The Experts below are selected from a list of 36144 Experts worldwide ranked by ideXlab platform
George Orphanides - One of the best experts on this subject based on the ideXlab platform.
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anti proliferative effect of estrogen in breast cancer cells that re express erα is mediated by aberrant regulation of cell cycle genes
Journal of Molecular Endocrinology, 2005Co-Authors: Jonathan G. Moggs, Fei Ling Lim, Ruth Stuckey, Kate Antrobus, Ian Kimber, David Moore, Tracy C. Murphy, George OrphanidesAbstract:Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERalpha in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17beta-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERalpha has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERalpha through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, Cyclin B1, Cyclin B2, Cyclin G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERalpha has been reintroduced.
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anti proliferative effect of estrogen in breast cancer cells that re express erα is mediated by aberrant regulation of cell cycle genes
Journal of Molecular Endocrinology, 2005Co-Authors: Jonathan G. Moggs, Fei Ling Lim, Ruth Stuckey, Kate Antrobus, Ian Kimber, David Moore, Tracy C. Murphy, George OrphanidesAbstract:Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERalpha in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17beta-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERalpha has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERalpha through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, Cyclin B1, Cyclin B2, Cyclin G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERalpha has been reintroduced.
Yong Li - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effects of enterolactone on growth and metastasis in human breast cancer
Nutrition and Cancer, 2015Co-Authors: Xiangyang Xiong, Xiaojuan Hu, Yong LiAbstract:A lignan-rich diet is associated with a lower risk of human breast cancer. Enterolactone, an active polyphenol metabolites of lignan, was reported to have an antitumor effect. We investigated the mechanism for the effect of enterolactone against human breast cancer. Cellular changes, and associated genes induced by enterolactone, were investigated in MDA-MB-231 cells. Enterolactone showed an antiproliferative effect, and its IC50 was 261.9 ± 10.5 μM for a treatment period of 48 hr. The mRNA levels of the genes related to cell proliferation, Ki67, PCNA, and FoxM1, were reduced. Enterolactone induced accumulation of cells in the S phase, and a lower expression of Cyclin E1, Cyclin A2, Cyclin B1, and Cyclin B2 genes. There were almost no changes in the transcription levels of the genes that participate in G0/G1 phase regulation, CDK4, CDK6, and Cyclin D1. Furthermore, enterolactone interfered with the cytoskeleton by downregulating phosphorylation of the FAK/paxillin pathway, inhibiting migration and invasio...
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inhibitory effects of enterolactone on growth and metastasis in human breast cancer
Nutrition and Cancer, 2015Co-Authors: Xiangyang Xiong, Xiaojuan Hu, Yong LiAbstract:A lignan-rich diet is associated with a lower risk of human breast cancer. Enterolactone, an active polyphenol metabolites of lignan, was reported to have an antitumor effect. We investigated the mechanism for the effect of enterolactone against human breast cancer. Cellular changes, and associated genes induced by enterolactone, were investigated in MDA-MB-231 cells. Enterolactone showed an antiproliferative effect, and its IC50 was 261.9 ± 10.5 μM for a treatment period of 48 hr. The mRNA levels of the genes related to cell proliferation, Ki67, PCNA, and FoxM1, were reduced. Enterolactone induced accumulation of cells in the S phase, and a lower expression of Cyclin E1, Cyclin A2, Cyclin B1, and Cyclin B2 genes. There were almost no changes in the transcription levels of the genes that participate in G0/G1 phase regulation, CDK4, CDK6, and Cyclin D1. Furthermore, enterolactone interfered with the cytoskeleton by downregulating phosphorylation of the FAK/paxillin pathway, inhibiting migration and invasio...
Jonathan G. Moggs - One of the best experts on this subject based on the ideXlab platform.
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anti proliferative effect of estrogen in breast cancer cells that re express erα is mediated by aberrant regulation of cell cycle genes
Journal of Molecular Endocrinology, 2005Co-Authors: Jonathan G. Moggs, Fei Ling Lim, Ruth Stuckey, Kate Antrobus, Ian Kimber, David Moore, Tracy C. Murphy, George OrphanidesAbstract:Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERalpha in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17beta-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERalpha has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERalpha through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, Cyclin B1, Cyclin B2, Cyclin G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERalpha has been reintroduced.
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anti proliferative effect of estrogen in breast cancer cells that re express erα is mediated by aberrant regulation of cell cycle genes
Journal of Molecular Endocrinology, 2005Co-Authors: Jonathan G. Moggs, Fei Ling Lim, Ruth Stuckey, Kate Antrobus, Ian Kimber, David Moore, Tracy C. Murphy, George OrphanidesAbstract:Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERalpha in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17beta-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERalpha has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERalpha through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, Cyclin B1, Cyclin B2, Cyclin G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERalpha has been reintroduced.
