The Experts below are selected from a list of 20385 Experts worldwide ranked by ideXlab platform
Karl Munger - One of the best experts on this subject based on the ideXlab platform.
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the human papillomavirus type 16 e6 Oncoprotein activates mtorc1 signaling and increases protein synthesis
Journal of Virology, 2010Co-Authors: Jennifer M Spangle, Karl MungerAbstract:The mammalian target of rapamycin (mTOR) kinase acts as a cellular rheostat that integrates signals from a variety of cellular signal transduction pathways that sense growth factor and nutrient availability as well as intracellular energy status. It was previously reported that the human papillomavirus type 16 (HPV16) E6 Oncoprotein may activate the S6 protein kinase (S6K) through binding and E6AP-mediated degradation of the mTOR inhibitor tuberous sclerosis complex 2 (TSC2) (Z. Lu, X. Hu, Y. Li, L. Zheng, Y. Zhou, H. Jiang, T. Ning, Z. Basang, C. Zhang, and Y. Ke, J. Biol. Chem. 279:35664-35670, 2004; L. Zheng, H. Ding, Z. Lu, Y. Li, Y. Pan, T. Ning, and Y. Ke, Genes Cells 13:285-294, 2008). Our results confirmed that HPV16 E6 expression causes an increase in mTORC1 activity through enhanced phosphorylation of mTOR and activation of downstream signaling pathways S6K and eukaryotic initiation factor binding protein 1 (4E-BP1). However, we did not detect a decrease in TSC2 levels in HPV16 E6-expressing cells. We discovered, however, that HPV16 E6 expression causes AKT activation through the upstream kinases PDK1 and mTORC2 under conditions of nutrient deprivation. We show that HPV16 E6 expression causes an increase in protein synthesis by enhancing translation initiation complex assembly at the 5′ mRNA cap and an increase in cap-dependent translation. The increase in cap-dependent translation likely results from HPV16 E6-induced AKT/mTORC1 activation, as the assembly of the translation initiation complex and cap-dependent translation are rapamycin sensitive. Lastly, coexpression of the HPV16 E6 and E7 Oncoproteins does not affect HPV16 E6-induced activation of mTORC1 and cap-dependent translation. HPV16 E6-mediated activation of mTORC1 signaling and cap-dependent translation may be a mechanism to promote viral replication under conditions of limited nutrient supply in differentiated, HPV Oncoprotein-expressing proliferating cells.
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centrosomes genomic instability and cervical carcinogenesis
Critical Reviews in Eukaryotic Gene Expression, 2003Co-Authors: Stefan Duensing, Karl MungerAbstract:: High-risk human papillomavirus (HPV)-associated carcinogenesis of the uterine cervix is a particularly useful model to study basic mechanisms of genomic instability in cancer. Cervical carcinogenesis is associated with the expression of two high-risk HPV-encoded Oncoproteins, E6 and E7. Aneuploidy, the most frequent form of genomic instability in human carcinomas, develops as early as in nonmalignant cervical precursor lesions. In addition, cervical neoplasia is frequently associated with abnormal multipolar mitotic figures, suggesting disturbances of the cell-division process as a mechanism for chromosome segregation defects. Spindle poles are formed by centrosomes, and the high-risk HPV E6 and E7 Oncoproteins can each induce abnormal centrosome numbers. These two HPV Oncoproteins, however, induce centrosome abnormalities through fundamentally different mechanisms and, presumably, with different functional consequences. High-risk HPV E7, which targets the pRB tumor suppressor pathway, can provoke abnormal centrosome duplication in phenotypically normal cells. On the contrary, cells expressing the HPV E6 Oncoprotein, which inactivates p53, accumulate abnormal numbers of centrosomes in parallel with multinucleation and nuclear atypia. These two pathways are not mutually exclusive, since co-expression of HPV E6 and E7 has synergistic effects on centrosome abnormalities and chromosomal instability. Taken together, these findings support the general model in which chromosomal instability arises as a direct consequence of oncogenic insults and can develop at early stages of tumor progression.
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the human papillomavirus type 16 e6 and e7 Oncoproteins independently induce numerical and structural chromosome instability
Cancer Research, 2002Co-Authors: Stefan Duensing, Karl MungerAbstract:The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 Oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV Oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV Oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.
