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Robert A. Weinberg - One of the best experts on this subject based on the ideXlab platform.
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OncoGenes and tumor Suppressor Genes
CA: a cancer journal for clinicians, 1994Co-Authors: Robert A. WeinbergAbstract: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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tumor Suppressor Genes
Current Opinion in Genetics & Development, 1994Co-Authors: Philip W Hinds, Robert A. WeinbergAbstract:The mutation of tumor Suppressor Genes is thought to contribute to tumor growth by inactivating proteins that normally act to limit cell proliferation. Several tumor Suppressor proteins have been identified in recent years, but only two of them, p53 and pRb, are understood in detail. In the past year, a role has become apparent for both of these proteins in transcription and phosphorylation events required for passage of a cell from G1 to S phase. The pRb protein appears to prevent the function of transcription factors and other proteins needed for S phase until its inactivation by cyclin-dependent kinases in late G1. Induction of p53 by DNA damage may act to cause cell cycle arrest or cell death by altering the transcription program of damaged cells. A detailed molecular understanding of these growth regulators is now emerging, and is the subject of this review.
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Tumor Suppressor Genes
Neuron, 1993Co-Authors: Robert A. WeinbergAbstract:For the past two decades, oncoGenes have captured the lion’s share of attention among those interested in the molecular and genetic bases of cell transformation. These Genes have presented a powerful paradigm of how cell transformation takes place when triggered by viral infections or somatic mutation. Yet we now realize that there is an equally important second side of the coin, presented by a distinct class of Genes known variously as tumor Suppressor Genes or anti-oncoGenes. The existence of tumor Suppressor Genes could have been predicted from first principles, but few had the temerity to do so. The logic of their function is simple and straightforward. Cellular oncoGenes represent deregulated, hyperactive forms of normal cellular growth-promoting Genes (proto-oncoGenes). The activation of an oncogene in the genome of a normal cell results in the release of a steady stream of mitogenie signals that forces a cell and its descendants through unrelenting rounds of division. Logic dictates an equally elaborate array of growthconstraining elements in the cell’s signaling circuitry that serve as a counterweight to the growth-promoting proto-oncoGenes. Their loss through mutational inactivation might lead to runaway cell growth. We now know that tumor cell growth often depends on the confluence of both types of genetic change, yielding hyperactivegrowth-promotingGenes(oncoGenes) on the one hand and inactive versions of the growthconstraining Genes (tumor Suppressors) on the other. The very existence of such Suppressor Genes becomes apparent only when they are lost from the cell genome. This experimental difficulty has kept progress in the field studying these Genes a decade behind that devoted to research on oncoGenes. But this substantial inconvenience has been swept aside by new and powerful means of detecting tumor Suppressor Genes and isolating them through molecular cloning. We now have a collection of more than a half dozen of these Genes in cloned form. Inactivated versions of each can be found in the genomes of a variety of tumor cell types (see Table 1).
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Tumor Suppressor Genes
Science (New York N.Y.), 1991Co-Authors: Robert A. WeinbergAbstract:For the past decade, cellular oncoGenes have attracted the attention of biologists intent on understanding the molecular origins of cancer. As the present decade unfolds, oncoGenes are yielding their place at center stage to a second group of actors, the tumor Suppressor Genes, which promise to teach us equally important lessons about the molecular mechanisms of cancer pathoGenesis.
Sam W Lee - One of the best experts on this subject based on the ideXlab platform.
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Emerging roles of p53 and other tumour-Suppressor Genes in immune regulation
Nature Reviews Immunology, 2016Co-Authors: César Muñoz-fontela, Stuart A Aaronson, Anna Mandinova, Sam W LeeAbstract:Tumour-Suppressor Genes are indispensable for the maintenance of genomic integrity. Recently, several of these Genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour- Suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-Suppressor Genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-Suppressor Genes are emerging as potential guardians of immune integrity. The role of tumour Suppressors in immunity is strongly linked to maintenance of genomic integrity. Impaired expression of tumour Suppressor Genes such as those that encode p53, retinoblastoma-associated gene 1 (RB1), phosphatase and tensin homologue (PTEN) and ARF results in susceptibility to chronic inflammatory responses triggered by pathogens and environmental stress. The tumour Suppressor p53 and its transcriptional targets are involved in crucial aspects of tumour and pathogen immunology and in homeostatic regulation of immune responses. This pathway has an important role in host immunity influencing both innate and adaptive immune responses. A link between the tumour Suppressor p53 and immune checkpoint regulators, including programmed cell death 1 (PD1), PD1 ligand 1 (PDL1) and DD1α, has been identified in cancer cells. Several tumour Suppressor Genes including those encoding p53, ARF, RB1 and PTEN influence T cell fate by modulating the immune synapse through pattern recognition receptors, cytokine production and expression of MHC and co-inhibitory molecules. Tumour Suppressor gene function is emerging as a potential 'guardian of immune integrity'. The tumour Suppressor p53 has well-known functions in cell repair and cell death that have led to its title as the 'guardian of the genome'. Here, the authors discuss the less-well appreciated roles of p53 and other tumour Suppressor Genes in shaping immune responses; they propose that these Genes could also be considered to be 'guardians of immune integrity'.
