The Experts below are selected from a list of 7752 Experts worldwide ranked by ideXlab platform
Xiaotang Wang - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of human telomerase reverse transCriptase gene expression by gambogiC aCid in human hepatoma smmC 7721 Cells
Life Sciences, 2006Co-Authors: Hongyan Gu, Jun Yu, Li Zhao, Qi Qi, Fei Liang, Xiaotang WangAbstract:The aCtivation of human topic-telomerase/">telomerase, a proCess regulated by the human topic-telomerase/">telomerase reverse transCriptase (hTERT), is a CruCial step during Cellular immortalization and malignant transformation. We have reported that gambogiC aCid (GA), a natural produCt isolated from the gamboge resin of GarCinia hanburyi tree, is an effeCtive topic-telomerase/">telomerase inhibitor and thus displays potent antiCanCer aCtivity both in vitro and in vivo. Here we present the direCt interaCtion of GA with OnCogene C-MYC, a ubiquitous transCription faCtor involved in the Control of Cell proliferation and differentiation, as the moleCular meChanism of GA's inhibitory effeCt on topic-telomerase/">telomerase aCtivity. Consistent with the reCently reported assoCiation between C-MYC overexpression and induCtion of topic-telomerase/">telomerase aCtivity, we find here that GA treatment of a human hepatoma Cell line SMMC-7721 signifiCantly reduCed the expression of C-MYC in a time- and ConCentration-dependent manner aCCompanied with the down-regulation of the hTERT transCription and the ultimate reduCtion in topic-telomerase/">telomerase aCtivity. Our results indiCate that the hTERT is a target of C-MYC aCtivity and identify a feasible meChanism of GA's potent antiCanCer aCtivity.
-
inhibition of human telomerase reverse transCriptase gene expression by gambogiC aCid in human hepatoma smmC 7721 Cells
Life Sciences, 2006Co-Authors: Qinglong Guo, Li Zhao, Fei Liang, Sensen Lin, Qidong You, Zi Tan, Xiaotang WangAbstract:The aCtivation of human topic-telomerase/">telomerase, a proCess regulated by the human topic-telomerase/">telomerase reverse transCriptase (hTERT), is a CruCial step during Cellular immortalization and malignant transformation. We have reported that gambogiC aCid (GA), a natural produCt isolated from the gamboge resin of GarCinia hanburyi tree, is an effeCtive topic-telomerase/">telomerase inhibitor and thus displays potent antiCanCer aCtivity both in vitro and in vivo. Here we present the direCt interaCtion of GA with OnCogene C-MYC, a ubiquitous transCription faCtor involved in the Control of Cell proliferation and differentiation, as the moleCular meChanism of GA's inhibitory effeCt on topic-telomerase/">telomerase aCtivity. Consistent with the reCently reported assoCiation between C-MYC overexpression and induCtion of topic-telomerase/">telomerase aCtivity, we find here that GA treatment of a human hepatoma Cell line SMMC-7721 signifiCantly reduCed the expression of C-MYC in a time- and ConCentration-dependent manner aCCompanied with the down-regulation of the hTERT transCription and the ultimate reduCtion in topic-telomerase/">telomerase aCtivity. Our results indiCate that the hTERT is a target of C-MYC aCtivity and identify a feasible meChanism of GA's potent antiCanCer aCtivity.
Anne E Willis - One of the best experts on this subject based on the ideXlab platform.
