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Joseph R Nevins - One of the best experts on this subject based on the ideXlab platform.
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identification of e box factor tfe3 as a functional partner for the e2f3 transcription factor
Molecular and Cellular Biology, 2003Co-Authors: Paloma H Giangrande, Timothy C Hallstrom, Chainarong Tunyaplin, Kathryn Calame, Joseph R NevinsAbstract:The ability of the retinoblastoma (Rb) tumor suppressor protein to regulate cell growth is due, at least in part, to its ability to interact with and regulate the E2F family of transcription factors (8, 34). The E2F proteins have been shown to control the expression of a large number of genes involved in DNA replication, cell cycle progression, and cell fate determination. The E2F family is composed of six distinct gene products that form heterodimeric complexes with partners of the DP family. Sequence analysis reveals three distinct subfamilies of E2F genes: the E2F1, E2F2, and E2F3 genes, the E2F4 and E2F5 genes, and the E2F6 gene. This division also coincides with functional distinctions. The E2F1, E2F2, and E2F3 genes are tightly regulated by cell growth and during the cell cycle, whereas E2F4, E2F5 and E2F6 are constitutively expressed. This cell cycle regulation of E2F1, E2F2, and E2F3 transcription is complemented by mechanisms that tightly regulate the accumulation of the proteins. An N-terminal domain unique to E2F1 to E2F3 is responsible for both ubiquitin-mediated degradation of the proteins (29) and targeting by the cyclin A/cdk2 kinase, the latter leading to inhibition of DNA binding capacity (7, 22, 23, 53). The E2F proteins also vary in their role as transcriptional regulatory activities. While E2F1 to E2F3 act as positive regulators of transcription, E2F4 and E2F5 appear to function primarily as transcriptional repressors in concert with Rb family members. E2F6 also appears to function as a transcriptional repressor but in a manner independent of Rb (4, 10, 47, 48). Various experiments have suggested distinct functional roles for the activating E2F proteins E2F1, E2F2, and E2F3. The E2F3 protein appears to be particularly important for cell proliferation, as seen from the inhibition of E2F3 activity by antibody microinjection (25) as well as the results of deletion of the E2F3 gene (18). Moreover, the expression of a number of E2F target genes that encode key cell cycle regulatory proteins, including B-Myb, cyclin A, cdc2, cdc6, and dihydrofolate reductase, are reduced in E2F3 null fibroblasts but not in E2F1 null cells (18). In contrast, E2F1 appears to play a role in triggering an apoptotic response, either when overexpressed in the absence of survival signals (6, 21, 39, 43, 51) or in response to DNA damage (27). In addition, the ability of Myc to induce apoptosis is impaired in the absence of E2F1 function but unaltered by the absence of either E2F2 or E2F3 (26). Given the role of the E2F1, E2F2, and E2F3 proteins as transcriptional activators, the specificity of function might best be explained by an ability of these E2F proteins to activate distinct target genes that then carry out these functions of apoptosis or proliferation. As an example, the p19ARF gene has been shown to be an E2F1 target gene (2, 6), linking the action of the Rb/E2F pathway with the p53 response leading to apoptosis. Similarly, the Apaf1 gene appears to be activated specifically by E2F1 (30). Although one potential mechanism for such specificity could be an ability of these proteins to recognize subtle differences in cis-acting promoter sequences, there is little evidence for distinct DNA sequence recognition among the E2F isoforms. More importantly, analysis of the structure of an E2F-DNA complex did not show a capacity for distinct DNA sequence recognition when the amino acid variation within the E2F family is considered (56). An alternative mechanism for promoter specificity could involve distinct protein-protein interactions. Possibly, sequences within E2F3 allow interaction with a subset of cellular proteins that provide a basis for promoter specificity and that are distinct from the proteins that can interact with E2F1. For example, the interaction of the herpesvirus VP16 transcriptional activator protein with the cellular factor HCF-1 and the cellular Oct-1 transcription factor redirects Oct-1 to herpesvirus immediate-early promoters by virtue of expanded DNA sequence recognition (1). A further example of combinatorial specificity as a mechanism for the specificity of transcription factor function is the pancreatic islet factor STF-1, which interacts with Pbx in a cooperative fashion and targets Pbx to a subset of promoters containing STF-1 binding sites (38). Recently, we identified the YY1-binding protein RYBP as a factor which binds to E2F2 and E2F3 but not E2F1 and recruits these E2Fs to a subset of E2F target promoters containing YY1 binding sites (41). To further explore the mechanistic basis for the specificity of E2F transcription activation, we used yeast two-hybrid screens to identify proteins that specifically interact with E2F3. In so doing, we identified the TFE3 transcription factor as a specific partner for E2F3. Recent experiments identified TFE3 as an activity that can rescue Rb-mediated growth arrest, providing a functional link between TFE3 and the Rb/E2F pathway (M. Nijman, S. Hijmans, and R. Bernards, personal communication). Moreover, previous work identified TFE3 as a fusion partner in chromosomal rearrangements in renal cell carcinomas (14, 45, 50). We further show that TFE3 and E2F3 can act synergistically to activate the p68 subunit gene of DNA polymerase α, dependent on the ability of the two proteins to physically interact, and that the two activities associate with the p68 promoter within intact cells in a mutually dependent manner.
