p53 Suppressor Gene
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Several genetic events are necessary for a cell to become malignant. Some of these events are activation of proto-oncogenes, and other events are loss of normal function of tumor suppressor gene(s). Two or more different tumor suppressor genes may be inactivated in some tumors, and the same suppressor gene may be involved in different types of tumors. Loss of constitutional heterozygosity (LOH) in the tumor suggests that a certain tumor suppressor gene may reside near the locus of the probe by which the LOH was demonstrated. However, LOH is not necessarily found when a tumor suppressor gene is inactivated. The frequency of LOH found by a probe depends upon the distance between the probe and the tumor suppressor gene. Moreover, inactivation of the suppressor gene by point mutation or very small deletion does not cause any change in electrophoretic mobility of the DNA fragment detected by the probe. Treatment of a cancer by tumor suppressor gene(s) is not possible until a technique by which we can introduce the gene into all the tumor cells is established. At present, clinicians should cooperate with basic scientists in the search for tumor suppressor genes. The comparison of clinical features and the genetic alterations in the tumor will shed light on the malignant behavior of the tumor cells such as rapid growth and/or tendency to metastasis.
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This chapter describes the tumor suppressor genes and retinoblastoma gene. It emphasizes that the human body has mechanisms exerted by tumor suppressor genes that normally “police” the processes that regulate cell numbers and ensure that new cells receive DNA that has been precisely replicated. The chapter then investigates how tumor suppressor gene products may inhibit the cell cycle, promote differentiation, or trigger apoptosis. It reviews the implications if both copies of a tumor suppressor gene become inactivated by mutation or epigenetic changes. Finally, the chapter explores the mutations in the RB pathway, p53 pathway, and cancer. It then considers the interaction of DNA viral protein products with RB and p53, and targeting of the p53 pathway.
Retinoblastoma
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Retinoblastoma protein
Cyclin-dependent kinase 8
E2F1
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BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common human tumors in Asia and Africa. The molecular genetic changes involving both protooncogenes and tumor suppressor genes are known to be involved in hepatocarcinogenesis, but the roles of the known tumor suppressor genes in hepatocarcinogenesis are not fully elucidated. In this study, the authors analyzed the loss of heterozygosity (LOH) of known tumor suppressor genes in HCC and evaluated the relationship between LOH of tumor suppressor genes and clinicopathologic features. METHODS The authors assessed the LOH of the 10 known tumor suppressor genes (VHL, APC, EXT1, WT1, Rb1, p53, BRCA1, nm23, DPC4, and DCC) with microsatellite markers in 29 consecutively resected HCC specimens. RESULTS The authors found frequent LOH of tumor suppressor genes in HCC. Twenty five of 29 cases (86%) had LOH of tumor suppressor genes and 17 cases (59%) had LOHs involving 2-4 tumor suppressor genes. Among the tumor suppressor genes, frequent LOH was noted in the p53 (66%), Rb1 (33%), EXT1 (33%), and APC (20%) genes. LOH of the p53 gene and multiple LOH of the tumor suppressor genes were more frequent in poorly differentiated HCCs (P = 0.02). CONCLUSIONS The LOH of tumor suppressor genes is frequent in HCCs and LOH of the p53 gene and accumulated LOHs are related to poorly differentiated HCC. Abnormalities of the p53 gene or the accumulated abnormalities of the tumor suppressor genes may play a role in the aggressive progression of HCC. Cancer 1997; 80:865-72. © 1997 American Cancer Society.
