The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis

Megan Romeo, Tetiana Hutchison, Aditi Malu, Averi White, Janice Kim, Rachel Gardner, Katie Smith, Katherine Nelson, Rachel Bergeson, Ryan McKee, Carolyn Harrod, Lee Ratner, Bernhard Lüscher, Ernest Martinez, Robert Harrod

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8 Scopus citations

Abstract

In normal cells, aberrant oncogene expression leads to the accumulation of cytotoxic metabolites, including reactive oxygen species (ROS), which can cause oxidative DNA-damage and apoptosis as an intrinsic barrier against neoplastic disease. The c-Myc oncoprotein is overexpressed in many lymphoid cancers due to c-myc gene amplification and/or 8q24 chromosomal translocations. Intriguingly, p53 is a downstream target of c-Myc and hematological malignancies, such as adult T-cell leukemia/lymphoma (ATL), frequently contain wildtype p53 and c-Myc overexpression. We therefore hypothesized that p53-regulated pro-survival signals may thwart the cell's metabolic anticancer defenses to support oncogene-activation in lymphoid cancers. Here we show that the Tp53-induced glycolysis and apoptosis regulator (TIGAR) promotes c-myc oncogene-activation by the human T-cell leukemia virus type-1 (HTLV-1) latency-maintenance factor p30II, associated with c-Myc deregulation in ATL clinical isolates. TIGAR prevents the intracellular accumulation of c-Myc-induced ROS and inhibits oncogene-induced cellular senescence in ATL, acute lymphoblastic leukemia, and multiple myeloma cells with elevated c-Myc expression. Our results allude to a pivotal role for p53-regulated antioxidant signals as mediators of c-Myc oncogenic functions in viral and non-viral lymphoid tumors.

Original languageEnglish
Pages (from-to)103-115
Number of pages13
JournalVirology
Volume518
DOIs
StatePublished - May 2018

Keywords

  • ATL
  • HTLV-1
  • Oncogene
  • ROS
  • TIGAR
  • p53

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    Romeo, M., Hutchison, T., Malu, A., White, A., Kim, J., Gardner, R., Smith, K., Nelson, K., Bergeson, R., McKee, R., Harrod, C., Ratner, L., Lüscher, B., Martinez, E., & Harrod, R. (2018). The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis. Virology, 518, 103-115. https://doi.org/10.1016/j.virol.2018.02.010