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Charles Spruck - One of the best experts on this subject based on the ideXlab platform.
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scffbxw7 hcdc4 targets Cyclin E2 for ubiquitin dependent proteolysis
Experimental Cell Research, 2009Co-Authors: Kathleen Klotz, Diana Cepeda, Yingmeei Tan, Dahui Sun, Olle Sangfelt, Charles SpruckAbstract:Abstract E-type Cyclins (E1 and E2) regulate the S phase program in the mammalian cell division cycle. Expression of Cyclin E1 and E2 is frequently deregulated in a variety of cancer types and a wealth of experimental evidence supports an oncogenic role of these proteins in human tumorigenesis. Although the molecular mechanisms responsible for Cyclin E1 deregulation in cancer are well defined, little is known regarding Cyclin E2. Here we report that Cyclin E2 is targeted for ubiquitin-dependent proteolysis by the ubiquitin ligase SCFFbxw7/hCdc4. Ubiquitylation is triggered by phosphorylation of Cyclin E2 on residues Thr392 and Ser396, and to a lesser extent Thr74, contained in two consensus Cdc4-phosphodegrons. Furthermore, we found that ectopic expression of Cyclin E1 enhances the ubiquitin-dependent proteolysis of Cyclin E2 in vivo, suggesting a potential cross-talk in the regulation of E-type Cyclin activity. Since SCFFbxw7/hCdc4 is functionally inactivated in several human cancer types, alteration of this molecular pathway could contribute to the deregulation of Cyclin E2 in tumorigenesis.
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SCFFbxw7/hCdc4 targets Cyclin E2 for ubiquitin-dependent proteolysis
Experimental cell research, 2008Co-Authors: Kathleen Klotz, Diana Cepeda, Yingmeei Tan, Dahui Sun, Olle Sangfelt, Charles SpruckAbstract:Abstract E-type Cyclins (E1 and E2) regulate the S phase program in the mammalian cell division cycle. Expression of Cyclin E1 and E2 is frequently deregulated in a variety of cancer types and a wealth of experimental evidence supports an oncogenic role of these proteins in human tumorigenesis. Although the molecular mechanisms responsible for Cyclin E1 deregulation in cancer are well defined, little is known regarding Cyclin E2. Here we report that Cyclin E2 is targeted for ubiquitin-dependent proteolysis by the ubiquitin ligase SCFFbxw7/hCdc4. Ubiquitylation is triggered by phosphorylation of Cyclin E2 on residues Thr392 and Ser396, and to a lesser extent Thr74, contained in two consensus Cdc4-phosphodegrons. Furthermore, we found that ectopic expression of Cyclin E1 enhances the ubiquitin-dependent proteolysis of Cyclin E2 in vivo, suggesting a potential cross-talk in the regulation of E-type Cyclin activity. Since SCFFbxw7/hCdc4 is functionally inactivated in several human cancer types, alteration of this molecular pathway could contribute to the deregulation of Cyclin E2 in tumorigenesis.
C. Elizabeth Caldon - One of the best experts on this subject based on the ideXlab platform.
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Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer
Cancers, 2020Co-Authors: Christine S. L. Lee, Andrew Burgess, C. Marcelo Sergio, Samuel Rogers, Kristine J. Fernandez, Sarah Alexandrou, Niantao Deng, C. Elizabeth CaldonAbstract:Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes Cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both Cyclin E1 (CCNE1) and Cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that Cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that Cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low Cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high Cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while Cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, Cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.
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Cyclin E2 is the predominant E-Cyclin associated with NPAT in breast cancer cells
Cell Division, 2015Co-Authors: Samuel Rogers, Claudio Marcelo Sergio, Andrew Burgess, E A Musgrove, Marcel E. Dinger, Brian S. Gloss, C. Elizabeth CaldonAbstract:Background The Cyclin E oncogene activates CDK2 to drive cells from G_1 to S phase of the cell cycle to commence DNA replication. It coordinates essential cellular functions with the cell cycle including histone biogenesis, splicing, centrosome duplication and origin firing for DNA replication. The two E-Cyclins, E1 and E2, are assumed to act interchangeably in these functions. However recent reports have identified unique functions for Cyclins E1 and E2 in different tissues, and particularly in breast cancer. Findings Cyclins E1 and E2 localise to distinct foci in breast cancer cells as well as co-localising within the cell. Both E-Cyclins are found in complex with CDK2, at centrosomes and with the splicing machinery in nuclear speckles. However Cyclin E2 uniquely co-localises with NPAT, the main activator of cell-cycle regulated histone transcription. Increased Cyclin E2, but not Cyclin E1, expression is associated with high expression of replication-dependent histones in breast cancers. Conclusions The preferential localisation of Cyclin E1 or Cyclin E2 to distinct foci indicates that each E-Cyclin has unique roles. Cyclin E2 uniquely interacts with NPAT in breast cancer cells, and is associated with higher levels of histones in breast cancer. This could explain the unique correlations of high Cyclin E2 expression with poor outcome and genomic instability in breast cancer.
