The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Dean W Felsher - One of the best experts on this subject based on the ideXlab platform.
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myc master regulator of immune privilege
Trends in Immunology, 2017Co-Authors: Stephanie C Casey, Virginie Baylot, Dean W FelsherAbstract:Cancers are often initiated by genetic events that activate proto-Oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that Oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many Oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how Oncogenes, and in particular MYC, suppress immune surveillance, and how oncogene-targeted therapies may restore the immune response against tumors.
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bim mediated apoptosis and oncogene addiction
Aging (Albany NY), 2016Co-Authors: Yulin Li, Anja Deutzmann, Dean W FelsherAbstract:Oncogene addiction is a phenomenon whereby suppression of a driver oncogene is associated with dramatic tumor regression that has been observed in experimental models and in response to targeted therapies [1]. However, the mechanism by which oncogene inactivation induces this massive reduction in tumor burden is not clear. In tumors addicted to the MYC oncogene, suppression of this oncogene leads to tumor regression that is associated with a marked increase in apoptosis. This at first glance appears to be paradoxical since generally oncogene activation, and MYC activation in particular, is associated with increased apoptosis. Recently, we have described a possible mechanism that may explain why inactivation of pro-apoptotic Oncogenes, such as MYC, induce apoptosis [2].
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myc inactivation elicits oncogene addiction through both tumor cell intrinsic and host dependent mechanisms
Genes & Cancer, 2010Co-Authors: Dean W FelsherAbstract:Tumorigenesis is generally caused by genetic changes that activate Oncogenes or inactivate tumor suppressor genes. The targeted inactivation of Oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell–intrinsic and host-dependent mechanisms.
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MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell–Intrinsic and Host-Dependent Mechanisms
Genes & Cancer, 2010Co-Authors: Dean W FelsherAbstract:Tumorigenesis is generally caused by genetic changes that activate Oncogenes or inactivate tumor suppressor genes. The targeted inactivation of Oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell–intrinsic and host-dependent mechanisms.
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tumor dormancy and oncogene addiction
Apmis, 2008Co-Authors: Dean W FelsherAbstract:Cancer is caused by genetic changes that activate Oncogenes or inactivate tumor suppressor genes. The repair or inactivation of mutant genes may be effective in the treatment of cancer. Indeed, drugs that target Oncogenes can be effective in the treatment of cancer. However, it is still unclear why the inactivation of a single cancer-associated gene would ever result in the elimination of tumor cells. In experimental transgenic mouse models the consequences of oncogene inactivation depend upon the genetic and cellular context. In some cases, oncogene inactivation results in the elimination of all or almost all tumor cells through apoptosis by the phenomenon described as oncogene addiction. In other cases, oncogene inactivation predominantly results in the terminal differentiation or cellular senescence of tumor cells. In yet others, oncogene inactivation results in the apparent loss of the neoplastic properties of tumor cells, which now appear and behave like normal cells; however, upon oncogene reactivation at least some of these cells rapidly recover their neoplastic phenotype. Thus, oncogene inactivation can result in a state of tumor dormancy. Hence, understanding when and how oncogene inactivation induces apoptosis, differentiation, and senescence within a tumor will be important when developing effective strategies for the treatment of cancer.
Thanos D Halazonetis - One of the best experts on this subject based on the ideXlab platform.
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intragenic origins due to short g1 phases underlie oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability. Oncogenes can cause genome instability by inducing replication stress, but the molecular mechanisms that underpin this process were unknown. Morgane Macheret and Thanos Halazonetis demonstrate that oncogene activation in human cancer cells results in firing of ectopic origins of replication within transcribed genes. These origins are normally quiescent, as they are suppressed by transcription. When activated, these intragenic origins lead to conflicts between replication and transcription, resulting in collapsed replication forks, double-stranded breaks and translocations. Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer1,2,3,4. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
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intragenic origins due to short g1 phases underlie oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
Morgane Macheret - One of the best experts on this subject based on the ideXlab platform.
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intragenic origins due to short g1 phases underlie oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability. Oncogenes can cause genome instability by inducing replication stress, but the molecular mechanisms that underpin this process were unknown. Morgane Macheret and Thanos Halazonetis demonstrate that oncogene activation in human cancer cells results in firing of ectopic origins of replication within transcribed genes. These origins are normally quiescent, as they are suppressed by transcription. When activated, these intragenic origins lead to conflicts between replication and transcription, resulting in collapsed replication forks, double-stranded breaks and translocations. Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer1,2,3,4. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
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intragenic origins due to short g1 phases underlie oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
Donald S. Torry - One of the best experts on this subject based on the ideXlab platform.