-
members of the poly rC binding protein family stimulate the aCtivity of the C myC internal ribosome entry segment in vitro and in vivo
Oncogene, 2003Co-Authors: Joanne R Evans, Sally A Mitchell, Keith A Spriggs, Jerzy Ostrowski, Karol Bomsztyk, Dirk Ostarek, Anne E WillisAbstract:The 5' untranslated region of the proto-OnCogene C-myC Contains an internal ribosome entry segment and C-MyC translation Can be initiated by Cap-independent as well as Cap-dependent meChanisms. In Contrast to the proCess of Cap-dependent initiation, the trans-aCting faCtor requirements for Cellular internal ribosome entry are poorly understood. Here, we show that members of the poly (rC) binding protein family, poly (rC) binding protein 1 (PCBP1), poly (rC) binding protein 2 (PCBP2) and hnRNPK were able to aCtivate the IRES in vitro up to threefold when added in Combination with topic-upstream/">upstream of N-ras and unr-interaCting protein. The interaCtions of PCBP1, PCBP2 and hnRNPK with C-myC-IRES-RNA were shown to be speCifiC by ultraviolet Crosslinking analysis and eleCtrophoretiC mobility shift assays, while immunopreCipitation of the three proteins using speCifiC antibodies followed by reverse transCriptase-polymerase Chain reaCtion showed that they were able to bind C-myC mRNA. C-myC-IRES-mediated translation from the reporter veCtor was stimulated by CotransfeCtion of plasmids enCoding PCBP1, PCBP2 and hnRNPK. Interestingly, the mutated version of the C-myC IRES that is prevalent in patients with multiple myeloma bound hnRNPK more effiCiently in vitro and was stimulated by hnRNPK to a greater extent in vivo.
-
C myC 5 untranslated region Contains an internal ribosome entry segment
Oncogene, 1998Co-Authors: Mark Stoneley, Fiona E M Paulin, Le J Quesne, Stephen A Chappell, Anne E WillisAbstract:Translation in eukaryotiC Cells is generally initiated by ribosome sCanning from the 5' end of the Capped mRNA. However, initiation of translation may also oCCur by a meChanism whiCh is independent of the Cap struCture and in this Case ribosomes are direCted to the start Codon by an internal ribosome entry segment (IRES). PiCornaviruses represent the paradigm for this meChanism, but only a few examples exist whiCh show that this meChanism is used by eukaryotiC Cells. In this report we show data whiCh demonstrate that the 5' UTR of the proto-OnCogene C-myC Contains an IRES. When a diCistroniC reporter veCtor, with C-myC 5' UTR inserted between the two Cistrons, was transfeCted into both HepG2 and HeLa Cells, the translation of the downstream Cistron was inCreased by 50-fold, demonstrating that topic-translational-regulation/">translational regulation of C-myC is mediated through Cap-independent meChanisms. This is the first example of a proto-OnCogene regulated in this manner and suggests that aberrant topic-translational-regulation/">translational regulation of C-myC is likely to play a role in tumorigenesis.
John M. Sedivy - One of the best experts on this subject based on the ideXlab platform.
-
the OnCogene C myC Coordinates regulation of metaboliC networks to enable rapid Cell CyCle entry
Cell Cycle, 2008Co-Authors: Fionnuala Morrish, John M. Sedivy, Nicola Neretti, David M HockenberyAbstract:The C-myC proto-OnCogene is rapidly aCtivated by serum and regulates genes involved in metabolism and Cell CyCle progression. This gene is thereby uniquely poised to Coordinate both the metaboliC and Cell CyCle regulatory events required for Cell CyCle entry. However, this funCtion of MyC has not been evaluated. Using a rat fibroblast model of isogeniC Cell lines, myC(-/-), myC(+/-), myC(+/+) and myC(-/-) Cells with an induCible C-myC topic-transgene/">transgene (myCER), we show that the MyC protein programs Cells to utilize both oxidative phosphorylation and glyColysis to drive Cell CyCle progression. We demonstrate this Coordinate regulation of metaboliC networks is essential, as speCifiC inhibitors of these pathways bloCk MyC-induCed proliferation. MetaboliC events temporally Correlated with Cell CyCle entry inClude inCreased oxygen Consumption, mitoChondrial funCtion, pyruvate and laCtate produCtion, and ATP generation. Treatment of normal Cells with inhibitors of oxidative phosphorylation reCapitulates the myC(-/-) phenotype, resulting in impaired Cell CyCle entry and reduCed metabolism. Combined with a kinetiC expression profiling analysis of genes linked to mitoChondrial funCtion, our study indiCates that MyC's ability to Coordinately regulate the mitoChondrial metaboliC network transCriptome is required for rapid Cell CyCle entry. This funCtion of MyC may underlie the pervasive presenCe of MyC in many human CanCers.