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Cyclin E2 is the predominant E-Cyclin associated with NPAT in breast cancer cells
Cell Division, 2015Co-Authors: Samuel Rogers, Claudio Marcelo Sergio, Andrew Burgess, Marcel E. Dinger, Brian S. Gloss, Elizabeth A Musgrove, C. Elizabeth CaldonAbstract:Background The Cyclin E oncogene activates CDK2 to drive cells from G_1 to S phase of the cell cycle to commence DNA replication. It coordinates essential cellular functions with the cell cycle including histone biogenesis, splicing, centrosome duplication and origin firing for DNA replication. The two E-Cyclins, E1 and E2, are assumed to act interchangeably in these functions. However recent reports have identified unique functions for Cyclins E1 and E2 in different tissues, and particularly in breast cancer. Findings Cyclins E1 and E2 localise to distinct foci in breast cancer cells as well as co-localising within the cell. Both E-Cyclins are found in complex with CDK2, at centrosomes and with the splicing machinery in nuclear speckles. However Cyclin E2 uniquely co-localises with NPAT, the main activator of cell-cycle regulated histone transcription. Increased Cyclin E2, but not Cyclin E1, expression is associated with high expression of replication-dependent histones in breast cancers. Conclusions The preferential localisation of Cyclin E1 or Cyclin E2 to distinct foci indicates that each E-Cyclin has unique roles. Cyclin E2 uniquely interacts with NPAT in breast cancer cells, and is associated with higher levels of histones in breast cancer. This could explain the unique correlations of high Cyclin E2 expression with poor outcome and genomic instability in breast cancer.
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Cyclin E2 induces genomic instability by mechanisms distinct from Cyclin E1.
Cell cycle (Georgetown Tex.), 2013Co-Authors: C. Elizabeth Caldon, Andrew Burgess, C. Marcelo Sergio, Robert L. Sutherland, Andrew J. Deans, Elizabeth A MusgroveAbstract:Cyclins E1 drives the initiation of DNA replication, and deregulation of its periodic expression leads to mitotic delay associated with genomic instability. Since it is not known whether the closely related protein Cyclin E2 shares these properties, we overexpressed Cyclin E2 in breast cancer cells. This did not affect the duration of mitosis, nor did it cause an increase in p107 association with CDK2. In contrast, Cyclin E1 overexpression led to inhibition of the APC complex, prolonged metaphase and increased p107 association with CDK2. Despite these different effects on the cell cycle, elevated levels of either Cyclin E1 or E2 led to hallmarks of genomic instability, i.e., an increased proportion of abnormal mitoses, micronuclei and chromosomal aberrations. Cyclin E2 induction of genomic instability by a mechanism distinct from Cyclin E1 indicates that these two proteins have unique functions in a cancer setting.
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Differences in degradation lead to asynchronous expression of Cyclin E1 and Cyclin E2 in cancer cells.
Cell cycle (Georgetown Tex.), 2013Co-Authors: C. Elizabeth Caldon, C. Marcelo Sergio, Robert L. Sutherland, Elizabeth A MusgroveAbstract:Cyclin E1 is expressed at the G₁/S phase transition of the cell cycle to drive the initiation of DNA replication and is degraded during S/G₂M. Deregulation of its periodic degradation is observed in cancer and is associated with increased proliferation and genomic instability. We identify that in cancer cells, unlike normal cells, the closely related protein Cyclin E2 is expressed predominantly in S phase, concurrent with DNA replication. This occurs at least in part because the ubiquitin ligase component that is responsible for Cyclin E1 downregulation in S phase, Fbw7, fails to effectively target Cyclin E2 for proteosomal degradation. The distinct cell cycle expression of the two E-type Cyclins in cancer cells has implications for their roles in genomic instability and proliferation and may explain their associations with different signatures of disease.
