibility by examining DNA from 40 cases of endometriosis for clonal status, alterations in TP53 and RASK, and allelic losses at candidate ovarian tumor suppressor loci on chromosome arms 6q, 9p, l1q, 17p, l7q, and 22q. The majority of endometriotic cysts were monoclonal, but interestingly, 8 of 10 normal endometrial glands were also monoclonal, demonstrating that both are able to develop from a single progenitor cell. No mutations were detected in TP53 or RASK. Loss of heterozygosity (LOH) was detected on chromosomes 9p (18%), 1lq (18%), and 22q (15%). In total, 11 of 40 (28%) cases demonstrated LOH at one or more of these loci. This study, which is the first to report LOH in endometriosis, supports the notion that tumor suppressor gene inactivation may play a role in the development of at least a subset of cases.
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PMID:Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. 875 23

Hepatitis B virus (HBV) is a co-factor in some hepatocellular carcinomas (HCC). Chronic infection with HBV is a risk factor for tumor development, suggesting the accumulation of cellular genetic changes. HBV DNA is frequently found integrated at random sites in HCC, with chromosomal deletions and rearrangements being common at the sites of viral integration. Tumor suppressor gene p53 is frequently altered in HCC. Environmental carcinogens are factors in HCC development in certain geographic locations. HBV encodes a protein (X) known to transactivate viral and cellular genes; the X gene is often retained in HCC. To learn more about X gene function. We employed the yeast two-hybrid genetic system to seek X-interactive proteins. A cellular protein, designated XAP-1, was recovered that interacts specifically with the X protein. XAP-1 is the human homologue of the monkey UV-damaged DNA-binding protein (UV-DDB); the UV-DDB protein functions in DNA repair and is defective in some xeroderma pigmentosum group E patients. The interaction between XAP-1 and HBV X protein was confirmed by several independent methods. This suggests that cellular DNA repair processes may be affected by HBV and that the resulting genetic instability may contribute to hepatocellular carcinogenesis. A unifying model of the molecular basis of HBV involvement in HCC development is presented. Fundamental components of the model are chronic infection by HBV and viral effects on cellular DNA repair. This model has implications for the possible role of HCV infection in the induction of HCV-associated HCC.
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PMID:Viral co-factors in liver cancer: lessons from hepatitis B virus. 887 24

We previously reported that a transgenic mouse line containing the fetal globin promoter linked to the SV40 T antigen (T Ag) viral oncogene (Ggamma/T-15) resulted in prostate tumors. In this study, we further explored tumor origin, frequency, invasiveness, androgen sensitivity, and gene expression pattern. T Ag was detected in adult but not fetal and neonatal prostates, suggesting a role for androgens in tumor progression. However, castration shortly after prostate morphogenesis did not prevent tumor development, suggesting an androgen-independent phenotype. Tumors originated within ventral or dorsal prostate lobes and involved intraepithelial neoplasia, rapid growth in the pelvic region, and metastasis to lymph nodes and distant sites. In addition, the primary cancers could be propagated in nude mice or nontransgenic mice. Seventy-five percent of hemizygous and 100% of homozygous transgenic males developed prostate tumors, suggesting a T Ag dosage effect. Biochemical characterization of advanced tumors revealed markers of both neuroendocrine and epithelial phenotypes; markers of terminal differentiation are lost early in tumorigenesis. Tumor suppressor genes (p53 and Rb), normally bound to T Ag, were up-regulated; bcl-2 proto-oncogene, which prevents apoptosis, was slightly up-regulated. Myc, a stimulus to cell cycle progression, was unchanged. We propose the Ggamma/T-15 transgenic line as a model of highly aggressive androgen-independent metastatic prostate carcinoma with features similar to end-stage prostate cancer in humans.
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PMID:Prostate cancer progression, metastasis, and gene expression in transgenic mice. 904 Nov 92

Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes which, when activated, become dominant events characterized by the gain of function, and tumor suppressor genes which become recessive events characterized by the loss of function. Alterations in proto-oncogenes and tumor suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. Proto-oncogenes are activated mainly by point mutations; however, amplification and translocation events are also common. Tumor suppressor genes are inactivated by an allelic loss followed by a point mutation of the remaining allele. The prototype suppressor genes are the retinoblastoma (RB) gene and the TP53 (also known as p53) genes. Recent studies have shown that inactivation of TP53 and RB occur in bladder tumors that have a more aggressive clinical outcome and poor prognosis. We will review the molecular abnormalities associated with both oncogenes and tumor suppressor genes in bladder tumors, and also discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance our ability to assess tumor biological activities and to design effective treatment regimes.
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PMID:Genetic studies and molecular markers of bladder cancer. 925 87

In normal cells the cell cycle, cell proliferation and differentiation are precisely regulated by a variety of different players. These include cyclins, which help to drive cells into mitosis, as well as cyclin-dependent kinase inhibitors which may be viewed as cell cycle brakes. Alterations in such genes and their products are frequent in human cancer. Overexpression of cyclins has been identified in lymphoma and in non-small cell lung cancer. Mutations in cyclin-dependent kinase inhibitors, such as the p16 gene, are particularly frequent in human cancer cell lines. Tumor suppressor genes, including the retinoblastoma gene and the p53 gene, are also crucial in this context, and their inactivation through gene mutations in cancer is frequent. Assessing alterations of genes associated with cell cycle regulation in malignancy or their protein products is of clinical interest. Molecular and immunological techniques to identify such alterations may provide unique markers of prognostic and predictive value in cancer. In addition, the technology is being developed for the treatment of such genetic alteration in cancer cells at the molecular-genetic level. Protocols introducing the wild-type p53 gene in tumors with p53 inactivations are on the way and clinical trials, although very preliminary, seem to be opening up completely new avenues for cancer treatment. Investigating cell cycle alterations in cancer is no longer the exclusive province of experimental research, but has rapidly developed into an area of unique clinical relevance.
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PMID:[Cancer and the cell cycle: a current merry-go-round in oncology of clinical relevance]. 961 6

Tumor suppressor gene p53 is a critical regulator of the cellular response to DNA damage. To examine the function of p53 in postmitotic CNS neurons, we cultured cerebellar granule cells from 15-day-old wild type and p53-deficient mice, and analyzed changes of protein expression in apoptosis elicited by DNA damage. When cerebellar granule cells from wild type mice were treated with bleomycin, a DNA strand-break inducing agent, neuronal death occurred. In contrast, cells from p53-deficient mice were resistant to bleomycin-induced neuronal death. Furthermore, cells from p53 heterozygous mice showed an intermediate resistance between wild type and p53-deficient mice. These results show that p53 is required for the bleomycin-induced cerebellar granule cell death. To examine which proteins are involved in this apoptosis, we examined changes in protein levels of the Bcl-2 family, including Bcl-2, Bcl-X and Bax. The relative amounts of these proteins did not change after bleomycin treatment, suggesting that the changes in the levels of these Bcl-2 family proteins are not necessary for apoptosis in this system. In contrast, the levels of c-Jun protein significantly increased 6 h after treatment with bleomycin in wild type but not in p53-deficient cerebellar granule cells. These results raise the possibility that c-Jun is required for p53-dependent neuronal apoptosis induced by bleomycin.
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PMID:Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin. 962 42


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