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interaction of yy1 with e2fs mediated by rybp provides a mechanism for specificity of e2f function
The EMBO Journal, 2002Co-Authors: Susanne Schlisio, Joseph R Nevins, Terri J Halperin, Miguel VidalAbstract:To explore mechanisms for specificity of function within the family of E2F transcription factors, we have identified proteins that interact with individual E2F proteins. A two-hybrid screen identified RYBP (Ring1- and YY1-binding protein) as a protein that interacts specifically with the E2F2 and E2F3 family members, dependent on the marked box domain in these proteins. The Cdc6 promoter contains adjacent E2F- and YY1-binding sites, and both are required for promoter activity. In addition, YY1 and RYBP, in combination with either E2F2 or E2F3, can stimulate Cdc6 promoter activity synergistically, dependent on the marked box domain of E2F3. Using chromatin immunoprecipitation assays, we show that both E2F2 and E2F3, as well as YY1 and RYBP, associate with the Cdc6 promoter at G1/S of the cell cycle. In contrast, we detect no interaction of E2F1 with the Cdc6 promoter. We suggest that the ability of RYBP to mediate an interaction between E2F2 or E2F3 and YY1 is an important component of Cdc6 activation and provides a basis for specificity of E2F function.
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identification of a novel e2f3 product suggests a mechanism for determining specificity of repression by rb proteins
Molecular and Cellular Biology, 2000Co-Authors: Gustavo Leone, Rosalie C Sears, Faison Nuckolls, Alexander Miron, Laszlo Jakoi, Seiichi Ishida, Monique R Adams, Joseph R NevinsAbstract:The tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes. Here we describe a novel E2F product that specifically interacts with Rb in quiescent cells. This novel E2F, which we term E2F3b, is encoded by a unique mRNA transcribed from an intronic promoter within the E2F3 locus. The E2F3b RNA differs from the previously characterized E2F3 RNA, which we now term E2F3a, by the utilization of a unique coding exon. In contrast to the E2F3a product that is tightly regulated by cell growth, the E2F3b product is expressed equivalently in quiescent and proliferating cells. But, unlike the E2F4 and E2F5 proteins, which are also expressed in quiescent cells and form complexes with the p130 protein, the E2F3b protein associates with Rb and represents the predominant E2F-Rb complex in quiescent cells. Thus, the previously described specificity of Rb function as a transcriptional repressor in quiescent cells coincides with the association of Rb with this novel E2F product.
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E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control.
Molecular cell, 2000Co-Authors: Stefan Gaubatz, David M Livingston, Laszlo Jakoi, Joseph R Nevins, Geoffrey J. Lindeman, Seiichi Ishida, Rachel E RempelAbstract:Abstract E2F transcription factors are major regulators of cell proliferation. The diversity of the E2F family suggests that individual members perform distinct functions in cell cycle control. E2F4 and E2F5 constitute a defined subset of the family. Until now, there has been little understanding of their individual biochemical and biological functions. Here, we report that simultaneous inactivation of E2F4 and E2F5 in mice results in neonatal lethality, suggesting that they perform overlapping functions during mouse development. Embryonic fibroblasts isolated from these mice proliferated normally and reentered from Go with normal kinetics compared to wild-type cells. However, they failed to arrest in G1 in response to p16 INK4a . Thus, E2F4 and E2F5 are dispensable for cell cycle progression but necessary for pocket protein–mediated G1 arrest of cycling cells.