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the human papillomavirus type 16 e6 and e7 Oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Stefan Duensing, Lily Y Lee, Anette Duensing, John R Basile, Siribangon Piboonniyom, Sonia L Gonzalez, Christopher P Crum, Karl MungerAbstract:Loss of genomic integrity is a defining feature of many human malignancies, including human papillomavirus (HPV)-associated preinvasive and invasive genital squamous lesions. Here we show that aberrant mitotic spindle pole formation caused by abnormal centrosome numbers represents an important mechanism in accounting for numeric chromosomal alterations in HPV-associated carcinogenesis. Similar to what we found in histopathological specimens, HPV-16 E6 and E7 Oncoproteins cooperate to induce abnormal centrosome numbers, aberrant mitotic spindle pole formation, and genomic instability. The low-risk HPV-6 E6 and E7 proteins did not induce such abnormalities. Whereas the HPV-16 E6 Oncoprotein has no immediate effects on centrosome numbers, HPV-16 E7 rapidly induces abnormal centrosome duplication. Thus our results suggest a model whereby HPV-16 E7 induces centrosome-related mitotic disturbances that are potentiated by HPV-16 E6.
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a novel human dnaj protein htid 1 a homolog of the drosophila tumor suppressor protein tid56 can interact with the human papillomavirus type 16 e7 Oncoprotein
Virology, 1998Co-Authors: Boris Schilling, Tali Demedina, Josh Syken, Marc Vidal, Karl MungerAbstract:Abstract We have cloned hTid-1, a human homolog of the Drosophila tumor suppressor protein Tid56, by virtue of its ability to form complexes with the human papillomavirus E7 Oncoprotein. The carboxyl terminal cysteine-rich metal binding domain of E7 is the major determinant for interaction with hTid-1. The carboxyl terminus of E7 is essential for the functional and structural integrity of E7 and has previously been shown to function as a multimerization domain. The hTid-1 protein is a member of the DnaJ-family of chaperones. Its mRNA is widely expressed in human tissues, including the HPV-18-positive cervical carcinoma cell line HeLa and human genital keratinocytes, the normal host cells of the HPVs. The hTid-1 gene has been mapped to the short arm of chromosome 16. The large tumor antigens of polyomaviruses encode functional J-domains that are important for viral replication as well as cellular transformation. The ability of HPV E7 to interact with a cellular DnaJ protein suggests that these two viral Oncoproteins may target common regulatory pathways through J-domains.
Peter M Howley - One of the best experts on this subject based on the ideXlab platform.
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the transcriptional transactivation function of wild type p53 is inhibited by sv40 large t antigen and by hpv 16 e6 Oncoprotein
The EMBO Journal, 1992Co-Authors: Judy A Mietz, Jon M Huibregtse, Tamar Unger, Peter M HowleyAbstract:The observed interaction between p53 and the Oncoproteins encoded by several DNA tumor viruses suggests that these viruses mediate their transforming activities at least in part by altering the normal growth regulatory function of p53. In this study we examined the effect of viral Oncoprotein expression on the transcriptional transactivation function of wild-type p53 in human cells. Plasmids expressing human p53 were cotransfected with either SV40 large T-antigen or human papillomavirus (HPV) type 16 E6 expression plasmids and assayed for transactivation function using a reporter gene driven by a p53-responsive promoter containing multiple copies of the consensus p53 DNA binding motif, TGCCT. Both large T-antigen and E6 were able to inhibit transactivation by wild-type p53. Furthermore, SV40 T-antigen mutants that are defective for p53 binding were not able to inhibit transactivation and HPV E6 proteins that were either mutant or derived from non-oncogenic HPV types and unable to bind p53, had no effect on p53 transactivation. These results demonstrate the physiological relevance of the interaction of SV40 T-antigen and HPV E6 Oncoproteins with p53 in vivo and suggest that the transforming functions of these viral Oncoproteins may be linked to their ability to inhibit p53-mediated transcriptional activation.