Wei Tao - One of the best experts on this subject based on the ideXlab platform.
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knockdown of long non coding rna kcnq1ot1 restrained glioma cells malignancy by activating mir 370 ccnE2 axis
Frontiers in Cellular Neuroscience, 2017Co-Authors: Wei Gong, Jian Zheng, Xiaobai Liu, Yunhui Liu, Junqing Guo, Yana Gao, Wei TaoAbstract:Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. Here, we elucidated the function and possible molecular mechanisms of lncRNA KCNQ1OT1 in human glioma U87 and U251 cells. Quantitative Real-Time polymerase chain reaction (qRT-PCR) demonstrated that KCNQ1OT1 expression was up-regulated in glioma tissues and cells. Knockdown of KCNQ1OT1 exerted tumor-suppressive function in glioma cells. Moreover, a binding region was confirmed between KCNQ1OT1 and miR-370 by dual-luciferase assays. qRT-PCR showed that miR-370 was down-regulated in human glioma tissue and cells. In addition, restoration of miR-370 exerted tumor-suppressive function via inhibiting cell proliferation, migration and invasion, while promoting the apoptosis of human glioma cells. Knockdown of KCNQ1OT1 decreased the expression level of Cyclin E2 (CCNE2) by binding to miR-370. Further, miR-370 bound to CCNE2 3'UTR region and decreased the expression of CCNE2. These results provided a comprehensive analysis of KCNQ1OT1-miR-370-CCNE2 axis in human glioma cells and might provide a novel strategy for glioma treatment.
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Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells' Malignancy by Activating miR-370/CCNE2 Axis.
Frontiers in cellular neuroscience, 2017Co-Authors: Wei Gong, Jian Zheng, Xiaobai Liu, Yunhui Liu, Junqing Guo, Yana Gao, Wei Tao, Jiajia ChenAbstract:Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. Here, we elucidated the function and possible molecular mechanisms of lncRNA KCNQ1OT1 in human glioma U87 and U251 cells. Quantitative Real-Time polymerase chain reaction (qRT-PCR) demonstrated that KCNQ1OT1 expression was up-regulated in glioma tissues and cells. Knockdown of KCNQ1OT1 exerted tumor-suppressive function in glioma cells. Moreover, a binding region was confirmed between KCNQ1OT1 and miR-370 by dual-luciferase assays. qRT-PCR showed that miR-370 was down-regulated in human glioma tissue and cells. In addition, restoration of miR-370 exerted tumor-suppressive function via inhibiting cell proliferation, migration and invasion, while promoting the apoptosis of human glioma cells. Knockdown of KCNQ1OT1 decreased the expression level of Cyclin E2 (CCNE2) by binding to miR-370. Further, miR-370 bound to CCNE2 3'UTR region and decreased the expression of CCNE2. These results provided a comprehensive analysis of KCNQ1OT1-miR-370-CCNE2 axis in human glioma cells and might provide a novel strategy for glioma treatment.
Kathleen Klotz - One of the best experts on this subject based on the ideXlab platform.
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scffbxw7 hcdc4 targets Cyclin E2 for ubiquitin dependent proteolysis
Experimental Cell Research, 2009Co-Authors: Kathleen Klotz, Diana Cepeda, Yingmeei Tan, Dahui Sun, Olle Sangfelt, Charles SpruckAbstract:Abstract E-type Cyclins (E1 and E2) regulate the S phase program in the mammalian cell division cycle. Expression of Cyclin E1 and E2 is frequently deregulated in a variety of cancer types and a wealth of experimental evidence supports an oncogenic role of these proteins in human tumorigenesis. Although the molecular mechanisms responsible for Cyclin E1 deregulation in cancer are well defined, little is known regarding Cyclin E2. Here we report that Cyclin E2 is targeted for ubiquitin-dependent proteolysis by the ubiquitin ligase SCFFbxw7/hCdc4. Ubiquitylation is triggered by phosphorylation of Cyclin E2 on residues Thr392 and Ser396, and to a lesser extent Thr74, contained in two consensus Cdc4-phosphodegrons. Furthermore, we found that ectopic expression of Cyclin E1 enhances the ubiquitin-dependent proteolysis of Cyclin E2 in vivo, suggesting a potential cross-talk in the regulation of E-type Cyclin activity. Since SCFFbxw7/hCdc4 is functionally inactivated in several human cancer types, alteration of this molecular pathway could contribute to the deregulation of Cyclin E2 in tumorigenesis.