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distinct roles for e2f proteins in cell growth control and apoptosis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: James Degregori, Gustavo Leone, Alexander Miron, Laszlo Jakoi, Joseph R NevinsAbstract:E2F transcription activity is composed of a family of heterodimers encoded by distinct genes. Through the overproduction of each of the five known E2F proteins in mammalian cells, we demonstrate that a large number of genes encoding proteins important for cell cycle regulation and DNA replication can be activated by the E2F proteins and that there are distinct specificities in the activation of these genes by individual E2F family members. Coexpression of each E2F protein with the DP1 heterodimeric partner does not significantly alter this specificity. We also find that only E2F1 overexpression induces cells to undergo apoptosis, despite the fact that at least two other E2F family members, E2F2 and E2F3, are equally capable of inducing S phase. The ability of E2F1 to induce apoptosis appears to result from the specific induction of an apoptosis-promoting activity rather than the lack of induction of a survival activity, because co-expression of E2F2 and E2F3 does not rescue cells from E2F1-mediated apoptosis. We conclude that E2F family members play distinct roles in cell cycle control and that E2F1 may function as a specific signal for the initiation of an apoptosis pathway that must normally be blocked for a productive proliferation event.
Gustavo Leone - One of the best experts on this subject based on the ideXlab platform.
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division and apoptosis of e2f deficient retinal progenitors
Nature, 2009Co-Authors: Danian Chen, Gustavo Leone, Marek Pacal, Pamela L Wenzel, Paul S Knoepfler, Rod BremnerAbstract:The activating E2f transcription factors (E2f1, E2f2 and E2f3) induce transcription and are widely viewed as essential positive cell cycle regulators. Indeed, they drive cells out of quiescence, and the 'cancer cell cycle' in Rb1 null cells is E2f-dependent. Absence of activating E2fs in flies or mammalian fibroblasts causes cell cycle arrest, but this block is alleviated by removing repressive E2f or the tumour suppressor p53, respectively. Thus, whether activating E2fs are indispensable for normal division is an area of debate. Activating E2fs are also well known pro-apoptotic factors, providing a defence against oncogenesis, yet E2f1 can limit irradiation-induced apoptosis. In flies this occurs through repression of hid (also called Wrinkled; Smac/Diablo in mammals). However, in mammals the mechanism is unclear because Smac/Diablo is induced, not repressed, by E2f1, and in keratinocytes survival is promoted indirectly through induction of DNA repair targets. Thus, a direct pro-survival function for E2f1-3 and/or its relevance beyond irradiation has not been established. To address E2f1-3 function in normal cells in vivo we focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer. Here we show that unlike fibroblasts, E2f1-3 null retinal progenitor cells or activated Muller glia can divide. We attribute this effect to functional interchangeability with Mycn. However, loss of activating E2fs caused downregulation of the p53 deacetylase Sirt1, p53 hyperacetylation and elevated apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo. Thus, activating E2fs are not universally required for normal mammalian cell division, but have an unexpected pro-survival role in development.
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cloning and characterization of mouse e2f8 a novel mammalian e2f family member capable of blocking cellular proliferation
Journal of Biological Chemistry, 2005Co-Authors: Baidehi Maiti, Alain De Bruin, Faye Gordon, Cynthia Timmers, Rene Opavsky, Kaustubha Patil, John Tuttle, Whitney M Cleghorn, Gustavo LeoneAbstract:The E2F transcription factor family plays a crucial and well established role in cell cycle progression. Deregulation of E2F activities in vivo leads to developmental defects and cancer. Based on current evidence in the field, mammalian E2Fs can be functionally categorized into either transcriptional activators (E2F1, E2F2, and E2F3a) or repressors (E2F3b, E2F4, E2F5, E2F6, and E2F7). We have identified a novel E2F family member, E2F8, which is conserved in mice and humans and has its counterpart in Arabidopsis thaliana (E2Ls). Interestingly, E2F7 and E2F8 share unique structural features that distinguish them from other mammalian E2F repressor members, including the presence of two distinct DNA-binding domains and the absence of DP-dimerization, retinoblastoma-binding, and transcriptional activation domains. Similar to E2F7, overexpression of E2F8 significantly slows down the proliferation of primary mouse embryonic fibroblasts. These observations, together with the fact that E2F7 and E2F8 can homodimerize and are expressed in the same adult tissues, suggest that they may have overlapping and perhaps synergistic roles in the control of cellular proliferation.
