A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70

Leuk Res. 2009 Aug;33(8):1100-7. doi: 10.1016/j.leukres.2008.10.025. Epub 2008 Dec 5.

Abstract

The interaction of viral proteins with host-cellular proteins elicits the activation of numerous cellular signal transduction pathways possibly leading to the viral pathogenesis. We previously demonstrated that infection with Friend leukemia virus (FLV) radiosensitizes murine hematopoietic cells via a p53-dependent apoptotic pathway in C3H hosts. Here, we show that the transduction of the env-gene (gp70) of Friend murine leukemia virus (F-MuLV) sensitized C3H-derived myeloid leukemia cells to DNA-damage (ionizing radiation as well as doxorubicin)-induced apoptosis through the activation of DNA-dependent protein kinase (DNA-PK) and P53. Knockdown of DNA-PK by siRNA inhibited the radiosensitization induced by gp70. In association with gp70 and DNA-PK, the acinus and MCM2 proteins were host-specifically overexpressed in C3H-derived cells. Taken together, these data suggested that gp70 enhances cellular DNA-damage-induced signaling in association with host-specific cellular proteins including acinus and MCM2 resulting in the activation of DNA-PK to phosphorylate P53. This in vitro study clearly indicates that the enhancement of DNA-damage-induced apoptosis by gp70 is not caused by the bone marrow environment of the host but is introduced by modified signaling in hematopoietic cells. The mechanisms involved in the ability of a viral protein to regulate cellular gene expression could provide invaluable insight into the manipulation of cellular pro-apoptotic signaling and the development of novel therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis*
  • DNA Damage*
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / adverse effects
  • Doxorubicin / pharmacology
  • Friend murine leukemia virus / genetics
  • Friend murine leukemia virus / metabolism*
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Leukemic / genetics
  • Gene Expression Regulation, Leukemic / radiation effects
  • Gene Products, env / biosynthesis*
  • Gene Products, env / genetics
  • Genetic Therapy
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / metabolism*
  • Leukemia, Experimental / therapy
  • Mice
  • Mice, Inbred C3H
  • Minichromosome Maintenance Complex Component 2
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Phosphorylation / radiation effects
  • Radiation, Ionizing
  • Retroviridae Infections / genetics
  • Retroviridae Infections / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects
  • Transduction, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Virus Infections / genetics
  • Tumor Virus Infections / metabolism

Substances

  • Antibiotics, Antineoplastic
  • DNA-Binding Proteins
  • Gene Products, env
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Minichromosome Maintenance Complex Component 2