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Title: Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC

Abstract

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30{sup II} protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30{sup II} interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30{sup II} and c-MYC remain to be completely understood. Herein we demonstrate that p30{sup II} induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30{sup II} in c-myc{sup −/−} HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30{sup II} is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30{sup II} inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30{sup II}/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. - Highlights: • Acetylation of c-MYC is required for oncogenic transformation by HTLV-1 p30{sup II}/c-MYC. • Acetylation-defective c-MYC mutants are impaired for foci-formation by p30{sup II}/c-MYC. • The HTLV-1 p30{sup II} protein induces lysine-acetylation of c-MYC. • p30{sup II} is presentmore » in c-MYC nucleoprotein complexes in HTLV-1-transformed T-cells. • HTLV-1 p30{sup II} inhibits apoptosis in c-MYC-expressing proliferating cells.« less

Authors:
; ; ; ; ; ; ;  [1];  [2];  [3];  [4];  [5];  [6];  [7];  [1]
  1. Laboratory of Molecular Virology, Department of Biological Sciences, and The Dedman College Center for Drug Discovery, Design, and Delivery, Southern Methodist University, Dallas, TX 75275-0376 (United States)
  2. Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)
  3. University of California-Davis, School of Veterinary Medicine, One Shields Avenue, Davis, CA 95618 (United States)
  4. Department of Biochemistry, University of California, Riverside, CA 92521 (United States)
  5. Institute of Biochemistry, Klinikum, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen (Germany)
  6. Northern Institute for Cancer Research, Newcastle University, The Medical School, Newcastle upon Tyne, NE2 4HH (United Kingdom)
  7. Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm (Sweden)
Publication Date:
OSTI Identifier:
22470153
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 476; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLATION; APOPTOSIS; CARCINOGENESIS; CHROMATIN; COOPERATION; GENES; HUMAN POPULATIONS; LEUKEMIA; LYMPHOCYTES; LYSINE; ONCOGENIC TRANSFORMATIONS; PROTEINS; STRESSES; TRANSFORMATIONS