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Inactivation of E2F3 results in centrosome amplification
Cancer cell, 2003Co-Authors: Harold I Saavedra, Baidehi Maiti, Cynthia Timmers, Rachel A. Altura, Yukari Tokuyama, Kenji Fukasawa, Gustavo LeoneAbstract:The E2F family of transcription factors is critical for the control of cell cycle progression. We now show that the specific inactivation of E2F3 in mouse embryo fibroblasts (MEFs) results in a disruption of the centrosome duplication cycle. Loss of E2F3, but not E2F1, E2F2, E2F4, or E2F5 results in unregulated cyclin E-dependent kinase activity, defects in nucleophosmin B association with centrosomes, and premature centriole separation and duplication. Consequently, this defect leads to centrosome amplification, mitotic spindle defects, and aneuploidy. Our findings implicate the E2F3 transcription factor as an important link that orchestrates DNA and centrosome duplication cycles, ensuring the faithful transmission of genetic material to daughter cells.
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myc requires distinct e2f activities to induce s phase and apoptosis
Molecular Cell, 2001Co-Authors: Gustavo Leone, Rosalie C Sears, Erich Huang, Rachel E Rempel, Faison Nuckolls, Chi Hyun Park, Paloma H Giangrande, Harold I Saavedra, Seth J Field, Margaret A ThompsonAbstract:Previous work has shown that the Myc transcription factor induces transcription of the E2F1, E2F2, and E2F3 genes. Using primary mouse embryo fibroblasts deleted for individual E2F genes, we now show that Myc-induced S phase and apoptosis requires distinct E2F activities. The ability of Myc to induce S phase is impaired in the absence of either E2F2 or E2F3 but not E2F1 or E2F4. In contrast, the ability of Myc to induce apoptosis is markedly reduced in cells deleted for E2F1 but not E2F2 or E2F3. From this data, we propose that the induction of specific E2F activities is an essential component in the Myc pathways that control cell proliferation and cell fate decisions.
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identification of a novel e2f3 product suggests a mechanism for determining specificity of repression by rb proteins
Molecular and Cellular Biology, 2000Co-Authors: Gustavo Leone, Rosalie C Sears, Faison Nuckolls, Alexander Miron, Laszlo Jakoi, Seiichi Ishida, Monique R Adams, Joseph R NevinsAbstract:The tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes. Here we describe a novel E2F product that specifically interacts with Rb in quiescent cells. This novel E2F, which we term E2F3b, is encoded by a unique mRNA transcribed from an intronic promoter within the E2F3 locus. The E2F3b RNA differs from the previously characterized E2F3 RNA, which we now term E2F3a, by the utilization of a unique coding exon. In contrast to the E2F3a product that is tightly regulated by cell growth, the E2F3b product is expressed equivalently in quiescent and proliferating cells. But, unlike the E2F4 and E2F5 proteins, which are also expressed in quiescent cells and form complexes with the p130 protein, the E2F3b protein associates with Rb and represents the predominant E2F-Rb complex in quiescent cells. Thus, the previously described specificity of Rb function as a transcriptional repressor in quiescent cells coincides with the association of Rb with this novel E2F product.
David G Johnson - One of the best experts on this subject based on the ideXlab platform.
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distinct and overlapping roles for e2f family members in transcription proliferation and apoptosis
Current Molecular Medicine, 2006Co-Authors: James Degregori, David G JohnsonAbstract:Since the discovery almost fifteen years ago that E2F transcription factors are key targets of the retinoblastoma protein (RB), studies of the E2F family have uncovered critical roles in the control of transcription , cell cycle and apoptosis. E2F proteins are encoded by at least eight genes, E2F1 through E2F8. While specific roles for individual E2Fs in mediating the effects of RB loss are emerging, it is also becoming clear that there are no simple divisions of labor among the E2F family. Instead, an individual E2F can function to activate or repress transcription, promote or impede cell cycle progression and enhance or inhibit cell death, dependent on the cellular context. While functional redundancy among E2Fs and the striking influences of cellular context on the effects of E2F loss or gain of function have prevented a simple delineation of unique functions within the E2F family, these complexities undoubtedly reflect the extensive regulation and importance of this transcription factor family.