HCCS
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BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common human tumors in Asia and Africa. The molecular genetic changes involving both protooncogenes and tumor suppressor genes are known to be involved in hepatocarcinogenesis, but the roles of the known tumor suppressor genes in hepatocarcinogenesis are not fully elucidated. In this study, the authors analyzed the loss of heterozygosity (LOH) of known tumor suppressor genes in HCC and evaluated the relationship between LOH of tumor suppressor genes and clinicopathologic features. METHODS The authors assessed the LOH of the 10 known tumor suppressor genes (VHL, APC, EXT1, WT1, Rb1, p53, BRCA1, nm23, DPC4, and DCC) with microsatellite markers in 29 consecutively resected HCC specimens. RESULTS The authors found frequent LOH of tumor suppressor genes in HCC. Twenty five of 29 cases (86%) had LOH of tumor suppressor genes and 17 cases (59%) had LOHs involving 2-4 tumor suppressor genes. Among the tumor suppressor genes, frequent LOH was noted in the p53 (66%), Rb1 (33%), EXT1 (33%), and APC (20%) genes. LOH of the p53 gene and multiple LOH of the tumor suppressor genes were more frequent in poorly differentiated HCCs (P = 0.02). CONCLUSIONS The LOH of tumor suppressor genes is frequent in HCCs and LOH of the p53 gene and accumulated LOHs are related to poorly differentiated HCC. Abnormalities of the p53 gene or the accumulated abnormalities of the tumor suppressor genes may play a role in the aggressive progression of HCC. Cancer 1997; 80:865-72. © 1997 American Cancer Society.
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Tumor suppressor genes are wild-type alleles of genes that play regulatory roles in cell proliferation, differentiation, and other cellular and systemic processes. It is their loss or inactivation that is oncogenic. The first evidence of tumor suppressor genes appeared in the early 1970s, but only within the past few years has a wealth of new information illuminated the central importance of these genes. Two or more different suppressor genes may be inactivated in the same tumors, and the same suppressors may be inactive in different tumor types (for example, lung, breast, and colon). The suppressor genes already identified are involved in cell cycle control, signal transduction, angiogenesis, and development, indicating that they contribute to a broad array of normal and tumor-related functions. It is proposed that tumor suppressor genes provide a vast untapped resource for anticancer therapy.
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Objective To investigate the effect of tumor suppressor gene on tumourigenesis in multiple primary malignant neoplasm (MPMN). Methods The retrospective analysis was used to summarize several common tumor suppressor genes correlation to MPMN. Results At current study of the tumor suppressor genes, the common genes studied in MPMN were p53, APC, p16, BRCA1, BRCA2 and PTEN/MMAC1, etc. The same mutation of tumor suppressor genes could be detected from PMNNs. Conclusion [WT5”BZ]There are significant relations between MPMN and inactivation of tumor suppressor gene. By the study of tumor suppressor gene, it can reveal some common rules of tumourigenesis of MPMN.
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In the past 15 years, many of the mechanisms underlying the molecular origins of cancer have been uncovered, and a clear picture of the role of oncogenes and tumor suppressor genes in carcinogenesis has developed. This article reviews the mechanisms by which oncogenes and tumor suppressor genes participate in the creation of tumors.
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The p53 gene is a 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 375-amino acid nuclear phosphoprotein which involves in the regulation of cell proliferation. The p53 gene was originally regarded as a dominant oncogene because its overexpression resulted in the immortalization of rodent cells, and the p53 gene could transform rat embryonic fibroblasts in concert with an activated ras gene. It soon became clear, however, that many of the p53 clones that had been studied were in fact mutated versions of the gene, and the wild-type p53 actually acts as a tumor suppressor. Loss of normal p53 function has been associated with the cell transformation in vitro and the development of neoplasms in vivo. More than one-half of human malignancies derived from the epithelial, mesenchymal, hematopoietic, and lymphoid tissues, as well as the central nervous system, analyzed thus far, were shown to contain an altered p53 gene. Most p53 gene alterations are the missense mutations, giving rise to an altered protein. These mutations are most frequently located in the evolutionally conserved areas. Furthermore, it has been demonstrated that the SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein can bind to wild-type p53 protein and presumably lead to inactivation of this gene product as well. Therefore, the inactivation of normal (or wild-type) p53 is currently regarded as an important genetic pathway for human carcinogenesis generated by endogenous factors and exogenous carcinogens, as well as several tumor viruses. The current data on the p53 gene and its alterations in human malignancies, particularly those in the gastrointestinal tract, are reviewed.
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Neoplastic transformation
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Gene targeting
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Retinoblastoma
Suppression subtractive hybridization
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Malignant Transformation
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SOCS6
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