RRC ID 68693
Author Abe S, Kurata M, Suzuki S, Yamamoto K, Aisaki K, Kanno J, Kitagawa M.
Title Minichromosome maintenance 2 bound with retroviral Gp70 is localized to cytoplasm and enhances DNA-damage-induced apoptosis.
Journal PLoS One
Abstract The interaction of viral proteins with host-cellular proteins elicits the activation of cellular signal transduction pathways and possibly leads to viral pathogenesis as well as cellular biological events. Apoptotic signals induced by DNA-damage are remarkably up-regulated by Friend leukemia virus (FLV) exclusively in C3H hosts; however, the mechanisms underlying the apoptosis enhancement and host-specificity are unknown. Here, we show that C3H mouse-derived hematopoietic cells originally express higher levels of the minichromosome maintenance (MCM) 2 protein than BALB/c- or C57BL/6-deriverd cells, and undergo more frequent apoptosis following doxorubicin-induced DNA-damage in the presence of the FLV envelope protein gp70. Dual transfection with gp70/Mcm2 reproduced doxorubicin-induced apoptosis even in BALB/c-derived 3T3 cells. Immunoprecipitation assays using various deletion mutants of MCM2 revealed that gp70 bound to the nuclear localization signal (NLS) 1 (amino acids 18-24) of MCM2, interfered with the function of NLS2 (amino acids 132-152), and suppressed the normal nuclear-import of MCM2. Cytoplasmic MCM2 reduced the activity of protein phosphatase 2A (PP2A) leading to the subsequent hyperphosphorylation of DNA-dependent protein kinase (DNA-PK). Phosphorylated DNA-PK exhibited elevated kinase activity to phosphorylate P53, thereby up-regulating p53-dependent apoptosis. An apoptosis-enhancing domain was identified in the C-terminal portion (amino acids 703-904) of MCM2. Furthermore, simultaneous treatment with FLV and doxorubicin extended the survival of SCID mice bearing 8047 leukemia cells expressing high levels of MCM2. Thus, depending on its subcellular localization, MCM2 plays different roles. It participates in DNA replication in the nucleus as shown previously, and enhances apoptosis in the cytoplasm.
Volume 7(6)
Pages e40129
Published 2012-1-1
DOI 10.1371/journal.pone.0040129
PII PONE-D-12-06565
PMID 22768239
PMC PMC3387003
MeSH 3T3 Cells Animals Apoptosis* / drug effects Apoptosis* / genetics Cell Cycle Proteins / chemistry Cell Cycle Proteins / metabolism* Cytoplasm / drug effects Cytoplasm / metabolism* DNA Damage* / genetics DNA-Activated Protein Kinase / metabolism Doxorubicin / pharmacology Friend murine leukemia virus / metabolism* Gene Expression Regulation / drug effects Mice Mice, Inbred BALB C Mice, Inbred C57BL Minichromosome Maintenance Complex Component 2 Models, Biological Mutant Proteins / metabolism Nuclear Localization Signals Nuclear Proteins / chemistry Nuclear Proteins / metabolism* Phosphorylation / drug effects Protein Binding / drug effects Protein Phosphatase 2 / metabolism Protein Transport / drug effects RNA, Messenger / genetics RNA, Messenger / metabolism Retroviridae Infections / genetics Retroviridae Infections / pathology Retroviridae Infections / virology Transfection Viral Envelope Proteins / metabolism*
IF 2.74
Human and Animal Cells 32D(RCB1145)