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the state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Martin Scheffner, Karl Munger, Janet C Byrne, Peter M HowleyAbstract:Human cervical carcinoma cell lines that were either positive or negative for human papillomavirus (HPV) DNA sequences were analyzed for evidence of mutation of the p53 and retinoblastoma genes. Each of five HPV-positive cervical cancer cell lines expressed normal pRB and low levels of wild-type p53 proteins, which are presumed to be altered in function as a consequence of association with HPV E7 and E6 Oncoproteins, respectively. In contrast, mutations were identified in the p53 and RB genes expressed in the C-33A and HT-3 cervical cancer cell lines, which lack HPV DNA sequences. Mutations in the p53 genes mapped to codon 273 and codon 245 in the C33-A and HT-3 cell lines, respectively, located in the highly conserved regions of p53, where mutations appear in a variety of human cancers. Mutations in RB occurred at splice junctions, resulting in in-frame deletions, affecting exons 13 and 20 in the HT-3 and C-33A cell lines, respectively. These mutations resulted in aberrant proteins that were not phosphorylated and were unable to complex with the adenovirus E1A Oncoprotein. These results support the hypothesis that the inactivation of the normal functions of the tumor-suppressor proteins pRB and p53 are important steps in human cervical carcinogenesis, either by mutation or from complex formation with the HPV E6 and E7 Oncoproteins.
Denise A Galloway - One of the best experts on this subject based on the ideXlab platform.
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elevated wild type p53 protein levels in human epithelial cell lines immortalized by the human papillomavirus type 16 e7 gene
Virology, 1994Co-Authors: G W Demers, Christine L Halbert, Denise A GallowayAbstract:The role tumor suppressors p53 and retinoblastoma (RB) play in the transformation process has become central to understanding the pathogenesis of DNA tumor viruses. The two Oncoproteins of human papillomavirus (HPV)-16, E6 and E7, bind to p53 and RB, respectively, thus inactivating the function of these tumor suppressor genes. Immortalization of primary human foreskin epithelial cells by HPV requires expression of the E7 protein, and the E6 protein greatly enhances the immortalization frequency. Two of three cell lines immortalized by the HPV-16 E7 Oncoprotein expressed wild-type p53 and only one of the three cell lines had acquired a p53 mutation and loss of heterozygosity at 17p during the immortalization process. All three E7-immortalized lines contained higher steady-state levels of p53 protein. Mutation of the p53 gene is not required for immortalization in the absence of the HPV-16 E6 inactivation of the p53 protein, and 16E7 expression leads to the stabilization of wild-type p53.
Masayoshi Uehara - One of the best experts on this subject based on the ideXlab platform.
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effect of herbimycin a an inhibitor of tyrosine kinase on protein tyrosine kinase activity and phosphotyrosyl proteins of ph1 positive leukemia cells
Leukemia Research, 1994Co-Authors: Mihiro Okabe, Kenichi Kawamura, Takuto Miyagishima, Toshiyuki Itaya, Deborah Goodwyn, Mamoru Shoji, William R Vogler, Keisuke Sakurada, Masayoshi Uehara, Tamotsu MiyazakiAbstract:Herbimycin A, a benzoquinonoid anasamycin antibiotic, preferentially inhibited the in vitro growth of Ph1-positive leukemia cell lines. On the other hand, genistein, which was developed as an inhibitor of receptor-type tyrosine kinase, and other protein kinase inhibitors showed no selective inhibition of Ph1-positive leukemia cell growth. Herbimycin A also displayed an abrogative effect on the transformation of murine hematopoietic cells by transfection with a bcr/abl Oncoprotein-expressing retroviral vector. The antitumor action of herbimycin A on Ph1-positive leukemia cells is related to an inhibition of activity of bcr/abl protein tyrosine kinase and a subsequent reduction of the constitutive phosphotyrosyl proteins, however, the antibiotic has no effect on the expression of bcr/abl mRNA and Oncoprotein. Therefore, herbimycin A may provide an important insight into the oncogenic action of bcr/abl Oncoprotein and the future development of Oncoprotein-targeted therapeutic agents.
