Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70. 1905 49

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.
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PMID:Minichromosome maintenance 2 bound with retroviral Gp70 is localized to cytoplasm and enhances DNA-damage-induced apoptosis. 2276 39

Radiation therapy, inducing DNA damage, is one of the most effective tools for treatments of human cancers, but the effectiveness of the therapy is largely depending on the host specific conditions. Recently genetic constitution has proven to be important for apoptosis-induction responding to DNA damage. Regarding the host-specific manner of responses against DNA-damage in animal model, we have reported that infection with Friend leukemia virus (FLV) enhances the DNA damage-induced apoptosis in hematopoietic cells derived from C3H but DBA/2 mice. Furthermore, p53 or ATM knockout mice of C3H background and DNA-PK-deficient C3H SCID mice did not show the enhanced apoptosis by FLV. Recently, we could show that this host-specific apoptosis was mediated by the kinase activity of DNA-PK in association with FLV env-coding protein, gp70. Interestingly, two host proteins, acinus and MCM2, were also associated with DNA-PK and gp70 and were host-specifically overexpressed in C3H-derived cells. Our data suggest 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. By introducing gp70/acinus/MCM2-associated pathways into tumor cells, cancer therapy with DNA damage-inducing agents might become much more effective. Our aim is to develop a novel form of targeted therapy that can be combined with other treatment modalities, such as radiotherapy and chemotherapy, using the host-specific regulatory mechanisms of apoptotic enhancement.
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PMID:DNA damage-induced apoptosis and genetic background of the host: host-specific signaling enhancers of apoptosis. 2389 90


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