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

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.
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PMID:Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. 134 43

Astrocytomas, including the most malignant form, glioblastoma multiforme, are the most frequent and deadly primary tumors of the human nervous system. Recent molecular genetic analyses of astrocytomas have demonstrated frequent chromosome 17 deletions involving the telomeric region of the short arm (17p12-pter). This region contains a candidate tumor suppressor gene, TP53, which has recently been implicated in the etiology of a broad array of human cancers. To study the possible role of TP53 in astrocytoma development, 24 randomly chosen human astrocytic tumors were examined for genomic TP53 sequence aberrations using primer-directed DNA amplification in conjunction with direct sequencing. Five of the 11 grade III astrocytomas (glioblastoma multiforme), but only one of seven grade II astrocytomas (anaplastic astrocytoma) and none of either the grade I astrocytomas or oligodendrogliomas demonstrated distinct point mutations involving the TP53 gene. These data suggest that TP53 mutations may play a role in astrocytoma development and are predominantly associated with higher grade tumors.
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PMID:TP53 gene mutations and 17p deletions in human astrocytomas. 168 25

This report reviewed recent remarkable progresses on the cytomolecular mechanisms in colorectal carcinogenesis. Colorectal carcinoma is a good model for the study of multi-step progression, because we can obtain adenomatous polyps which are considered as a precancerous form. Furthermore, a familial syndrome, which is characterized by numerous adenomas of the colon, is available for linkage analysis. Recently, the p53 and DCC genes have been identified as candidate tumor suppressor genes on chromosome 17p and 18q respectively. In this paper, we present the multiple genetic alterations in colorectal carcinoma, including activation of K-ras gene and inactivation of tumor suppressor gene such as p53 and DCC genes as well as loss of heterozygosity and approach to the gene responsible for adenomatous polyposis coli by reverse genetics.
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PMID:[Cytomolecular aspects of colorectal carcinoma]. 184 88

Recent efforts have been directed at identifying and characterizing candidate tumor suppressor genes and the activities of oncogenes in primary brain tumors. The p53 gene mapping to region p13 of chromosome 17 has several characteristics as a tumor suppressor gene. The wild-type p53 protein, which is a transcriptional activator, may serve as a barrier to the progression of neoplastic processes, and alterations of p53 are involved in genesis of various cancers including astrocytomas. The NF1 gene, which is responsible for the susceptibility to neurofibromatosis type 1, has recently been isolated. This gene is assumed to play a role in the signal transduction pathway by interacting with the ras gene product. Recent observation revealed that the NF1 gene may regulate the neuronal differentiation, and the alteration in regulation of the NF1 transcript is potentially related to the progression of neuroectodermal tumors. Restriction fragment length polymorphism studies have also shown chromosomal losses associated with chromosome 9, 10 and 17. These losses of genetic material are suspected to involve loci near or at the p53 gene for chromosome 17, and neighboring the interferon genes on chromosome 9. Although no sublocalization of chromosome 10 deletions has been accomplished, all of these loci are thought to harbor tumor suppressor genes. Recent advances in oncogene research have focused on understanding the mechanisms of action of growth factors, growth factor receptors, and their substrates, particularly in glial oncogenesis. Fibroblast growth factor, epidermal growth factor, and their respective receptors are of particular interest. However, the ROS oncogene, which is expressed and rearranged in some glioma cell lines, may not be a critical factor in the development of gliomas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathways of oncogenesis in primary brain tumors. 190

