21 results on '"Helin, Kristian"'
Search Results
2. NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling.
- Author
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Sørensen CS, Melixetian M, Klein DK, and Helin K
- Subjects
- Cell Line, Tumor, Checkpoint Kinase 1, G2 Phase, Humans, Mitosis, Models, Biological, NIMA-Related Kinases, Neoplasms enzymology, Neoplasms pathology, Neoplasms therapy, Precancerous Conditions enzymology, Precancerous Conditions pathology, Cell Cycle, DNA Damage, Protein Kinases metabolism, Signal Transduction, cdc25 Phosphatases metabolism
- Abstract
The DNA damage induced G(2)/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events that lead to its recognition by the ubiquitin ligase beta-TrCP. Recently we have identified NEK11, a member of NIMA-related kinase family, as the critical kinase triggering CDC25A degradation. NEK11 controls degradation of CDC25A by directly phosphorylating CDC25A on residues whose phosphorylation is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1, a strong candidate target for the development of novel anticancer drugs. Here we further support this notion by showing results suggesting that NEK11 expression increases during colon cancer development.
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- 2010
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3. E2F-dependent induction of p14ARF during cell cycle re-entry in human T cells.
- Author
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del Arroyo AG, El Messaoudi S, Clark PA, James M, Stott F, Bracken A, Helin K, and Peters G
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- Base Sequence, Cell Line, Cells, Cultured, Humans, Molecular Sequence Data, T-Lymphocytes physiology, Cell Cycle physiology, E2F Transcription Factors physiology, T-Lymphocytes cytology, T-Lymphocytes metabolism, Tumor Suppressor Protein p14ARF biosynthesis, Tumor Suppressor Protein p14ARF genetics
- Abstract
The ARF protein, encoded by alternate exon usage within the CDKN2A locus, provides a link between the retinoblastoma (pRb) and p53 tumor suppressor pathways. Agents that disable pRb or otherwise impinge on the E2F family of transcription factors induce expression of ARF, resulting in stabilization of p53 and activation of p53-regulated genes. However, in some cell types ARF is not induced upon cell cycle re-entry, as expected of a conventional E2F target gene, leading to the suggestion that the ARF promoter only responds to supra-physiological or aberrant levels of E2F. These properties have recently been attributed to a variant E2F binding site but attempts to map specific response elements within the ARF promoter have generally yielded confusing answers. Here we show that in IL2-dependent T-lymphocytes, ARF expression is induced as cells progress from G(0) into S phase, in parallel with other bona fide E2F target genes. This is accompanied by increased association of E2F1 with the endogenous ARF promoter. Our findings suggest that the ability of ARF to register normal proliferative cues depends on the levels of E2F generated in different settings and argue against the idea that it reacts exclusively to oncogenic signals.
- Published
- 2007
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4. The E2F family: specific functions and overlapping interests.
- Author
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Attwooll C, Lazzerini Denchi E, and Helin K
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- Animals, Cell Cycle Proteins classification, Cell Cycle Proteins genetics, Cell Proliferation, DNA-Binding Proteins classification, DNA-Binding Proteins genetics, E2F Transcription Factors, Phenotype, Protein Binding, Transcription Factors classification, Transcription Factors genetics, Cell Cycle physiology, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Gene Expression Regulation, Transcription Factors metabolism
- Abstract
The E2F transcription factors are key regulators of cell cycle progression and the E2F field has made rapid advances since its advent in 1986. Yet, while our understanding of the roles and functions of the E2F family has made enormous progress, with each discovery new questions arise. In this review, we summarise the most recent advances in the field and discuss the remaining key questions. In particular, we will focus on how specificity is achieved among the E2Fs.
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- 2004
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5. E2F target genes: unraveling the biology.
- Author
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Bracken AP, Ciro M, Cocito A, and Helin K
- Subjects
- Animals, DNA Damage, E2F Transcription Factors, Forecasting, Humans, Apoptosis, Cell Cycle physiology, Cell Cycle Proteins physiology, Cell Differentiation, DNA Repair physiology, DNA Replication physiology, DNA-Binding Proteins physiology, Mitosis physiology, Transcription Factors physiology
- Abstract
The E2F transcription factors are downstream effectors of the retinoblastoma protein (pRB) pathway and are required for the timely regulation of numerous genes essential for DNA replication and cell cycle progression. Several laboratories have used genome-wide approaches to discover novel target genes of E2F, leading to the identification of several hundred such genes that are involved not only in DNA replication and cell cycle progression, but also in DNA damage repair, apoptosis, differentiation and development. These new findings greatly enrich our understanding of how E2F controls transcription and cellular homeostasis.