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emerging roles of p53 and other tumour Suppressor Genes in immune regulation
Nature Reviews Immunology, 2016Co-Authors: Cesar Munozfontela, Sam W Lee, Anna Mandinova, Stuart A AaronsonAbstract:Tumour-Suppressor Genes are indispensable for the maintenance of genomic integrity. Recently, several of these Genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour- Suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-Suppressor Genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-Suppressor Genes are emerging as potential guardians of immune integrity.
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positive selection of candidate tumor Suppressor Genes by subtractive hybridization
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Sam W Lee, Catherine Tomasetto, Ruth SagerAbstract:Abstract A positive selection system designed to identify and recover candidate tumor-Suppressor Genes is described. The system compares mRNA expression of Genes from normal and tumor-derived human mammary epithelial cells grown in a special medium that supports similar growth rates of the two cell types. mRNAs uniquely expressed in normal cells are recovered as cDNAs after subtraction with mRNA from tumor cells. Seven different clones, from 0.6 to 4.8 kilobases in transcript size and including both rare and abundunt transcripts, were recovered in the first 23 clones analyzed. Among the isolated clones were Genes encoding the gap-junction protein connexin 26, two different keratins, and glutathione-S-transferase pi, as well as an unknown gene in the S100 family of small calcium-binding proteins. In principle, tumor-Suppressor Genes include two classes: class I, in which loss of function results from mutation or deletion of DNA and class II, in which loss of function is from a regulatory block to expression. A class II Suppressor gene is assumed to be regulated by a different Suppressor gene that lost its function by mutation or deletion. Both classes of tumor-Suppressor Genes may provide valuable proteins with clinical applications in cancer diagnosis or therapy. Class II Suppressors may be especially useful because the normal Genes are present and their reexpression may be inducible by drugs or other treatments.
Josep M Llovet - One of the best experts on this subject based on the ideXlab platform.
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genome wide methylation analysis and epigenetic unmasking identify tumor Suppressor Genes in hepatocellular carcinoma
Gastroenterology, 2013Co-Authors: Kate Revill, Timothy C Wang, Anja Lachenmayer, Kensuke Kojima, Andrew N Harrington, Yujin Hoshida, Josep M LlovetAbstract:Background & Aims Epigenetic silencing of tumor Suppressor Genes contributes to the pathoGenesis of hepatocellular carcinoma (HCC). To identify clinically relevant tumor Suppressor Genes silenced by DNA methylation in HCC, we integrated DNA methylation data from human primary HCC samples with data on up-regulation of gene expression after epigenetic unmasking. Methods We performed genome-wide methylation analysis of 71 human HCC samples using the Illumina HumanBeadchip27K array; data were combined with those from microarray analysis of gene re-expression in 4 liver cancer cell lines after their exposure to reagents that reverse DNA methylation (epigenetic unmasking). Results Based on DNA methylation in primary HCC and gene re-expression in cell lines after epigenetic unmasking, we identified 13 candidate tumor Suppressor Genes. Subsequent validation led us to focus on functionally characterizing 2 candidates, sphingomyelin phosphodiesterase 3 ( SMPD3 ) and neurofilament, heavy polypeptide ( NEFH ), which we found to behave as tumor Suppressor Genes in HCC. Overexpression of SMPD3 and NEFH by stable transfection of inducible constructs into an HCC cell line reduced cell proliferation by 50% and 20%, respectively (SMPD3, P = .003 and NEFH, P = .003). Conversely, knocking down expression of these Genes with small hairpin RNA promoted cell invasion and migration in vitro (SMPD3, P = .0001 and NEFH, P = .022), and increased their ability to form tumors after subcutaneous injection or orthotopic transplantation into mice, confirming their role as tumor Suppressor Genes in HCC. Low levels of SMPD3 were associated with early recurrence of HCC after curative surgery in an independent patient cohort ( P = .001; hazard ratio = 3.22; 95% confidence interval: 1.6−6.5 in multivariate analysis). Conclusions Integrative genomic analysis identified SMPD3 and NEFH as tumor Suppressor Genes in HCC. We provide evidence that SMPD3 is a potent tumor Suppressor gene that could affect tumor aggressiveness; a reduced level of SMPD3 is an independent prognostic factor for early recurrence of HCC.