The evidence for human tumor suppressor genes is reviewed. Initial evidence was provided by somatic cell hybridization, where somatic cell hybrids derived from the fusion of malignant and normal parental cells were found to be transformed but nontumorigenic. Tumorigenic segregants appeared at later intervals and were associated with the loss of specific normal chromosomes. Evidence for loss of tumor suppressor genes in many human malignancies was provided by a combination of cytogenetic and restriction fragment length polymorphism analyses. Functional analyses, using monochromosome transfer from normal cells into cancer cells, have confirmed the existence of suppressor genes and their critical role in control of tumor formation. Recently, the tumor suppressor gene Rb-1 has been cloned and also shown to have tumor-suppressing properties. Most recently, a candidate tumor suppressor gene on chromosome 17 (p53) has been implicated in colorectal carcinomas and other human malignancies. It is of interest to note that this gene was originally described as an oncogene. The biological mechanism of tumor suppression has been linked to the induction of differentiation in both somatic cell hybrids and osteosarcoma cells transfected with the normal Rb-1 gene. However, recent studies with monochromosome transfer into neuroblastoma cells indicates that differentiation may be dissociated from tumor suppression. Tumor suppressor genes do not act directly as negative regulators of conventional "dominantly-acting" oncogenes and therefore cannot be considered as anti-oncogenes in the sense of directly interacting with and regulating the expression of such oncogenes as ras and myc. However, it is speculated that they may negatively regulate an, as yet undiscovered, family of oncogenes which would not be dominantly expressed.
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PMID:The evidence for human tumor suppressor genes. 257 36

The complex but poorly understood human male germ cell tumors offer unusual opportunities for the genetic analysis of malignant transformation and embryonal differentiation in a pluripotential stem cell lineage. Histologically, these tumors are divided into two major subgroups, seminomas which are characterized by inability to express embryonal differentiation, and non-seminomas which are characterized by ability to express embryonal as well as extra-embryonal patterns of differentiation. To understand the role of genetic factors in the development of these tumors and the regulation of differentiation expressed by them, we carried out a detailed allelotype analysis by the loss of heterozygosity assay. This analysis revealed frequent deletions in known tumor suppressor genes (RB1, DCC, NME), a number of previously described sites of candidate tumor suppressor genes (3p, 9p, 9q, 10q, 11p, 11q and 17p), as well as several novel sites (2p, 3q, 5p, 12q, 18p and 20p). Our results also showed that well differentiated teratomas exhibit a significantly higher level of allelic loss compared to the less differentiated embryonal carcinomas. In addition, certain loci and genes exhibited frequent non-random deletion in teratomas (D3S32, D3S42, D5S12, D10S25, D11S12, RB1, TP53, NME1, NME2, D17S4, D18S6 and D20S6) and embryonal carcinomas (IFNB, D9S27). Among these loci, the NME genes were notable for a high degree of genetic loss (> 70%) in teratomas. These results suggested that nonrandom loss or inactivation of certain genes may be associated with tumor development and loss or inactivation of other genes may be associated with somatic differentiation.
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PMID:Allelic loss and somatic differentiation in human male germ cell tumors. 751 76

Cyclin-dependent kinases (Cdks) are positive regulators of cell proliferation, whereas Cdk inhibitors (CKIs) inhibit proliferation. We describe a new CKI, p57KIP2, which is related to p21CIP1 and p27KIP1. p57KIP2 is a potent, tight-binding inhibitor of several G1 cyclin/Cdk complexes, and its binding is cyclin dependent. Unlike CIP1, KIP2 is not regulated by p53. Overexpression of p57KIP2 arrests cells in G1. p57KIP2 proteins have a complex structure. Mouse p57KIP2 consists of four structurally distinct domains: an amino-terminal Cdk inhibitory domain, a proline-rich domain, an acidic-repeat region, and a carboxy-terminal domain conserved with p27KIP1. Human p57KIP2 appears to have conserved the amino- and carboxy-terminal domains but has replaced the internal regions with sequences containing proline-alanine repeats. In situ hybridization during mouse embryogenesis revealed that KIP2 mRNA displays a striking pattern of expression during development, showing high level expression in skeletal muscle, brain, heart, lungs, and eye. Most of the KIP2-expressing cells are terminally differentiated, suggesting that p57KIP2 is involved in decisions to exit the cell cycle during development and differentiation. Human KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, marking it as a candidate tumor suppressor. The discovery of a new member of the p21CIP1 inhibitor family with novel structural features and expression patterns suggests a complex role for these proteins in cell cycle control and development.
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PMID:p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. 772 84