- Published
- 2004
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6. Loss of Geminin induces rereplication in the presence of functional p53.
- Author
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Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J, Lukas J, and Helin K
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- Cell Cycle Proteins genetics, Cell Death genetics, Cell Line, Tumor, Cell Nucleus genetics, Cell Nucleus metabolism, Cell Transformation, Neoplastic genetics, Checkpoint Kinase 1, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Geminin, Genes, cdc physiology, Histones genetics, Histones metabolism, Humans, Mitosis genetics, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polyploidy, Protein Kinases genetics, Protein Kinases metabolism, Rad51 Recombinase, Tumor Suppressor Protein p53 genetics, Cell Cycle genetics, Cell Cycle Proteins metabolism, DNA Replication genetics, Genomic Instability genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Strict regulation of DNA replication is essential to ensure proper duplication and segregation of chromosomes during the cell cycle, as its deregulation can lead to genomic instability and cancer. Thus, eukaryotic organisms have evolved multiple mechanisms to restrict DNA replication to once per cell cycle. Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. We found a CHK1-dependent checkpoint to be activated in rereplicating cells accompanied by formation of gammaH2AX and RAD51 nuclear foci. Abrogation of the checkpoint leads to abortive mitosis and death of rereplicated cells. In addition, we demonstrate that the induction of rereplication is dependent on the replication initiation factors CDT1 and CDC6, and independent of the functional status of p53. These data show that Geminin is required for maintaining genomic stability in human cells.
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- 2004
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- View/download PDF
7. E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes.
- Author
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Di Stefano L, Jensen MR, and Helin K
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cell Cycle genetics, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, DNA Primers, Dimerization, E2F Transcription Factors, E2F7 Transcription Factor, Gene Expression Regulation, Genes, Reporter, HeLa Cells, Humans, Luciferases metabolism, Molecular Sequence Data, Polymerase Chain Reaction, Rats, Recombinant Fusion Proteins metabolism, Recombinant Proteins metabolism, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Alignment, Sequence Homology, Amino Acid, Transcription Factors genetics, Transfection, Cell Cycle physiology, DNA-Binding Proteins, Repressor Proteins metabolism, Transcription Factors metabolism
- Abstract
The E2F family of transcription factors play an essential role in the regulation of cell cycle progression. In a screen for E2F-regulated genes we identified a novel E2F family member, E2F7. Like the recently identified E2F-like proteins of Arabidopsis, E2F7 has two DNA binding domains and binds to the E2F DNA binding consensus site independently of DP co-factors. Consistent with being an E2F target gene, we found that the expression of E2F7 is cell cycle regulated. Ectopic expression of E2F7 results in suppression of E2F target genes and accumulation of cells in G1. Furthermore, E2F7 associates with E2F-regulated promoters in vivo, and this association increases in S phase. Interestingly, however, E2F7 binds only a subset of E2F-dependent promoters in vivo, and in agreement with this, inhibition of E2F7 expression results in specific derepression of these promoters. Taken together, these data demonstrate that E2F7 is a unique repressor of a subset of E2F target genes whose products are required for cell cycle progression.
- Published
- 2003
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8. NPAT expression is regulated by E2F and is essential for cell cycle progression.
- Author
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Gao G, Bracken AP, Burkard K, Pasini D, Classon M, Attwooll C, Sagara M, Imai T, Helin K, and Zhao J
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- 3T3 Cells, Animals, Base Sequence, Binding Sites genetics, Cell Cycle genetics, Cell Line, DNA genetics, DNA metabolism, E2F Transcription Factors, E2F1 Transcription Factor, G1 Phase genetics, G1 Phase physiology, Gene Expression Regulation, Histones genetics, Humans, Mice, Molecular Sequence Data, Promoter Regions, Genetic, RNA Interference, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering genetics, RNA, Small Interfering pharmacology, S Phase genetics, S Phase physiology, Cell Cycle physiology, Cell Cycle Proteins, DNA-Binding Proteins, Nuclear Proteins, Proteins genetics, Proteins metabolism, Transcription Factors metabolism
- Abstract
NPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G(1)/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G(1)/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G(1)/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.