Kurt Engeland - One of the best experts on this subject based on the ideXlab platform.
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p53 can repress transcription of cell cycle genes through a p21 waf1 cip1 dependent switch from mmb to dream protein complex binding at chr promoter elements
Cell Cycle, 2012Co-Authors: Marianne Quaas, Gerd A Muller, Kurt EngelandAbstract:The tumor suppressor p53 plays an important role in cell cycle arrest by downregulating transcription. Many genes repressed by p53 code for proteins with functions in G₂/M. A large portion of these genes is controlled by cell cycle-dependent elements (CDE) and cell cycle genes homology regions (CHR) in their promoters. Cyclin B2 is an example of such a gene, with a function at the transition from G₂ to mitosis. We find that p53-dependent downregulation of Cyclin B2 promoter activity is dependent on an intact CHR element. In the presence of high levels of p53 or p21(WAF1/CIP1), protein binding to the CHR switches from MMB to DREAM complex by shifting MuvB core-associated proteins from B-Myb to E2F4/DP1/p130. The results suggest a model for p53-dependent transcriptional repression by which p53 directly activates p21(WAF1/CIP1). The inhibitor then prevents further phosphorylation of p130 by Cyclin-dependent kinases. The presence of hypophosphorylated pocket proteins shifts the equilibrium for complex formation from MMB to DREAM. In the case of promoters that do not hold CDE or E2F elements, binding of DREAM and MMB solely relies on a CHR site. Thus, p53 can repress target genes indirectly through CHR elements.
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chimpanzee orangutan mouse and human cell cycle promoters exempt ccaat boxes and chr elements from interspecies differences
Molecular Biology and Evolution, 2006Co-Authors: Gerd A Muller, Florian Heissig, Kurt EngelandAbstract:Mechanisms regulating the cell division cycle are well conserved among all eukaryotes. Consistently many proteins regulating the cell cycle are functionally interchangeable between many organisms. Cell division control is regulated on different levels of which the transcriptional level appears to be particularly important for controlling synthesis of many cell cycle proteins. We had earlier described transcription factor-binding sites essential for regulating genes important for the transition from the G(2) phase to mitosis. A tandem repressor site named cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) are responsible for the correct expression during the cell cycle. Another feature of these G(2)/M-specific promoters is the activation through 2 or 3 CCAAT boxes binding the transcription factor nuclear factor-Y (NF-Y). These major activating sites have to be spaced 32 or 33 bp apart to be fully functional. We were interested in looking at the evolutionary changes in regulatory elements and overall promoter structure of 3 well-characterized cell cycle genes. Here, we compare the DNA sequences and functional features of the cdc25C, Cyclin B1, and Cyclin B2 promoters from humans, mouse, chimpanzee, and orangutan. We find numerous differences in the nucleotide sequence between mouse and primate promoters. However, CHR and CCAAT boxes stand out in that they are perfectly conserved in all promoters tested. The CDE site contains nucleotide exchanges between mouse and primate promoters. Comparing sequences and functions of chimpanzee, orangutan, and human promoters, we observe a complete conservation in nucleotide sequence of the regulatory elements. Functional assays of the Cyclin B1, Cyclin B2, and cdc25C promoters yield moderate variations in activity and thereby a good conservation of function. Although we find nucleotide differences in cell cycle promoters between orangutan and humans of about 5%, there are never changes in any of the CCAAT boxes or CDE/CHR sites in the Cyclin B1, Cyclin B2, and cdc25C promoters. Furthermore, we describe the influence of the tumor suppressor p53 and the transcriptional activator NF-Y on regulation of the newly cloned primate promoters.
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nf y mediates the transcriptional inhibition of theCyclin b1 Cyclin B2 and cdc25cpromoters upon induced g2 arrest
Journal of Biological Chemistry, 2001Co-Authors: Isabella Manni, Karen Krause, Ulrike Haugwitz, Kurt Engeland, Roberto Mantovani, Giuseppina Mazzaro, Aymone Gurtner, Ada Sacchi, Silvia Soddu, Giulia PiaggioAbstract:During normal cell cycles, the function of mitotic Cyclin-cdk1 complexes, as well as of cdc25C phosphatase, is required for G2 phase progression. Accordingly, the G2 arrest induced by DNA damage is associated with a down-regulation of mitotic Cyclins, cdk1, and cdc25C phosphatase expression. We found that the promoter activity of these genes is repressed in the G2 arrest induced by DNA damage. We asked whether the CCAAT-binding NF-Y modulates mitoticCyclins, cdk1, and cdc25C gene transcription during this type of G2 arrest. In our experimental conditions, the integrity of the CCAAT boxes ofCyclin B1, Cyclin B2, and cdc25Cpromoters, as well as the presence of a functional NF-Y complex, is strictly required for the transcriptional inhibition of these promoters. Furthermore, a dominant-negative p53 protein, impairing doxorubicin-induced G2 arrest, prevents transcriptional down-regulation of the mitotic Cyclins, cdk1, and cdc25C genes. We conclude that, as already demonstrated for cdk1, NF-Y mediates the transcriptional inhibition of the mitotic Cyclins and the cdc25C genes during p53-dependent G2 arrest induced by DNA damage. These data suggest a transcriptional regulatory role of NF-Y in the G2 checkpoint after DNA damage.