The deleted in colorectal cancer (DCC) gene has been identified as a candidate tumor suppressor gene on the basis of frequent allelic loss and decreased or absent gene expression in several human cancer types, as well as somatic mutations in the gene in colorectal tumors. We have identified a Xenopus DCC homologue (XDCC alpha) predicted to encode a protein of 1427 amino acids and have characterized XDCC expression in developing embryos and adult tissues. The predicted amino acid sequences of XDCC alpha and human DCC are greater than 80% identical; each has four immunoglobulin-like domains, six fibronectin type III domains, and a cytoplasmic domain of about 325 amino acids. While RNase protection assays and immunoblotting studies failed to detect XDCC alpha expression in embryos prior to developmental stage 15, XDCC alpha expression was present in embryos from stages 19 to 46. Whole mount in situ hybridization studies localized XDCC alpha expression to developing forebrain, midbrain, and hindbrain regions. DCC expression was inhibited by treatments that altered the development of mature neural structures; specifically, uv-ventralized embryos and exogastrulae had reduced DCC expression. These results indicate that XDCC alpha is developmentally regulated and expressed as a consequence of neural induction. Moreover, unlike some well-characterized tumor suppressor genes, such as the p53 and retinoblastoma genes, that are not differentially expressed in developing Xenopus embryos, the DCC gene may have a specific role in the morphogenesis of the brain and perhaps other tissues and organs.
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PMID:Expression of a homologue of the deleted in colorectal cancer (DCC) gene in the nervous system of developing Xenopus embryos. 781 84

A number of candidate tumor suppressor genes located on the human chromosome 17 are thought to have a role to play in the development of breast cancer. In addition to the p53 gene on 17p13.1 and the BRCA1 gene mapped to 17q12-21, other chromosomal regions for tumor suppressor genes have been suggested to exist on 17p13.3 and both the central and the distal parts of 17q, although definitive functional proof of their involvement in breast cancer tumorigenesis is still lacking. In this report we show that microcell transfer of a human chromosome 17 into wild-type p53 breast cancer cells CAL51 results in loss of tumorigenicity and anchorage-independent growth, changes in cell morphology and a reduction of cell growth rates of the neo-selected microcell hybrids. In the hybrid cells, which express the p53 wild-type protein, only the p- and the distal parts of the q arm of donor chromosome 17 are transferred. Thus, our results provide functional evidence for the presence of one or more tumor suppressor gene(s) on chromosome 17, which are distinct from the p53 and the BRCA1 genes.
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PMID:Suppression of tumorigenicity of breast cancer cells by transfer of human chromosome 17 does not require transferred BRCA1 and p53 genes. 784 68

To identify the genetic events which may play a role in the development of cervical carcinoma, we performed a detailed allelotype analysis utilizing DNA from 53 primary tumors and corresponding normal cells and 57 polymorphic probes mapped to each of the chromosomal arms, excluding the short arms of the acrocentric chromosomes. Loss of heterozygosity (LOH) of > 25% was observed at sites on 11 chromosomal arms, which included 1q (26%), 3p (35%), 3q (31%), 4q (46%), 5p (53%), 5q (38%), 6p (28%), 10q (28%), 11p (42%), 18p (38%), and Xq (26%). The most frequent LOH was noted on 4q (ADH3) and 5p (D5S19), suggesting that loss of candidate tumor suppressor genes on these chromosomal arms may play a role in the development of cervical carcinoma. The two sites of deletions identified on 5p and Xq represent novel candidate tumor suppressor gene sites which have so far not been reported in any other tumor type. Human papilloma virus status did not correlate with any of the sites which showed frequent LOH. TP53 mutation analysis by single-strand conformation polymorphism analysis was performed in 17 tumors that either showed 17p deletions (TP53, D17S5, or D17S28) or were human papilloma virus negative. One of the 7 human papilloma virus-negative tumors, which also showed LOH at the D17S28 locus, had a mutation in exon 5. This study represents the first comprehensive genetic analysis of this cancer and identifies several novel features of significance to genetic etiology of cervical carcinoma.
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PMID:Allelotype analysis of cervical carcinoma. 804 99


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