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- 2003
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9. Loss of the Retinoblastoma Protein-Related p130 Protein in Small Cell Lung Carcinoma
- Author
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Helin, Kristian, Holm, Karin, Niebuhr, Anita, Eiberg, Hans, Tommerup, Niels, Hougaard, Susanne, Poulsen, Hans Skovgaard, Spang-Thomsen, Mogens, and Nørgaard, Peter
- Published
- 1997
10. The Histone Methyltransferase SET8 Is Required for S-Phase Progression
- Author
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Jørgensen, Stine, Elvers, Ingegerd, Trelle, Morten Beck, Menzel, Tobias, Eskildsen, Morten, Jensen, Ole Nørregaard, Helleday, Thomas, Helin, Kristian, and Sørensen, Claus Storgaard
- Published
- 2007
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11. Cell Cycle Regulation of the Cyclin A Gene Promoter is Mediated by a Variant E2F Site
- Author
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Schulze, Almut, Zerfass, Karin, Spitkovsky, Dimitry, Middendorp, Sandrine, Berges, Josette, Helin, Kristian, Jansen-Durr, Pidder, and Henglein, Berthold
- Published
- 1995
12. Transcriptional Inhibition by the Retinoblastoma Protein
- Author
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Fattaey, Ali, Helin, Kristian, and Harlow, Ed
- Published
- 1993
13. E2F activates late-G1 events but cannot replace E1A in inducing S phase in terminally differentiated skeletal muscle cells
- Author
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Pajalunga, Deborah, Tognozzi, Deborah, Tiainen, Marianne, D'Angelo, Marco, Ferrantelli, Flavia, Helin, Kristian, Sacchi, Ada, and Crescenzi, Marco
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- 1999
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14. E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription
- Author
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Cartwright, Peter, Müller, Heiko, Wagener, Christian, Holm, Karin, and Helin, Kristian
- Published
- 1998
- Full Text
- View/download PDF
15. MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells.
- Author
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Müller, Iris, Moroni, Ann Sophie, Shlyueva, Daria, Sahadevan, Sudeep, Schoof, Erwin M., Radzisheuskaya, Aliaksandra, Højfeldt, Jonas W., Tatar, Tülin, Koche, Richard P., Huang, Chang, and Helin, Kristian
- Subjects
PLURIPOTENT stem cells ,ULTRACOLD molecules ,ENDOGENOUS retroviruses ,CELL cycle ,EMBRYOLOGY ,EMBRYONIC stem cells ,CHROMATIN - Abstract
Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigenetic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together, our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3. Naïve pluripotency is characterized by distinctly open chromatin and repressed endogenous retroviruses. Here the authors show that MPP8 and its association with the core HUSH complex is essential for naïve pluripotent cells; also that repression of LINE1 elements by MPP8 does not require chromatin binding, nor H3K9me3. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
16. Isolation and characterization of DUSP11, a novel p53 target gene.
- Author
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Caprara, Greta, Zamponi, Raffaella, Melixetian, Marina, and Helin, Kristian
- Subjects
DNA damage ,GENE expression ,RNA-protein interactions ,CELL cycle ,CELL proliferation ,TISSUE culture - Abstract
p53 regulates the expression of genes involved in cell cycle control, apoptosis and DNA damage repair. Here we demonstrate that DUSP11 (dual specificity phosphatase 11), a member of the protein tyrosine phosphatase family that binds to RNA-RNP complexes and RNA splicing factors, is a p53 target gene. Consistent with this, the expression of DUSP11 is induced in a p53-dependent manner after treatment with DNA damaging agents. Chromatin immunoprecipitation analysis showed that p53 binds to 2 putative p53 DNA binding sites in the promoter region of DUSP11. Colony formation and proliferation assays demonstrated that the ectopic expression of wild-type, but not catalytical inactive, DUSP11 leads to growth arrest. Furthermore inhibition of DUSP11 expression by shRNA increases the proliferation of normal and DNA damaged cells in tissue culture. Finally we show that the splicing factor SAM68 (Src-associated protein in mitotic cells) binds to DUSP11 in vitro and in vivo. Taken together these results suggest that DUSP11 contributes to p53-dependent inhibition of cell proliferation and that it might be involved in regulating RNA splicing through SAM68. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
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17. Human Geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.