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E2F4 and E2F1 Have Similar Proliferative Properties but Different Apoptotic and Oncogenic Properties In Vivo
Molecular and cellular biology, 2000Co-Authors: Dawei Wang, Jamie L. Russell, David G JohnsonAbstract:Loss of retinoblastoma (Rb) tumor suppressor function, as occurs in many cancers, leads to uncontrolled proliferation, an increased propensity to undergo apoptosis, and tumorigenesis. Rb negatively regulates multiple E2F transcription factors, but the role of the different E2F family members in manifesting the cellular response to Rb inactivation is unclear. To study the effect of deregulated E2F4 activity on cell growth control and tumorigenesis, transgenic mouse lines expressing the E2F4 gene under the control of a keratin 5 (K5) promoter were developed, and their phenotypes were compared to those of previously generated K5 E2F1 transgenic mice. In contrast to what has been observed in vitro, ectopically expressed E2F4 was found to localize to the nucleus and induce proliferation to an extent similar to that induced by E2F1 in transgenic tissue. Unlike E2F1, E2F4 does not induce apoptosis, and this correlates with the differential abilities of these two E2F species to stimulate p19ARF expression in vivo. To examine the role of E2F4 in tumor development, the mouse skin two-stage carcinogenesis model was utilized. Unlike E2F1 transgenic mice, E2F4 transgenic mice developed skin tumors with a decreased latency and increased incidence compared to those characteristics in wild-type controls. These findings demonstrate that while the effects of E2F1 and E2F4 on cell proliferation in vivo are similar, their apoptotic and oncogenic properties are quite different.
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Differential activities of E2F family members: unique functions in regulating transcription.
Molecular carcinogenesis, 1998Co-Authors: Angela M. Pierce, Robin Schneider-broussard, Jennifer L. Philhower, David G JohnsonAbstract:Several regulators of E2F transcriptional activity, including the retinoblastoma tumor suppressor (Rb) protein, p16Ink4a, cyclin D1, and cyclin-dependent kinase 4, have been shown to be targets for genetic alterations that underlie the development of human cancers. Deregulation of E2F transcription factors as a result of these genetic alterations is believed to contribute to tumor development. This hypothesis is supported by the finding that at least some members of the E2F gene family can contribute to oncogenic transformation when overexpressed. Each E2F family member can dimerize with DP proteins, bind consensus E2F sites, and activate transcription. Several pieces of evidence suggest, however, that the various E2F species have unique functions in regulating transcription. We compared the abilities of E2F1, E2F4, and E2F5 to activate transcription from a variety of gene promoters and found that in all cases E2F1 was the most potent activator, followed by E2F4 and then by E2F5. Construction of chimeric proteins between E2F1 and E2F4 demonstrated that either the carboxy terminus or the amino terminus of E2F1 could make E2F4 a more potent activator. In contrast, neither the carboxy terminus nor the amino terminus of E2F1 could significantly increase the activity of E2F5. We found that, consistent with a role for E2F5 in transcriptional repression, E2F5's binding partner p130, like Rb, could also actively repress transcription when directly bound to a target promoter. Mol. Carcinog. 22:190–198, 1998. © 1998 Wiley-Liss, Inc.
Alain De Bruin - One of the best experts on this subject based on the ideXlab platform.
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cyclin f dependent degradation of e2f7 is critical for dna repair and g2 phase progression
The EMBO Journal, 2019Co-Authors: Ruixue Yuan, Alain De Bruin, Bart Westendorp, Qingwu Liu, Hendrika A Segeren, Laurensia Yuniati, Daniele Guardavaccaro, Robert Jan LebbinkAbstract:E2F7 and E2F8 act as tumor suppressors via transcriptional repression of genes involved in S-phase entry and progression. Previously, we demonstrated that these atypical E2Fs are degraded by APC/CCdh1 during G1 phase of the cell cycle. However, the mechanism driving the downregulation of atypical E2Fs during G2 phase is unknown. Here, we show that E2F7 is targeted for degradation by the E3 ubiquitin ligase SCFcyclin F during G2. Cyclin F binds via its cyclin domain to a conserved C-terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin F nor the CY motifs in the C-terminus of E2F8, implying a different regulatory mechanism than for E2F7. Importantly, depletion of cyclin F causes an atypical-E2F-dependent delay of the G2/M transition, accompanied by reduced expression of E2F target genes involved in DNA repair. Live cell imaging of DNA damage revealed that cyclin F-dependent regulation of atypical E2Fs is critical for efficient DNA repair and cell cycle progression.
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chk1 and 14 3 3 proteins inhibit atypical e2fs to prevent a permanent cell cycle arrest
The EMBO Journal, 2018Co-Authors: Ruixue Yuan, Alain De Bruin, Harmjan R. Vos, Robert M. Van Es, Jing Chen, Boudewijn M.t. Burgering, Bart WestendorpAbstract:The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. Strikingly, Chk1 phosphorylation and 14-3-3-binding did not relocate or degrade atypical E2Fs, but instead, 14-3-3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA-damaging therapeutic reagents.