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new insight into Oncoprotein targeted antitumor effect herbimycin a as an antagonist of protein tyrosine kinase against ph1 positive leukemia cells
Leukemia & Lymphoma, 1993Co-Authors: Mihiro Okabe, Masayoshi UeharaAbstract:Herbimycin A, a benzoquinonoid anasamycin antibiotic, has been shown to reserve the oncogenic phenotypes of p60v-src transformed cells by the virtue of the inhibition of src protein tyrosine kinase. Furthermore, we previously demonstrated that herbimycin A displayed the antitumor activity on Ph1-positive leukemia cells and bcr/abl Oncoprotein-associated transformed murine hematopoietic cells with the transfection of a retroviral vector expressing bcr/abl. Herbimycin A showed preferential inhibition on the in vitro growth of Ph1-positive leukemia cells and bcr/abl Oncoprotein-associated murine hematopoietic cells through the inhibition of bcr/abl tyrosine kinase activity and the reduction of subsequent phosphotyrosyl proteins. Recently, from the view of investigating the oncogenic significance or of developing a future clinical application in malignancies, several developing agents targeted against Oncoprotein have been tried. We reviewed the present progress in the mechanism of Oncoprotein-targeted antitu...
Stefan Duensing - One of the best experts on this subject based on the ideXlab platform.
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centrosomes genomic instability and cervical carcinogenesis
Critical Reviews in Eukaryotic Gene Expression, 2003Co-Authors: Stefan Duensing, Karl MungerAbstract:: High-risk human papillomavirus (HPV)-associated carcinogenesis of the uterine cervix is a particularly useful model to study basic mechanisms of genomic instability in cancer. Cervical carcinogenesis is associated with the expression of two high-risk HPV-encoded Oncoproteins, E6 and E7. Aneuploidy, the most frequent form of genomic instability in human carcinomas, develops as early as in nonmalignant cervical precursor lesions. In addition, cervical neoplasia is frequently associated with abnormal multipolar mitotic figures, suggesting disturbances of the cell-division process as a mechanism for chromosome segregation defects. Spindle poles are formed by centrosomes, and the high-risk HPV E6 and E7 Oncoproteins can each induce abnormal centrosome numbers. These two HPV Oncoproteins, however, induce centrosome abnormalities through fundamentally different mechanisms and, presumably, with different functional consequences. High-risk HPV E7, which targets the pRB tumor suppressor pathway, can provoke abnormal centrosome duplication in phenotypically normal cells. On the contrary, cells expressing the HPV E6 Oncoprotein, which inactivates p53, accumulate abnormal numbers of centrosomes in parallel with multinucleation and nuclear atypia. These two pathways are not mutually exclusive, since co-expression of HPV E6 and E7 has synergistic effects on centrosome abnormalities and chromosomal instability. Taken together, these findings support the general model in which chromosomal instability arises as a direct consequence of oncogenic insults and can develop at early stages of tumor progression.
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the human papillomavirus type 16 e6 and e7 Oncoproteins independently induce numerical and structural chromosome instability
Cancer Research, 2002Co-Authors: Stefan Duensing, Karl MungerAbstract:The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 Oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV Oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV Oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.
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the human papillomavirus type 16 e6 and e7 Oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Stefan Duensing, Lily Y Lee, Anette Duensing, John R Basile, Siribangon Piboonniyom, Sonia L Gonzalez, Christopher P Crum, Karl MungerAbstract:Loss of genomic integrity is a defining feature of many human malignancies, including human papillomavirus (HPV)-associated preinvasive and invasive genital squamous lesions. Here we show that aberrant mitotic spindle pole formation caused by abnormal centrosome numbers represents an important mechanism in accounting for numeric chromosomal alterations in HPV-associated carcinogenesis. Similar to what we found in histopathological specimens, HPV-16 E6 and E7 Oncoproteins cooperate to induce abnormal centrosome numbers, aberrant mitotic spindle pole formation, and genomic instability. The low-risk HPV-6 E6 and E7 proteins did not induce such abnormalities. Whereas the HPV-16 E6 Oncoprotein has no immediate effects on centrosome numbers, HPV-16 E7 rapidly induces abnormal centrosome duplication. Thus our results suggest a model whereby HPV-16 E7 induces centrosome-related mitotic disturbances that are potentiated by HPV-16 E6.
