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Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization.

Publication ,  Journal Article
McFadden, K; Hafez, AY; Kishton, R; Messinger, JE; Nikitin, PA; Rathmell, JC; Luftig, MA
Published in: Proc Natl Acad Sci U S A
February 9, 2016

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that has been causally linked to the development of B-cell and epithelial malignancies. Early after infection, EBV induces a transient period of hyperproliferation that is suppressed by the activation of the DNA damage response and a G1/S-phase growth arrest. This growth arrest prevents long-term outgrowth of the majority of infected cells. We developed a method to isolate and characterize infected cells that arrest after this early burst of proliferation and integrated gene expression and metabolic profiling to gain a better understanding of the pathways that attenuate immortalization. We found that the arrested cells have a reduced level of mitochondrial respiration and a decrease in the expression of genes involved in the TCA cycle and oxidative phosphorylation. Indeed, the growth arrest in early infected cells could be rescued by supplementing the TCA cycle. Arrested cells were characterized by an increase in the expression of p53 pathway gene targets, including sestrins leading to activation of AMPK, a reduction in mTOR signaling, and, consequently, elevated autophagy that was important for cell survival. Autophagy was also critical to maintain early hyperproliferation during metabolic stress. Finally, in assessing the metabolic changes from early infection to long-term outgrowth, we found concomitant increases in glucose import and surface glucose transporter 1 (GLUT1) levels, leading to elevated glycolysis, oxidative phosphorylation, and suppression of basal autophagy. Our study demonstrates that oncogene-induced senescence triggered by a combination of metabolic and genotoxic stress acts as an intrinsic barrier to EBV-mediated transformation.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 9, 2016

Volume

113

Issue

6

Start / End Page

E782 / E790

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptome
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Stress, Physiological
  • Signal Transduction
  • Oncogenes
  • Multiprotein Complexes
  • Mitochondria
  • Metabolomics
 

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McFadden, K., Hafez, A. Y., Kishton, R., Messinger, J. E., Nikitin, P. A., Rathmell, J. C., & Luftig, M. A. (2016). Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization. Proc Natl Acad Sci U S A, 113(6), E782–E790. https://doi.org/10.1073/pnas.1517141113
McFadden, Karyn, Amy Y. Hafez, Rigel Kishton, Joshua E. Messinger, Pavel A. Nikitin, Jeffrey C. Rathmell, and Micah A. Luftig. “Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization.Proc Natl Acad Sci U S A 113, no. 6 (February 9, 2016): E782–90. https://doi.org/10.1073/pnas.1517141113.
McFadden K, Hafez AY, Kishton R, Messinger JE, Nikitin PA, Rathmell JC, et al. Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization. Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):E782–90.
McFadden, Karyn, et al. “Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization.Proc Natl Acad Sci U S A, vol. 113, no. 6, Feb. 2016, pp. E782–90. Pubmed, doi:10.1073/pnas.1517141113.
McFadden K, Hafez AY, Kishton R, Messinger JE, Nikitin PA, Rathmell JC, Luftig MA. Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization. Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):E782–E790.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 9, 2016

Volume

113

Issue

6

Start / End Page

E782 / E790

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptome
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Stress, Physiological
  • Signal Transduction
  • Oncogenes
  • Multiprotein Complexes
  • Mitochondria
  • Metabolomics