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the tumour suppressor protein p53 can repress transcription of Cyclin b
Nucleic Acids Research, 2000Co-Authors: Karen Krause, Mark Wasner, Wibke Reinhard, Ulrike Haugwitz, Christine Langezu Dohna, Joachim Mossner, Kurt EngelandAbstract:The tumour suppressor protein p53 has functions in controlling the G(1)/S and G(2)/M transitions. Central regulators for progression from G(2) to mitosis are B-type Cyclins complexed with cdc2 kinase. In mammals two Cyclin B proteins are found, Cyclin B1 and B2. We show that upon treatment of HepG2 cells with 5-fluorouracil or methotrexate, p53 levels increase while concentrations of Cyclin B2 mRNA, measured by RT-PCR with the LightCycler system, are reduced. In DLD-1 colorectal adenocarcinoma cells (DLD-1-tet-off-p53) Cyclin B1 and B2 mRNA levels drop after expression of wild-type p53 but not after induction of a DNA binding-deficient mutant of p53. Analysis of the Cyclin B2 promoter reveals specific repression of this gene by p53. Transfection of wild-type p53 into SaOS-2 cells shuts off transcription from a Cyclin B2 promoter-luciferase construct whereas a p53 mutant protein does not. The Cyclin B2 promoter does not contain a consensus p53 binding site. Most of the p53-dependent transcriptional responsiveness resides in its 226 bp core promoter. Taken together with earlier observations on p53-dependent transcription of Cyclin B1, our results suggest that one way of regulating G(2) arrest may be a reduction in Cyclin B levels through p53-dependent transcriptional repression.
Tim Hunt - One of the best experts on this subject based on the ideXlab platform.
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Cyclin B2 null mice develop normally and are fertile whereas Cyclin b1 null mice die in utero
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Michael Brandeis, Ian Rosewell, Mark Carrington, Tessa Crompton, Mary Ann Jacobs, Jane Kirk, Julian Gannon, Tim HuntAbstract:Two B-type Cyclins, B1 and B2, have been identified in mammals. Proliferating cells express both Cyclins, which bind to and activate p34cdc2. To test whether the two B-type Cyclins have distinct roles, we generated lines of transgenic mice, one lacking Cyclin B1 and the other lacking Cyclin B2. Cyclin B1 proved to be an essential gene; no homozygous B1-null pups were born. In contrast, nullizygous B2 mice developed normally and did not display any obvious abnormalities. Both male and female Cyclin B2-null mice were fertile, which was unexpected in view of the high levels and distinct patterns of expression of Cyclin B2 during spermatogenesis. We show that the expression of Cyclin B1 overlaps the expression of Cyclin B2 in the mature testis, but not vice versa. Cyclin B1 can be found both on intracellular membranes and free in the cytoplasm, in contrast to Cyclin B2, which is membrane-associated. These observations suggest that Cyclin B1 may compensate for the loss of Cyclin B2 in the mutant mice, and implies that Cyclin B1 is capable of targeting the p34cdc2 kinase to the essential substrates of Cyclin B2.
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the proteolysis of mitotic Cyclins in mammalian cells persists from the end of mitosis until the onset of s phase
The EMBO Journal, 1996Co-Authors: Michael Brandeis, Tim HuntAbstract:We have studied how the cell cycle-specific oscillations of mitotic B-type Cyclins are generated in mouse fibroblasts. A reporter enzyme comprising the N-terminus of a B-type Cyclin fused to bacterial chloramphenicol acetyl transferase (CAT) was degraded at the end of mitosis like endogenous Cyclins. Point mutations in the destruction box of this construct completely abolished its mitotic instability. When the destructible reporter was driven by the Cyclin B2 promoter, CAT activity mimicked the oscillations in the level of the endogenous Cyclin B2. These oscillations were largely conserved when the reporter was transcribed constitutively from the SV40 promoter. Pulse-chase experiments or addition of the proteasome inhibitors lactacystin and ALLN showed that Cyclin synthesis continued after the end of mitosis. The destruction box-specific degradation of Cyclins normally ceases at the onset of S phase, and is active in fibroblasts arrested in G0 and in differentiated C2 myoblasts. We were able to reproduce this proteolysis in vitro in extracts of synchronized cells. Extracts of G1 cells degraded Cyclin B1 whereas p27Kip1 was stable, in contrast, Cyclin B1 remained stable and p27Kip1 was degraded in extracts of S phase cells.