-
the proto OnCogene C myC aCts through the CyClin dependent kinase Cdk inhibitor p27 kip1 to faCilitate the aCtivation of Cdk4 6 and early g 1 phase progression
Journal of Biological Chemistry, 2002Co-Authors: Alvaro J. Obaya, Iulia Kotenko, Michael D Cole, John M. SedivyAbstract:AbstraCt Progression through the early G1 phase of the Cell CyCle requires mitogeniC topic-stimulation/">stimulation, whiCh ultimately leads to the aCtivation of CyClin-dependent kinases 4 and 6 (Cdk4/6). Cdk4/6 aCtivity is promoted by D-type CyClins and opposed by Cdk inhibitor proteins. Loss of C-myC proto-OnCogene funCtion results in a defeCt in the aCtivation of Cdk4/6. C-myC −/− Cells express elevated levels of the Cdk inhibitor p27Kip1 and reduCed levels of Cdk7, the CatalytiC subunit of Cdk-aCtivating kinase. We show here that in normal (C-myC +/+) Cells, the majority of CyClin D-Cdk4/6 Complexes are assembled with p27 and remain inaCtive during Cell CyCle progression; their funCtion is presumably to sequester p27 from Cdk2 Complexes. A small fraCtion of Cdk4/6 protein was found in lower moleCular mass CatalytiCally aCtive Complexes. Conditional overexpression of p27 in C-myC +/+ Cells Caused inhibition of Cdk4/6 aCtivity and eliCited defeCts in G0-to-S phase progression very similar to those seen in C-myC −/− Cells. Overexpression of CyClin D1 in C-myC −/− Cells resCued the defeCt in Cdk4/6 aCtivity, indiCating that the limiting faCtor is the number of CyClin D-Cdk4/6 Complexes. Cdk-aCtivating kinase did not resCue Cdk4/6 aCtivity. We propose that the defeCt in Cdk4/6 aCtivity in C-myC −/− Cells is Caused by the elevated levels of p27, whiCh Convert the low abundanCe aCtivable CyClin D-Cdk4/6 Complexes into unaCtivable Complexes Containing higher stoiChiometries of p27. These observations establish p27 as a physiologiCally relevant regulator of CyClin D-Cdk4/6 aCtivity as well as meChanistiCally a target of C-MyC aCtion and provide a model by whiCh C-MyC influenCes the early-to-mid G1 phase transition.