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Chk1 and 14‐3‐3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest
The EMBO journal, 2018Co-Authors: Ruixue Yuan, Harmjan R. Vos, Robert M. Van Es, Jing Chen, Boudewijn M.t. Burgering, Bart Westendorp, Alain De BruinAbstract:The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. Strikingly, Chk1 phosphorylation and 14-3-3-binding did not relocate or degrade atypical E2Fs, but instead, 14-3-3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA-damaging therapeutic reagents.
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cloning and characterization of mouse e2f8 a novel mammalian e2f family member capable of blocking cellular proliferation
Journal of Biological Chemistry, 2005Co-Authors: Baidehi Maiti, Alain De Bruin, Faye Gordon, Cynthia Timmers, Rene Opavsky, Kaustubha Patil, John Tuttle, Whitney M Cleghorn, Gustavo LeoneAbstract:The E2F transcription factor family plays a crucial and well established role in cell cycle progression. Deregulation of E2F activities in vivo leads to developmental defects and cancer. Based on current evidence in the field, mammalian E2Fs can be functionally categorized into either transcriptional activators (E2F1, E2F2, and E2F3a) or repressors (E2F3b, E2F4, E2F5, E2F6, and E2F7). We have identified a novel E2F family member, E2F8, which is conserved in mice and humans and has its counterpart in Arabidopsis thaliana (E2Ls). Interestingly, E2F7 and E2F8 share unique structural features that distinguish them from other mammalian E2F repressor members, including the presence of two distinct DNA-binding domains and the absence of DP-dimerization, retinoblastoma-binding, and transcriptional activation domains. Similar to E2F7, overexpression of E2F8 significantly slows down the proliferation of primary mouse embryonic fibroblasts. These observations, together with the fact that E2F7 and E2F8 can homodimerize and are expressed in the same adult tissues, suggest that they may have overlapping and perhaps synergistic roles in the control of cellular proliferation.
Alexander Miron - One of the best experts on this subject based on the ideXlab platform.
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identification of a novel e2f3 product suggests a mechanism for determining specificity of repression by rb proteins
Molecular and Cellular Biology, 2000Co-Authors: Gustavo Leone, Rosalie C Sears, Faison Nuckolls, Alexander Miron, Laszlo Jakoi, Seiichi Ishida, Monique R Adams, Joseph R NevinsAbstract:The tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes. Here we describe a novel E2F product that specifically interacts with Rb in quiescent cells. This novel E2F, which we term E2F3b, is encoded by a unique mRNA transcribed from an intronic promoter within the E2F3 locus. The E2F3b RNA differs from the previously characterized E2F3 RNA, which we now term E2F3a, by the utilization of a unique coding exon. In contrast to the E2F3a product that is tightly regulated by cell growth, the E2F3b product is expressed equivalently in quiescent and proliferating cells. But, unlike the E2F4 and E2F5 proteins, which are also expressed in quiescent cells and form complexes with the p130 protein, the E2F3b protein associates with Rb and represents the predominant E2F-Rb complex in quiescent cells. Thus, the previously described specificity of Rb function as a transcriptional repressor in quiescent cells coincides with the association of Rb with this novel E2F product.
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distinct roles for e2f proteins in cell growth control and apoptosis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: James Degregori, Gustavo Leone, Alexander Miron, Laszlo Jakoi, Joseph R NevinsAbstract:E2F transcription activity is composed of a family of heterodimers encoded by distinct genes. Through the overproduction of each of the five known E2F proteins in mammalian cells, we demonstrate that a large number of genes encoding proteins important for cell cycle regulation and DNA replication can be activated by the E2F proteins and that there are distinct specificities in the activation of these genes by individual E2F family members. Coexpression of each E2F protein with the DP1 heterodimeric partner does not significantly alter this specificity. We also find that only E2F1 overexpression induces cells to undergo apoptosis, despite the fact that at least two other E2F family members, E2F2 and E2F3, are equally capable of inducing S phase. The ability of E2F1 to induce apoptosis appears to result from the specific induction of an apoptosis-promoting activity rather than the lack of induction of a survival activity, because co-expression of E2F2 and E2F3 does not rescue cells from E2F1-mediated apoptosis. We conclude that E2F family members play distinct roles in cell cycle control and that E2F1 may function as a specific signal for the initiation of an apoptosis pathway that must normally be blocked for a productive proliferation event.