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SCFFbxw7/hCdc4 targets Cyclin E2 for ubiquitin-dependent proteolysis
Experimental cell research, 2008Co-Authors: Kathleen Klotz, Diana Cepeda, Yingmeei Tan, Dahui Sun, Olle Sangfelt, Charles SpruckAbstract:Abstract E-type Cyclins (E1 and E2) regulate the S phase program in the mammalian cell division cycle. Expression of Cyclin E1 and E2 is frequently deregulated in a variety of cancer types and a wealth of experimental evidence supports an oncogenic role of these proteins in human tumorigenesis. Although the molecular mechanisms responsible for Cyclin E1 deregulation in cancer are well defined, little is known regarding Cyclin E2. Here we report that Cyclin E2 is targeted for ubiquitin-dependent proteolysis by the ubiquitin ligase SCFFbxw7/hCdc4. Ubiquitylation is triggered by phosphorylation of Cyclin E2 on residues Thr392 and Ser396, and to a lesser extent Thr74, contained in two consensus Cdc4-phosphodegrons. Furthermore, we found that ectopic expression of Cyclin E1 enhances the ubiquitin-dependent proteolysis of Cyclin E2 in vivo, suggesting a potential cross-talk in the regulation of E-type Cyclin activity. Since SCFFbxw7/hCdc4 is functionally inactivated in several human cancer types, alteration of this molecular pathway could contribute to the deregulation of Cyclin E2 in tumorigenesis.
Xiaobai Liu - One of the best experts on this subject based on the ideXlab platform.
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knockdown of long non coding rna kcnq1ot1 restrained glioma cells malignancy by activating mir 370 ccnE2 axis
Frontiers in Cellular Neuroscience, 2017Co-Authors: Wei Gong, Jian Zheng, Xiaobai Liu, Yunhui Liu, Junqing Guo, Yana Gao, Wei TaoAbstract:Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. Here, we elucidated the function and possible molecular mechanisms of lncRNA KCNQ1OT1 in human glioma U87 and U251 cells. Quantitative Real-Time polymerase chain reaction (qRT-PCR) demonstrated that KCNQ1OT1 expression was up-regulated in glioma tissues and cells. Knockdown of KCNQ1OT1 exerted tumor-suppressive function in glioma cells. Moreover, a binding region was confirmed between KCNQ1OT1 and miR-370 by dual-luciferase assays. qRT-PCR showed that miR-370 was down-regulated in human glioma tissue and cells. In addition, restoration of miR-370 exerted tumor-suppressive function via inhibiting cell proliferation, migration and invasion, while promoting the apoptosis of human glioma cells. Knockdown of KCNQ1OT1 decreased the expression level of Cyclin E2 (CCNE2) by binding to miR-370. Further, miR-370 bound to CCNE2 3'UTR region and decreased the expression of CCNE2. These results provided a comprehensive analysis of KCNQ1OT1-miR-370-CCNE2 axis in human glioma cells and might provide a novel strategy for glioma treatment.
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Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells' Malignancy by Activating miR-370/CCNE2 Axis.
Frontiers in cellular neuroscience, 2017Co-Authors: Wei Gong, Jian Zheng, Xiaobai Liu, Yunhui Liu, Junqing Guo, Yana Gao, Wei Tao, Jiajia ChenAbstract:Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. Here, we elucidated the function and possible molecular mechanisms of lncRNA KCNQ1OT1 in human glioma U87 and U251 cells. Quantitative Real-Time polymerase chain reaction (qRT-PCR) demonstrated that KCNQ1OT1 expression was up-regulated in glioma tissues and cells. Knockdown of KCNQ1OT1 exerted tumor-suppressive function in glioma cells. Moreover, a binding region was confirmed between KCNQ1OT1 and miR-370 by dual-luciferase assays. qRT-PCR showed that miR-370 was down-regulated in human glioma tissue and cells. In addition, restoration of miR-370 exerted tumor-suppressive function via inhibiting cell proliferation, migration and invasion, while promoting the apoptosis of human glioma cells. Knockdown of KCNQ1OT1 decreased the expression level of Cyclin E2 (CCNE2) by binding to miR-370. Further, miR-370 bound to CCNE2 3'UTR region and decreased the expression of CCNE2. These results provided a comprehensive analysis of KCNQ1OT1-miR-370-CCNE2 axis in human glioma cells and might provide a novel strategy for glioma treatment.