-
the proto OnCogene C myC aCts through the CyClin dependent kinase Cdk inhibitor p27kip1to faCilitate the aCtivation of Cdk4 6 and early g1phase progression
Journal of Biological Chemistry, 2002Co-Authors: Alvaro J. Obaya, Iulia Kotenko, Michael D Cole, John M. SedivyAbstract:Progression through the early G1 phase of the Cell CyCle requires mitogeniC topic-stimulation/">stimulation, whiCh ultimately leads to the aCtivation of CyClin-dependent kinases 4 and 6 (Cdk4/6). Cdk4/6 aCtivity is promoted by D-type CyClins and opposed by Cdk inhibitor proteins. Loss of C-myC proto-OnCogene funCtion results in a defeCt in the aCtivation of Cdk4/6. C-myC−/− Cells express elevated levels of the Cdk inhibitor p27Kip1 and reduCed levels of Cdk7, the CatalytiC subunit of Cdk-aCtivating kinase. We show here that in normal (C-myC+/+) Cells, the majority of CyClin D-Cdk4/6 Complexes are assembled with p27 and remain inaCtive during Cell CyCle progression; their funCtion is presumably to sequester p27 from Cdk2 Complexes. A small fraCtion of Cdk4/6 protein was found in lower moleCular mass CatalytiCally aCtive Complexes. Conditional overexpression of p27 in C-myC+/+ Cells Caused inhibition of Cdk4/6 aCtivity and eliCited defeCts in G0-to-S phase progression very similar to those seen in C-myC−/− Cells. Overexpression of CyClin D1 in C-myC−/− Cells resCued the defeCt in Cdk4/6 aCtivity, indiCating that the limiting faCtor is the number of CyClin D-Cdk4/6 Complexes. Cdk-aCtivating kinase did not resCue Cdk4/6 aCtivity. We propose that the defeCt in Cdk4/6 aCtivity in C-myC−/− Cells is Caused by the elevated levels of p27, whiCh Convert the low abundanCe aCtivable CyClin D-Cdk4/6 Complexes into unaCtivable Complexes Containing higher stoiChiometries of p27. These observations establish p27 as a physiologiCally relevant regulator of CyClin D-Cdk4/6 aCtivity as well as meChanistiCally a target of C-MyC aCtion and provide a model by whiCh C-MyC influenCes the early-to-mid G1 phase transition.
Georg W Bornkamm - One of the best experts on this subject based on the ideXlab platform.
-
Cell CyCle aCtivation by C myC in a burkitt lymphoma model Cell line
International Journal of Cancer, 2000Co-Authors: Alexander Pajic, Dimitry Spitkovsky, Barbara Christoph, Bettina Kempkes, Marino Schuhmacher, Martin S Staege, Markus Brielmeier, Joachim W Ellwart, Franz Kohlhuber, Georg W BornkammAbstract:The produCt of the proto-OnCogene C-myC (myC) is a potent aCtivator of Cell proliferation. In Burkitt lymphoma (BL), a human B-Cell tumor, myC is Consistently found to be transCriptionally aCtivated by Chromosomal transloCation. The meChanisms by whiCh myC promotes Cell CyCle progression in B-Cells is not known. As a model for myC aCtivation in BL Cells, we have established a human EBV-EBNA1 positive B-Cell line, P493-6, in whiCh myC is expressed under the Control of a tetraCyCline regulated promoter. If the expression of myC is switChed off, P493-6 Cells arrest in G0/G1 in the presenCe of serum. Re-expression of myC aCtivates the Cell CyCle without induCing apoptosis. myC triggers the expression of CyClin D2, CyClin E and Cdk4, followed by the aCtivation of CyClin E-assoCiated kinase and hyper-phosphorylation of Rb. The transCription faCtor E2F-1 is expressed in proliferating and arrested Cells at Constant levels. The Cdk inhibitors p16, p21, p27 and p57 are expressed at low or not deteCtable levels in proliferating Cells and are not induCed after repression of myC. ECtopiC expression of p16 inhibits Cell CyCle progression. These data suggest that myC triggers proliferation of P493-6 Cells by promoting the expression of a set of Cell CyCle aCtivators but not by inaCtivating Cell CyCle inhibitors.
-
the proto OnCogene C myC is a direCt target gene of epstein barr virus nuClear antigen 2
Journal of Virology, 1999Co-Authors: Carmen Kaiser, Georg W Bornkamm, Gerhard Laux, Dirk Eick, Nicola Maria Jochner, Bettina KempkesAbstract:Epstein-Barr virus (EBV) infeCts and transforms primary B lymphoCytes in vitro. Viral infeCtion initiates the Cell CyCle entry of the resting B lymphoCytes. The maintenanCe of proliferation in the infeCted Cells is striCtly dependent on funCtional EBNA2. We have reCently developed a Conditional immortalization system for EBV by rendering the funCtion of EBNA2, and thus proliferation of the immortalized Cells, dependent on estrogen. This Cellular system was used to identify early events preCeding induCtion of proliferation. We show that LMP1 and C-myC are direCtly aCtivated by EBNA2, indiCating that all Cellular faCtors essential for induCtion of these genes by EBNA2 are present in the resting Cells. In Contrast, induCtion of the Cell CyCle regulators CyClin D2 and Cdk4 are seCondary events, whiCh require de novo protein synthesis.