Citation Formats

Romeo, Megan M., Ko, Bookyung, Kim, Janice, Brady, Rebecca, Heatley, Hayley C., He, Jeffrey, Harrod, Carolyn K., Barnett, Braden, Ratner, Lee, Lairmore, Michael D., Martinez, Ernest, Lüscher, Bernhard, Robson, Craig N., Henriksson, Marie, and Harrod, Robert, E-mail: rharrod@smu.edu. Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC. United States: N. p., 2015. Web. doi:10.1016/J.VIROL.2014.12.008.
Romeo, Megan M., Ko, Bookyung, Kim, Janice, Brady, Rebecca, Heatley, Hayley C., He, Jeffrey, Harrod, Carolyn K., Barnett, Braden, Ratner, Lee, Lairmore, Michael D., Martinez, Ernest, Lüscher, Bernhard, Robson, Craig N., Henriksson, Marie, & Harrod, Robert, E-mail: rharrod@smu.edu. Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC. United States. doi:10.1016/J.VIROL.2014.12.008.
Romeo, Megan M., Ko, Bookyung, Kim, Janice, Brady, Rebecca, Heatley, Hayley C., He, Jeffrey, Harrod, Carolyn K., Barnett, Braden, Ratner, Lee, Lairmore, Michael D., Martinez, Ernest, Lüscher, Bernhard, Robson, Craig N., Henriksson, Marie, and Harrod, Robert, E-mail: rharrod@smu.edu. Sun . "Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC". United States. doi:10.1016/J.VIROL.2014.12.008.
@article{osti_22470153,
title = {Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC},
author = {Romeo, Megan M. and Ko, Bookyung and Kim, Janice and Brady, Rebecca and Heatley, Hayley C. and He, Jeffrey and Harrod, Carolyn K. and Barnett, Braden and Ratner, Lee and Lairmore, Michael D. and Martinez, Ernest and Lüscher, Bernhard and Robson, Craig N. and Henriksson, Marie and Harrod, Robert, E-mail: rharrod@smu.edu},
abstractNote = {The human T-cell leukemia retrovirus type-1 (HTLV-1) p30{sup II} protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30{sup II} interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30{sup II} and c-MYC remain to be completely understood. Herein we demonstrate that p30{sup II} induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30{sup II} in c-myc{sup −/−} HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30{sup II} is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30{sup II} inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30{sup II}/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. - Highlights: • Acetylation of c-MYC is required for oncogenic transformation by HTLV-1 p30{sup II}/c-MYC. • Acetylation-defective c-MYC mutants are impaired for foci-formation by p30{sup II}/c-MYC. • The HTLV-1 p30{sup II} protein induces lysine-acetylation of c-MYC. • p30{sup II} is present in c-MYC nucleoprotein complexes in HTLV-1-transformed T-cells. • HTLV-1 p30{sup II} inhibits apoptosis in c-MYC-expressing proliferating cells.},
doi = {10.1016/J.VIROL.2014.12.008},
journal = {Virology},
number = ,
volume = 476,
place = {United States},
year = {Sun Feb 15 00:00:00 EST 2015},
month = {Sun Feb 15 00:00:00 EST 2015}
}
  • Overexpression of c-raf-1 and the myc family of protooncogenes is primarily associated with small cell carcinoma, which accounts for {approx} 25% of human lung cancer. To determine the functional significance of the c-raf-1 and/or c-myc gene expression in lung carcinogenesis and to delineate the relationship between protooncogene expression and tumor phenotype, the authors introduced both protooncogenes, alone or in combination, into human bronchial epithelial cells. Two retroviral recombinants, pZip-raf and pZip-myc, containing the complete coding sequences of the human c-raf-1 and murine c-myc genes, respectively, were constructed and transfected into simian virus 40 large tumor antigen-immortalized bronchial epithelial cells (BEAS-2B);more » this was followed by selection for G418 resistance. Cell lines established from tumors (designated RMT) revealed the presence of the cotransfected c-raf-1 and c-myc sequences and expressed morphological, chromosomal, and isoenzyme markers, which identified BEAS-2B cells as the progenitor line of the tumors. The data demonstrate that the concomitant expression of the c-raf and c-myc protooncogenes causes neoplastic transformation of human bronchial epithelial cells resulting in large cell carcinomas with certain neuroendocrine markers. The presented model system should be useful in studies of molecular events involved in multistage lung carcinogenesis.« less
  • A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C/sub 3/H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy ..gamma..-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-inducedmore » SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter ..gamma..-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues.« less
  • Uroepithelium cultured from normal patients without cancer (60 individuals) was found to segregate into four subtypes based on the level of carcinogen treatment needed to induce abnormal p53 and c-myc. Twenty-two percent of patient cultures never showed abnormal p53 expression, even after chronic exposure to nitrosamines, while a further 26% required only a single dose of radiation to induce the abnormal protein. The remaining patients had tissues which, while initially negative for stable p53, became positive when put into culture and stimulated to grow. The c-myc protein was overexpressed in all cultures with abnormal p53. It would appear that elevatedmore » expression of conformationally inactive p53 and of high levels of c-myc represents an early response of normal uroepithelial cells to carcinogen challenge. It also appears that a relatively high number of patients without cancer express these proteins when their cells are challenged to grow; a pre-exposure to environmental carcinogens such as nitrosamines in cigarette smoke is likely to be involved. 30 refs., 3 figs., 3 tabs.« less
  • Bcl3 is a member of the I{kappa}B family that regulates genes involved in cell proliferation and apoptosis. Recent reports indicated that Bcl3 is overexpressed in HTLV-1-infected T cells via Tax-mediated transactivation, and acts as a negative regulator of viral transcription. However, the role of Bcl3 in cellular signal transduction and the growth of HTLV-1-infected T cells have not been reported. In this study, we showed that the knockdown of Bcl3 by short hairpin RNA inhibited the growth of HTLV-1-infected T cells. Although phosphatidylinositol-3 kinase (PI3K) inhibitor reduced Bcl3 expression, inactivation of glycogen synthase kinase 3 (GSK3), an effector kinase ofmore » the PI3K/Akt signaling pathway, restored Bcl3 expression in Tax-negative but not in Tax-positive T cells. Our results indicate that the overexpression of Bcl3 in HTLV-1-infected T cells is regulated not only by transcriptional but also by post-transcriptional mechanisms, and is involved in overgrowth of HTLV-1-infected T cells.« less
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