- Author
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Ballabeni, Andrea, Melixetian, Marina, Zamponi, Raffaella, Masiero, Laura, Marinoni, Federica, and Helin, Kristian
- Subjects
CELL cycle ,BIOLOGICAL rhythms ,CELL proliferation ,DNA replication ,DNA synthesis ,CHROMOSOME replication ,MITOSIS - Abstract
Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts. Here we describe a novel function of Geminin. We demonstrate that human Geminin protects CDT1 from proteasome-mediated degradation by inhibiting its ubiquitination. In particular, Geminin ensures basal levels of CDT1 during S phase and its accumulation during mitosis. Consistently, inhibition of Geminin synthesis during M phase leads to impairment of pre-RC formation and DNA replication during the following cell cycle. Moreover, we show that inhibition of CDK1 during mitosis, and not Geminin depletion, is sufficient for premature formation of pre-RCs, indicating that CDK activity is the major mitotic inhibitor of licensing in human cells. Taken together with recent data from our laboratory, our results demonstrate that Geminin is both a negative and positive regulator of pre-RC formation in human cells, playing a positive role in allowing CDT1 accumulation in G2-M, and preventing relicensing of origins in S-G2. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
18. E2F1-mediated transcriptional inhibition of the plasminogen activator inhibitor type 1 gene.
- Author
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Koziczak, Magdalena, Müller, Heiko, Helin, Kristian, and Nagamine, Yoshikuni
- Subjects
GENE expression ,PLASMINOGEN activators - Abstract
Gene expression of the plasminogen activation system is cell-cycle dependent. Previously, we showed that ectopic expression of E2F1 repressed the plasminogen activator inhibitor type 1 (PAI-1) promoter in a manner dependent on the presence of DNA-binding and transactivation domains of E2F1 but independent of binding to pocket-binding proteins, suggesting a novel mechanism for E2F-mediated negative gene regulation [Koziczak, M., Krek, W. & Nagamine, Y. (2000) Mol. Cell. Biol. 20, 2014–2022]. However, it remains to be seen whether endogenous E2F can exert a similar effect. We report here that down-regulation of PAI-1 gene expression correlates with an increase in endogenous E2F activity. When cells were treated with a cdk2/4-specific inhibitor, which maintains E2F in an inactive state, the decline of serum-induced PAI-1 mRNA levels was suppressed. In mutant U2OS cells expressing a temperature-sensitive retinoblastoma protein (pRB), a shift to a permissive temperature induced PAI-1 mRNA expression. In U2OS cells stably expressing an E2F1-estrogen receptor chimeric protein that could be activated by tamoxifen, PAI-1 gene transcription was markedly reduced by tamoxifen even in the presence of cycloheximide. These results all indicate that endogenous E2F can directly repress the PAI-1 gene. DNase I hypersensitive-site analysis of the PAI-1 promoter suggested the involvement of conformation changes in chromatin structure of the PAI-1 promoter. 5′ deletion analysis of the PAI-1 promoter showed that multiple sites were responsible for the E2F negative regulation, some of which were promoter dependent. Interestingly, one of these sites is a p53-binding element. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
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19. Phosphorylation of mammalian CDC6 by Cyclin A/CDK2 regulates its subcellular localization.
- Author
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Petersen, Birgit Otzen, Lukas, Jiri, Sørensen, Claus Storgaard, Bartek, Jiri, and Helin, Kristian
- Subjects
PHOSPHORYLATION ,CYCLIN-dependent kinases ,GENETIC regulation ,DNA replication ,PROTEIN kinases ,CELL cycle ,DNA - Abstract
Cyclin-dependent kinases (CDKs) are essential for regulating key transitions in the cell cycle, including initiation of DNA replication, mitosis and prevention of re-replication. Here we demonstrate that mammalian CDC6, an essential regulator of initiation of DNA replication, is phosphorylated by CDKs. CDC6 interacts specifically with the active Cyclin A/CDK2 complex in vitro and in vivo, but not with Cyclin E or Cyclin B kinase complexes. The cyclin binding domain of CDC6 was mapped to an N-terminal Cy-motif that is similar to the cyclin binding regions in p21
WAF1/SDI1 and E2F-1. The in vivo phosphorylation of CDC6 was dependent on three N-terminal CDK consensus sites, and the phosphorylation of these sites was shown to regulate the subcellular localization of CDC6. Consistent with this notion, we found that the subcellular localization of CDC6 is cell cycle regulated. In G1 , CDC6 is nuclear and it relocalizes to the cytoplasm when Cyclin A/CDK2 is activated. In agreement with CDC6 phosphorylation being specifically mediated by Cyclin A/CDK2, we show that ectopic expression of Cyclin A, but not of Cyclin E, leads to rapid relocalization of CDC6 from the nucleus to the cytoplasm. Based on our data we suggest that the phosphorylation of CDC6 by Cyclin A/CDK2 is a negative regulatory event that could be implicated in preventing re-replication during S phase and G2 . [ABSTRACT FROM AUTHOR]- Published
- 1999
- Full Text
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20. SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation.