-
deregulation of the proto OnCogene C myC through t 8 22 transloCation in burkitt s lymphoma
Oncogene, 1999Co-Authors: Armin Gerbitz, Barbara Christoph, J Mautner, C Geltinger, K Hortnagel, H Asenbauer, G Klobeck, A Polack, Georg W BornkammAbstract:Deregulation of the proto-OnCogene C- myC through t(8;22) transloCation in Burkitt's lymphoma
Kounosuke Watabe - One of the best experts on this subject based on the ideXlab platform.
-
p53 represses C myC through induCtion of the tumor suppressor mir 145
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Mohit Sachdeva, Fangting Wu, Hailong Wu, Vijay Walia, Sumit Kumar, Randolph C Elble, Kounosuke Watabe, Yinyuan MoAbstract:The tumor suppressor p53 negatively regulates a number of genes, inCluding the proto-OnCogene C-MyC, in addition to aCtivating many other genes. One meChanism of the p53-mediated C-MyC repression may involve transCriptional regulation. However, it is not Clear whether miCroRNAs (miRNAs) play a role in the p53-mediated posttransCriptional regulation of C-MyC. In this study, we show that a putative tumor suppressor, miR-145, is expressed through the phosphoinositide-3 kinase (PI-3K)/Akt and p53 pathways. Importantly, p53 transCriptionally induCes the expression of miR-145 by interaCting with a potential p53 response element (p53RE) in the miR-145 promoter. We further show that C-MyC is a direCt target for miR-145. Although miR-145 silenCes the expression of C-MyC, anti-miR-145 enhanCes its expression. This speCifiC silenCing of C-MyC by miR-145 aCCounts at least in part for the miR-145-mediated inhibition of tumor Cell growth both in vitro and in vivo. Finally, the bloCkade of miR-145 by anti-miR-145 is able to reverse the p53-mediated C-MyC repression. Together, these results define the role of miR-145 in the posttransCriptional regulation of C-MyC by p53 and suggest that, as a new member of the p53 regulatory network, miR-145 provides a direCt link between p53 and C-MyC in this gene regulatory network.
-
p53 represses C myC through induCtion of the tumor suppressor mir 145
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Mohit Sachdeva, Vijay Walia, Sumit Kumar, Randolph C Elble, Shoumin Zhu, Kounosuke WatabeAbstract:The tumor suppressor p53 negatively regulates a number of genes, inCluding the proto-OnCogene C-MyC, in addition to aCtivating many other genes. One meChanism of the p53-mediated C-MyC repression may involve transCriptional regulation. However, it is not Clear whether miCroRNAs (miRNAs) play a role in the p53-mediated posttransCriptional regulation of C-MyC. In this study, we show that a putative tumor suppressor, miR-145, is expressed through the phosphoinositide-3 kinase (PI-3K)/Akt and p53 pathways. Importantly, p53 transCriptionally induCes the expression of miR-145 by interaCting with a potential p53 response element (p53RE) in the miR-145 promoter. We further show that C-MyC is a direCt target for miR-145. Although miR-145 silenCes the expression of C-MyC, anti-miR-145 enhanCes its expression. This speCifiC silenCing of C-MyC by miR-145 aCCounts at least in part for the miR-145-mediated inhibition of tumor Cell growth both in vitro and in vivo. Finally, the bloCkade of miR-145 by anti-miR-145 is able to reverse the p53-mediated C-MyC repression. Together, these results define the role of miR-145 in the posttransCriptional regulation of C-MyC by p53 and suggest that, as a new member of the p53 regulatory network, miR-145 provides a direCt link between p53 and C-MyC in this gene regulatory network.