Mitsuo Oshimura - One of the best experts on this subject based on the ideXlab platform.
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Studies of Tumor Suppressor Genes via Chromosome Engineering.
Cancers, 2015Co-Authors: Hiroyuki Kugoh, Takahito Ohira, Mitsuo OshimuraAbstract:The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor Suppressor Genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related Genes plays a crucial role in our understanding of the development and progression of malignant tumors. Chromosome engineering technology based on microcell-mediated chromosome transfer (MMCT) is an effective approach for identification of tumor Suppressor Genes. The studies have revealed at least five tumor suppression effects. The discovery of novel tumor Suppressor Genes provide greater understanding of the complex signaling pathways that underlie the development and progression of malignant tumors. These advances are being exploited to develop targeted drugs and new biological therapies for cancer.
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Metastasis Suppressor Genes for prostate cancer.
The Prostate. Supplement, 1996Co-Authors: Tomohiko Ichikawa, Ann M. Killary, Hiroyuki Kugoh, Naoki Nihei, Hiroaki Kuramochi, Yoko Kawana, Carrie W. Rinker-schaeffer, J. Carl Barrett, John T. Isaacs, Mitsuo OshimuraAbstract:To examine the role of human chromosomes in the development of metastatic prostate cancer, we introduced a copy of human chromosomes into highly metastatic Dunning R-3327 rat prostatic cancer cells by microcell-mediated chromosome transfer. Each microcell hybrid clones containing human chromosomes 8, 10, 11, and 17, respectively, showed decreased ability to metastasize to the lung, without any loss of tumorigenicity. This finding demonstrates that these human chromosomes contain metastasis Suppressor Genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in human chromosome 10, 11, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained metastasis Suppressor gene(s) for prostate cancer. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis Suppressor Genes on human chromosomes 8, 10, and 11 were located on 8p23-q12, 10q, 11p13-11.2, respectively. Further analyses are proposed to confirm the potentially useful advantage of this assay system to identify metastasis Suppressor gene(s) for prostate cancer.
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Tumor-Suppressor Genes
Gan to kagaku ryoho. Cancer & chemotherapy, 1991Co-Authors: Horikawa I, Mitsuo OshimuraAbstract:The existence of tumor-Suppressor Genes has been primarily suggested by three lines of evidences: 1) the suppression of transformed phenotypes of tumor cells by cell-cell hybridization with normal cells; 2) non-random chromosome deletions in a variety of tumors; 3) loss of heterozygosity in specific chromosomal regions in tumor cells. Results from monochromosome transfer experiments also suggest the existence of multiple, functionally distinct tumor-Suppressor Genes. Recently, several tumor-Suppressor Genes, which appeared to be functionally distinct, (i.e., Rb gene, WT gene and DCC gene) were isolated. Most recently, it was suggested that the inactivations of at least three different tumor-Suppressor Genes were required for the colorectal carcinoGenesis at different steps. Thus, these findings support that losses or alterations in the dosage of multiple tumor-Suppressor Genes play crucial roles during initiation and/or progression of a wide variety of cancers.
Joseph A Califano - One of the best experts on this subject based on the ideXlab platform.
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promoter methylation and inactivation of tumour Suppressor Genes in oral squamous cell carcinoma
Lancet Oncology, 2006Co-Authors: Joseph A CalifanoAbstract:Genetic alterations that lead to loss or changes in tumour-Suppressor Genes are known to contribute to oral carcinoGenesis. Traditional molecular methods to detect such losses have relied on mutation analysis or deletion of the gene. However, epigenetic mechanisms could also contribute to silencing of tumour-Suppressor Genes. Methylation regions rich in CpG promoters prevent DNA transcription by changing the binding of histone complexes. The substantial contribution of methylation, specifically in oral squamous-cell carcinoma, is now being realised and investigated.