- Author
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Jørgensen, Stine, Eskildsen, Morten, Fugger, Kasper, Hansen, Lisbeth, Larsen, Marie Sofie Yoo, Kousholt, Arne Nedergaard, Syljuåsen, Randi G., Trelle, Morten Beck, Jensen, Ole Nørregaard, Helin, Kristian, and Sørensen, Claus Storgaard
- Subjects
- *
EUKARYOTIC cells , *CELL cycle , *PHYSIOLOGICAL effects of ultraviolet radiation , *IRRADIATION , *ANTIGENS - Abstract
The eukaryotic cell cycle is regulated by multiple ubiquitin-mediated events, such as the timely destruction of cyclins and replication licensing factors. The histone H4 methyltransferase SET8 (Pr-Set7) is required for chromosome compaction in mitosis and for maintenance of genome integrity. In this study, we show that SET8 is targeted for degradation during S phase by the CRL4(CDT2) ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)--dependent manner. SET8 degradation requires a conserved degron responsible for its interaction with PCNA and recruitment to chromatin where ubiquitylation occurs. Efficient degradation of SET8 at the onset of S phase is required for the regulation of chromatin compaction status and cell cycle progression. Moreover, the turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. Removal of SET8 supports the modulation of chromatin structure after DNA damage. These results demonstrate a novel regulatory mechanism, linking for the first time the ubiquitin--proteasome system with rapid degradation of a histone methyltransferase to control cell proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
21. A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation
- Author
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Biagio Eugenio Leone, Roberto Giovannoni, Vittoria Cicirelli, Federica Giordano, Marialuisa Lavitrano, Fabio Pisano, Serena Bonin, Leonarda Ianzano, Annamaria Cialdella, Maria Grazia Cerrito, Emanuela Grassilli, Filomena D'Amato, Barbara Noli, Laura Masiero, Robert Narloch, Giorgio Stanta, Gian-Luca Ferri, Kristian Helin, Sara Bonomo, Carola Missaglia, Grassilli, E, Pisano, F, Cialdella, A, Bonomo, S, Missaglia, C, Cerrito, M, Masiero, L, Ianzano, L, Giordano, F, Cicirelli, V, Narloch, R, D’Amato, F, Noli, B, Ferri, G, Leone, B, Stanta, G, Bonin, S, Helin, K, Giovannoni, R, Lavitrano, M, Grassilli, Emanuela, Pisano, Fabio, Cialdella, Annamaria, Bonomo, Sara, Missaglia, Carola, Cerrito, Maria Grazia, Masiero, Laura, Ianzano, Leonarda, Giordano, Federica, Cicirelli, Vittoria, Narloch, Robert, D'Amato, Filomena, Noli, Barbara, Ferri, Gian Luca, Leone, Biagio, Stanta, Giorgio, Bonin, Serena, Helin, Kristian, Giovannoni, Roberto, and Lavitrano, Marialuisa
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Gene isoform ,Cancer Research ,MAP Kinase Signaling System ,Bruton's tyroine kinase ,Heterogeneous-Nuclear Ribonucleoprotein K ,03 medical and health sciences ,0302 clinical medicine ,Growth factor receptor ,oncogene ,Cell Line, Tumor ,Genetics ,Agammaglobulinaemia Tyrosine Kinase ,Bruton's tyrosine kinase ,Humans ,Protein Isoforms ,RAS-mediated transformation ,colon cancer ,RAS ,Protein kinase A ,Molecular Biology ,BTK ,isoform ,Oncogene ,biology ,Cell cycle ,Protein-Tyrosine Kinases ,Molecular biology ,030104 developmental biology ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,biology.protein ,Cancer research ,ras Proteins ,colon cancer, oncogene, Bruton's tyroine kinase, RAS ,Original Article ,5' Untranslated Regions ,Tyrosine kinase - Abstract
Bruton's tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumour tissue samples. p65BTK protein is expressed, through heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site-driven translation, from a transcript containing an alternative first exon in the 5'-untranslated region, and is post-transcriptionally regulated, via hnRNPK, by the mitogen-activated protein kinase (MAPK) pathway. p65BTK is endowed with strong transforming activity that depends on active signal-regulated protein kinases-1/2 (ERK1/2) and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.504.
- Published
- 2016
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