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Proto‐Oncogenes and Germ‐Cell Differentiation
American Journal of Reproductive Immunology, 1992Co-Authors: Donald S. TorryAbstract:: Oncogenes are identified functionally by their ability to induce neoplastic transformation of susceptible cells. The first Oncogenes to be characterized were isolated from acutely transforming retroviruses. Subsequently, it was determined that the retroviral Oncogenes were formed from normal, progenitor genes. These cellular homologs of the viral Oncogenes are termed proto-Oncogenes. The derivation of Oncogenes from proto-Oncogenes is the consequence of mutations that remove regulatory constraints from the proto-oncogene. The ability of Oncogenes to induce transformation implies that proto-Oncogenes may function in growth and differentiation pathways in normal cells. Although many proto-Oncogenes have been defined, the normal physiological function of most is not known. Studies of proto-oncogene expression during normal game-togenesis have determined that some genes are expressed in a stage-specific manner. The use of germ cells to provide homogeneous and defined normal cell populations facilitates identifying the roles proto-Oncogenes have in regulating cell growth and differentiation.
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Proto-Oncogenes and germ-cell differentiation.
American journal of reproductive immunology (New York N.Y. : 1989), 1992Co-Authors: Donald S. TorryAbstract:: Oncogenes are identified functionally by their ability to induce neoplastic transformation of susceptible cells. The first Oncogenes to be characterized were isolated from acutely transforming retroviruses. Subsequently, it was determined that the retroviral Oncogenes were formed from normal, progenitor genes. These cellular homologs of the viral Oncogenes are termed proto-Oncogenes. The derivation of Oncogenes from proto-Oncogenes is the consequence of mutations that remove regulatory constraints from the proto-oncogene. The ability of Oncogenes to induce transformation implies that proto-Oncogenes may function in growth and differentiation pathways in normal cells. Although many proto-Oncogenes have been defined, the normal physiological function of most is not known. Studies of proto-oncogene expression during normal game-togenesis have determined that some genes are expressed in a stage-specific manner. The use of germ cells to provide homogeneous and defined normal cell populations facilitates identifying the roles proto-Oncogenes have in regulating cell growth and differentiation.
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Proto-Oncogenes in development and cancer.
American Journal of Reproductive Immunology, 1991Co-Authors: Donald S. Torry, Geoffrey M CooperAbstract:: Although analogies are often made comparing development to cancer, there is of course a major difference. Normal development requires complex patterns of rigidly controlled cell proliferation and differentiation. In contrast, cancer represents the pathological condition that results when normal cell growth patterns are uncoupled from their regulatory influences. Genetic studies of RNA tumor viruses have provided insights into the relationships and differences of the genes responsible for normal development and cancer. The presence of discrete genes (Oncogenes) within the genome of oncogenic retroviruses is responsible for their tumor-igenic potential. Molecular genetic studies have found that normal eukaryotic cells possess genes that are quite homologous to the retroviral Oncogenes. These normal cellular genes (proto-Oncogenes) are involved in the regulation of proliferation and differentiation. However, if mutated, proto-Oncogenes have the potential for inducing neoplastic transformation. The conversion of a proto-oncogene to an oncogene is called activation. Proto-Oncogenes can become activated by a variety of genetic mechanisms including transduction, insertional mutagenesis, amplification, point mutations, and chromosomal translocations. In each instance the genetic aberration results in a proto-oncogene that is now free of its normal regulatory constraints. Such deregulation of function imparts a distinct growth advantage to the cell.
David P Bartel - One of the best experts on this subject based on the ideXlab platform.
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widespread shortening of 3 utrs by alternative cleavage and polyadenylation activates Oncogenes in cancer cells
Cell, 2009Co-Authors: Christine Mayr, David P BartelAbstract:In cancer cells, genetic alterations can activate proto-Oncogenes, thereby contributing to tumorigenesis. However, the protein products of Oncogenes are sometimes overexpressed without alteration of the proto-oncogene. Helping to explain this phenomenon, we found that when compared to similarly proliferating nontransformed cell lines, cancer cell lines often expressed substantial amounts of mRNA isoforms with shorter 3' untranslated regions (UTRs). These shorter isoforms usually resulted from alternative cleavage and polyadenylation (APA). The APA had functional consequences, with the shorter mRNA isoforms exhibiting increased stability and typically producing ten-fold more protein, in part through the loss of microRNA-mediated repression. Moreover, expression of the shorter mRNA isoform of the proto-oncogene IGF2BP1/IMP-1 led to far more oncogenic transformation than did expression of the full-length, annotated mRNA. The high incidence of APA in cancer cells, with consequent loss of 3'UTR repressive elements, suggests a pervasive role for APA in oncogene activation without genetic alteration.
